Polymorphic form of endopiroxostat addition salt and preparation method and application thereof

Abstract

The invention relates to a polymorphic form of an endopiroxostat addition salt as well as a preparation method and application of the polymorphic form. The acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, mesylate, benzene sulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate and fumarate, preferably hydrochloride. The endopiroxostat addition salt polymorph is high in stability, high in solubility, high in blood concentration, high in bioavailability and excellent in pharmacological action, so that the endopiroxostat addition salt is suitable for pharmaceutical preparations.

Description

Polymorphs of nepicastatin acid addition salts and preparation methods and uses thereof Technical Field The present invention relates to polymorphs of nepicastatin acid addition salts, a preparation method and uses thereof. The acid addition salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate and fumarate, preferably hydrochloride. Background Art Anxiety disorders are the most frequently occurring psychiatric disorders with a high economic burden. In addition to generalized anxiety disorders, they include post-traumatic stress disorder (PTSD), panic disorder, obsessive-compulsive disorder and social disorders and other phobias. Post-traumatic stress disorder can be severe and chronic, with some studies showing a lifetime incidence of 1.3% to 7.8% in the general population. Post-traumatic stress disorder is usually followed by a psychologically painful traumatic event. These events may, for example, include belligerence, terrorist incidents, physical assaults, sexual assaults, motor vehicle accidents, and natural disasters. The response to the event may include intense fear, helplessness, or terror. Most people recover from the traumatic event over time and return to normal life. In contrast, in patients with post-traumatic stress disorder, symptoms persist and may worsen over time, hindering return to normal life. Nepicastat (also known as SYN117 and RS-25560-197) is a highly selective dopamine β-hydroxylase (DBH) inhibitor having the following structural formula and is effective in treating PTSD. In addition, nepicastat has been studied as a possible treatment for congestive heart failure. Nepicastat and its analogs (such as etamitrastat) have common potential uses in the treatment of hypertension, cancer, etc. Nepicastat has also been reported to effectively reduce the mortality rate of sepsis and reduce sepsis-induced damage to multiple organs such as the heart, lungs, liver, and intestines. Nepicastat has also been reported to treat autoimmune diseases. Drug polymorphism has become an essential and important part of drug development and drug quality control. The study of drug polymorphism helps to select the biological activity of drug compounds, helps to increase the stability and solubility of drugs, and is conducive to the development of drug preparations and the storage of drugs, improves the quality of drug production, etc. It can also improve the bioavailability of compounds and enhance clinical efficacy. However, there is no report on the polymorphic form of nepicastatin acid addition salt in the prior art. Summary of the invention The technical problem to be solved by the present invention is to provide a polymorph of nepicastatin acid addition salt and a preparation method and use thereof. The inventors have found a method for preparing nepicastatin acid addition salt after a large number of experimental studies. The invention discloses a method for preparing a polymorph, and performs X-ray powder diffraction, TGA, DSC and other tests on the obtained polymorph and conducts stability studies. As a result, a polymorph of nepicastatin acid addition salt with good stability is found. The present invention solves the above technical problems through the following technical solutions: The present invention provides a crystalline form of an acid addition salt of nepicastatin, wherein the acid addition salt is selected from hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate and fumarate, preferably hydrochloride. The crystalline form of the acid addition salt is an anhydrate, a hydrate or a solvate. In some embodiments, the crystalline form of the picastatin acid addition salt is nepicastat hydrochloride form I, nepicastat hydrochloride form II, nepicastat hydrochloride form III, or nepicastat hydrochloride form IV. The nepicastat hydrochloride form I is a monohydrate, and its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 15.48±0.2°, 20.66±0.2°, 22.64±0.2°, 25.60±0.2°, 27.06±0.2°, 29.70±0.2°, 31.84±0.2° and 41.94±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 17.04±0.2°, 23.82±0.2°, 25.08±0.2°, 34.34±0 .2°, 36.78±0.2°, 43.88±0.2° and 44.12±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3, 4, 5, 6 or 7 characteristic peaks; more preferably further comprises at least one characteristic peak located at a diffraction angle (2θ) of 5.12±0.2°, 12.98±0.2°, 27.68±0.2°, 28.20±0.2° and 39.94±0.2°, such as 1, 2, 3, 4 or 5 characteristic peaks. In particular, the nepicastat hydrochloride form I has the XRPD characteristic peaks shown in Table 1: Table 1 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrochloride Form I is substantially as shown in FIG. 1 and FIG. 2 . Advantageously, the DSC spectrum of nepicastat hydrochloride form I shows four endothermic peaks at 130.8°C, 205.5°C, 251.8°C and 296.9°C and one exothermic peak at 210.9°C, more advantageously substantially as shown in FIG3 ; the TGA spectrum of nepicastat hydrochloride form I shows a weight loss of 5.15% from room temperature to 120°C, more advantageously substantially as shown in FIG4 . The nepicastat hydrochloride crystal form II is an anhydrous substance, and its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 20.62±0.2°, 21.90±0.2°, 25.04±0.2°, 28.28±0.2°, 30.05±0.2° and 31.46±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 10.88±0.2°, 13.60±0.2°, 14.84±0.2°, 17.96±0.2° and 27.32±0.2°. At least one characteristic peak at (2θ), for example 1, 2, 3, 4 or 5 characteristic peaks; more preferably further comprising at least one characteristic peak at a diffraction angle (2θ) of 7.12±0.2°, 16.74±0.2°, 18.57±0.2°, 23.01±0.2°, 24.64±0.2°, 34.54±0.2°, 40.17±0.2° and 45.56±0.2°, for example 1, 2, 3, 4, 5, 6, 7 or 8 characteristic peaks. In particular, Nepicastat hydrochloride Form II has the XRPD characteristic peaks shown in Table 2: Table 2 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrochloride Form II is substantially as shown in FIG. 1 and FIG. 10 . Advantageously, the DSC spectrum of nepicastat hydrochloride form II shows one endothermic peak at 266.2°C, more advantageously substantially as shown in FIG11 ; the TGA spectrum of nepicastat hydrochloride form II shows a weight loss of 0.40% from room temperature to 120°C, more advantageously substantially as shown in FIG12 . The nepicastat hydrochloride form III has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2θ) of 13.58±0.2°, 20.22±0.2°, 22.32±0.2°, 24.54±0.2°, 26.16±0.2°, 30.14±0.2° and 31.26±0.2°; preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 6.86±0.2°, 7.62±0.2°, 10.26±0.2°, 11.14±0.2°, 13.03±0.2° and 40.76±0.2°, for example 1, 2, 3, 4, 5 or 6 characteristic peaks. In particular, Nepicastat hydrochloride Form III has the XRPD characteristic peaks shown in Table 3: Table 3 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrochloride Form III is substantially as shown in FIG. 1 and FIG. 16 . Advantageously, the DSC spectrum of nepicastat hydrochloride form III shows one endothermic peak at 267.1°C, more advantageously substantially as shown in FIG17 ; the TGA spectrum of nepicastat hydrochloride form III shows a weight loss of 2.17% from room temperature to 120°C, more advantageously substantially as shown in FIG18 . Nepicastat hydrochloride form IV, whose X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 13.60±0.2°, 20.70±0.2°, 21.94±0.2°, 24.99±0.2° and 25.64±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 15.56±0.2°, 16.78±0.2°, 22.68±0.2°, 26.18±0.2°, 27.32±0.2°, 28.23±0.2° and 31.44±0.2°, for example 1, 2, 3, 4, 5, 6 or 7 characteristic peaks. more preferably further comprises at least one characteristic peak at a diffraction angle (2θ) of 10.95±0.2°, 13.06±0.2°, 14.84±0.2°, 17.93±0.2° and 29.95±0.2°, for example 1, 2, 3, 4 or 5 characteristic peaks, even more preferably further comprises at least one characteristic peak at a diffraction angle (2θ) of 5.23±0.2°, 7.12±0.2°, 23.80±0.2°, 34.52±0.2°, 33.16±0.2° and 38.48±0.2°, for example 1, 2, 3, 4, 5 or 6 characteristic peaks. In particular, Nepicastat hydrochloride Form IV has the XRPD characteristic peaks shown in Table 4: Table 4 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrochloride Form IV is substantially as shown in FIG. 19 . In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat sulfate (1:0.5) crystalline form I, nepicastat sulfate (1:0.5) crystalline form II or nepicastat sulfate (1:1) crystalline form III. It is understood that the compounds corresponding to nepicastat sulfate (1:0.5) crystalline form I and nepicastat sulfate (1:0.5) crystalline form II are nepicastat sulfate, and the compound corresponding to nepicastat sulfate (1:1) crystalline form III is nepicastat hydrogen sulfate. The X-ray powder diffraction pattern of nepicastat sulfate (1:0.5) Form I comprises characteristic peaks at diffraction angles (2θ) of 9.90±0.2°, 14.78±0.2°, 16.72±0.2°, 19.82±0.2°, 22.08±0.2°, 22.40±0.2° and 24.86±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 25.56±0.2°, 26.72±0.2°, 27.82±0.2°, 28.08±0.2°, 28.40±0.2° and 29.86±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 25.56±0.2°, 26.72±0.2°, 28.82±0.2°, 28.08±0.2°, 28.40±0.2° and 29.86±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 25.56±0.2°, 28. At least one characteristic peak at a diffraction angle (2θ) of 26.19±0.2°, 28.42±0.2° and 30.68±0.2°, for example 1, 2, 3 or 4 characteristic peaks; more preferably further comprising at least one characteristic peak at a diffraction angle (2θ) of 35.16±0.2°, 35.80±0.2° and 40.26±0.2°, for example 1, 2 or 3 characteristic peaks. In particular, the nepicastat sulfate (1:0.5) Form I has the XRPD characteristic peaks shown in Table 5: Table 5 More specifically, the X-ray powder diffraction pattern of Nepicastat sulfate (1:0.5) Form I is substantially as shown in FIG. 26 . Advantageously, the DSC spectrum of nepicastat sulfate (1:0.5) Form I shows three endothermic peaks at 112.6°C, 127.3°C and 187.2°C and one exothermic peak at 207.3°C, more advantageously substantially as shown in FIG27 ; the TGA spectrum of nepicastat sulfate (1:0.5) Form I shows a weight loss of 6.51% from room temperature to 120°C, more advantageously substantially as shown in FIG28 . The X-ray powder diffraction pattern of nepicastat sulfate (1:0.5) Form II comprises characteristic peaks at diffraction angles (2θ) of 4.56±0.2°, 8.24±0.2°, 9.02±0.2°, 16.08±0.2°, 16.58±0.2°, 17.90±0.2°, 22.01±0.2° and 25.12±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 19.48±0.2°, 23.68±0.2° and 27.14±0.2°, for example 1, 2 or 3 characteristic peaks; In particular, the nepicastat sulfate (1:0.5) Form II has the XRPD characteristic peaks shown in Table 6: Table 6 More specifically, the X-ray powder diffraction pattern of nepicastat sulfate (1:0.5) Form II is substantially as shown in FIG. 29 . Advantageously, the DSC spectrum of nepicastat sulfate (1:0.5) Form II shows one endothermic peak at 252.1°C, more advantageously substantially as shown in FIG30 ; the TGA spectrum of nepicastat sulfate (1:0.5) Form II shows a weight loss of 0.07% from room temperature to 120°C, more advantageously substantially as shown in FIG31 . The X-ray powder diffraction pattern of nepicastat sulfate (1:1) Form III comprises characteristic peaks at diffraction angles (2θ) of 9.92±0.2°, 16.82±0.2°, 19.84±0.2°, 22.10±0.2°, 22.44±0.2°, 25.18±0.2° and 28.42±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 12.40±0.2°, 14.26±0.2°, 24.06±0.2°, 30.68±0.2°, 31.00±0.2° and 35.28±0.2°, for example 1, 2, 3, 4, 5 or 6 characteristic peaks. In particular, the nepicastat sulfate (1:1) Form III has the XRPD characteristic peaks shown in Table 7: Table 7 More specifically, the X-ray powder diffraction pattern of nepicastat sulfate (1:1) Form III is substantially as shown in FIG. 32 . Advantageously, the DSC spectrum of nepicastat sulfate (1:1) form III shows two endothermic peaks at 101.5°C and 201.3°C, more advantageously substantially as shown in FIG33 ; the TGA spectrum of nepicastat sulfate (1:1) form III shows a weight loss of 4.51% from room temperature to 120°C, more advantageously substantially as shown in FIG34 . In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat phosphate salt Form I. The X-ray powder diffraction pattern of the nepicastat phosphate crystalline form I comprises characteristic peaks at diffraction angles (2θ) of 5.24±0.2°, 10.48±0.2°, 21.14±0.2°, 22.76±0.2°, 23.74±0.2°, 25.54±0.2°, 26.52±0.2° and 29.74±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 12.50±0.2°, 16.92±0.2°, 21.92±0.2° and 27.3 The invention relates to a novel nanostructured carbonyl crystal having a diffraction angle (2θ) of 14.5±0.2°, wherein the nanostructured carbonyl crystal has a diffraction angle (2θ) of 15.48±0.2°, 19.40±0.2°, 20.68±0.2°, 34.66±0.2°, 37.62±0.2° and 39.90±0.2°, wherein the nanostructured carbonyl crystal has ...5.48±0.2°, 19.40±0.2°, 20.68±0.2°, 34.66±0.2°, 37.62±0.2° and 39.90±0.2°, wherein the nanostructured carbonyl crystal has a diffraction angle (2θ) of 15.48±0.2°, 19.40±0.2°, 20.68±0.2°, 34.66±0.2°, 37.62±0.2° and 39.90±0.2°, wherein the nanostructured carbonyl crystal has a diffraction angle (2θ) of 15. In particular, the nepicastat phosphate crystal form I has the XRPD characteristic peaks shown in Table 8: Table 8 More specifically, the X-ray powder diffraction pattern of Nepicastat phosphate Form I is substantially as shown in Figure 35. Advantageously, the DSC spectrum of the nepicastat phosphate salt form I shows one endothermic peak at 227.1°C, more advantageously substantially as shown in FIG36 ; the TGA spectrum of the nepicastat phosphate salt form I shows a weight loss of 0.12% from room temperature to 120°C, more advantageously substantially as shown in FIG37 . In some embodiments, the crystalline form of the nepicastatin acid addition salt is nepicastatin mesylate Form I. The X-ray powder diffraction pattern of the crystalline form I of nepicastat mesylate comprises characteristic peaks at diffraction angles (2θ) of 17.52±0.2°, 19.74±0.2°, 20.38±0.2°, 20.10±0.2°, 25.00±0.2° and 27.36±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 7.90±0.2°, 13.48±0.2°, 15.06±0.2°, 22.88±0 .2° and 23.28±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks; more preferably further comprises at least one characteristic peak located at a diffraction angle (2θ) of 28.50±0.2°, 29.08±0.2°, 31.42±0.2°, 32.94±0.2° and 36.36±0.2°, such as 1, 2, 3, 4 or 5 characteristic peaks. In particular, the nepicastat mesylate Form I has the XRPD characteristic peaks shown in Table 9: Table 9 More specifically, the X-ray powder diffraction pattern of Nepicastat mesylate Form I is substantially as shown in Figure 38. Advantageously, the DSC spectrum of the crystalline form I of nepicastat mesylate shows one endothermic peak at 280.7°C, more advantageously substantially as shown in FIG39 ; the TGA spectrum of the crystalline form I of nepicastat mesylate shows a weight loss of 0.06% from room temperature to 120°C, more advantageously substantially as shown in FIG40 . In some embodiments, the crystalline form of the nepicastatin acid addition salt is nepicastatin besylate Form I. The X-ray powder diffraction pattern of the nepicastat besylate crystalline form I comprises characteristic peaks at diffraction angles (2θ) of 14.00±0.2°, 16.62±0.2°, 17.96±0.2°, 22.70±0.2°, 24.66±0.2° and 26.86±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 7.38±0.2°, 8.06±0.2°, 11.84 ±0.2° and 20.42±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3 or 4 characteristic peaks; more preferably further comprising at least one characteristic peak located at a diffraction angle (2θ) of 19.34±0.2°, 21.62±0.2°, 28.50±0.2° and 30.42±0.2°, such as 1, 2, 3 or 4 characteristic peaks. In particular, the nepicastat besylate Form I has the XRPD characteristic peaks shown in Table 10: Table 10 More specifically, the X-ray powder diffraction pattern of Nepicastat besylate Form I is substantially as shown in Figure 41. Advantageously, the DSC spectrum of the crystalline form I of nepicastat benzenesulfonate shows an endothermic peak at 229.9°C, more advantageously substantially as shown in FIG. 42 ; the TGA spectrum of the crystalline form I of nepicastat benzenesulfonate shows an endothermic peak at 229.9°C from room temperature to The weight loss at 120°C was 0.35%, more advantageously substantially as shown in FIG. 43 . In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat tosylate Form I or nepicastat tosylate Form II. The X-ray powder diffraction pattern of nepicastat tosylate Form I comprises characteristic peaks at diffraction angles (2θ) of 13.40±0.2°, 15.52±0.2°, 19.38±0.2°, 19.78±0.2°, 23.52±0.2° and 28.74±0.2°. In particular, the nepicastat tosylate salt form I has the XRPD characteristic peaks shown in Table 11: Table 11 More specifically, the X-ray powder diffraction pattern of nepicastat tosylate Form I is substantially as shown in Figure 44. Advantageously, the DSC spectrum of the crystalline form I of nepicastat toluenesulfonate shows three endothermic peaks at 182.7°C, 215.2°C and 230.0°C and one exothermic peak at 238.0°C, more advantageously substantially as shown in Figure 45; the TGA spectrum of the crystalline form I of nepicastat toluenesulfonate shows a weight loss of 2.38% from room temperature to 120°C, more advantageously substantially as shown in Figure 46. The X-ray powder diffraction pattern of nepicastat tosylate crystalline form II comprises characteristic peaks at diffraction angles (2θ) of 4.80±0.2°, 16.62±0.2°, 17.04±0.2°, 17.54±0.2°, 19.34±0.2° and 20.14±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 9.44±0.2°, 15.46±0.2° and 21.46±0.2°, for example 1, 2 or 3 characteristic peaks; more preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 24.78±0.2°, 25.10±0.2°, 26.34±0.2° and 29.20±0.2°, for example 1, 2, 3 or 4 characteristic peaks. In particular, the nepicastat tosylate salt form II has the XRPD characteristic peaks shown in Table 12: Table 12 More specifically, the X-ray powder diffraction pattern of Nepicastat Tosylate Form II is substantially as shown in Figure 47. Advantageously, the DSC spectrum of nepicastat tosylate crystalline form II shows five endothermic peaks at 68.2°C, 175.3°C, 205.2°C, 212.2°C and 225.2°C and one exothermic peak at 233.6°C, more advantageously substantially as shown in Figure 48; the TGA spectrum of nepicastat tosylate crystalline form II shows a weight loss of 0.39% from room temperature to 120°C, more advantageously substantially as shown in Figure 49. In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat hydrobromide salt form I or nepicastat hydrobromide salt form II. The X-ray powder diffraction pattern of nepicastat hydrobromide form I comprises characteristic peaks at diffraction angles (2θ) of 13.88±0.2°, 14.60±0.2°, 17.74±0.2°, 18.14±0.2°, 22.84±0.2° and 25.76±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 20.34±0.2°, 24.14±0.2° and 26.52±0.2°, for example 1, 2 or 3 characteristic peaks; more preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 15.64±0.2°, 16.12±0.2°, 27.14±0.2° and 28.18±0.2°, for example 1, 2, 3 or 4 characteristic peaks. In particular, the nepicastat hydrobromide salt form I has the XRPD characteristic peaks shown in Table 13: Table 13 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrobromide Form I is substantially as shown in Figure 50. Advantageously, the DSC spectrum of the crystalline form I of nepicastat hydrobromide shows three endothermic peaks at 98.2°C, 149.5°C and 184.5°C, more advantageously substantially as shown in FIG51 ; the TGA spectrum of the crystalline form I of nepicastat hydrobromide shows a weight loss of 2.84% from room temperature to 120°C, more advantageously substantially as shown in FIG52 . The X-ray powder diffraction pattern of the nepicastat hydrobromide form II comprises characteristic peaks at diffraction angles (2θ) of 16.50±0.2°, 18.34±0.2°, 21.60±0.2°, 22.16±0.2°, 23.96±0.2°, 24.82±0.2°, 29.90±0.2° and 31.18±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 20.60±0.2°, 26.02±0.2°, 28.70±0.2°, 29.90±0.2° and 31.18±0.2°; , 26.42±0.2° and 27.30±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3 or 4 characteristic peaks; more preferably further comprises at least one characteristic peak located at a diffraction angle (2θ) of 7.34±0.2°, 14.74±0.2°, 28.20±0.2°, 34.98±0.2° and 37.16±0.2°, such as 1, 2, 3, 4 or 5 characteristic peaks. In particular, the nepicastat hydrobromide salt form II has the XRPD characteristic peaks shown in Table 14: Table 14 More specifically, the X-ray powder diffraction pattern of Nepicastat hydrobromide Form II is substantially as shown in Figure 53. Advantageously, the DSC spectrum of nepicastat hydrobromide form II shows one endothermic peak at 273.2°C, more advantageously substantially as shown in FIG54 ; the TGA spectrum of nepicastat hydrobromide form II shows a weight loss of 0.04% from room temperature to 120°C, more advantageously substantially as shown in FIG55 . In some embodiments, the crystalline form of the nepicastatin acid addition salt is nepicastatin maleate Form I. The X-ray powder diffraction pattern of the crystalline form I of nepicastat maleate comprises characteristic peaks at diffraction angles (2θ) of 12.81±0.2°, 16.76±0.2°, 23.96±0.2°, 24.58±0.2°, 25.02±0.2°, 25.94±0.2°, 26.34±0.2° and 28.38±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 14.98±0.2°, 18.64±0.2°, 19.36±0 .2°, 20.56±0.2° and 21.92±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks; more preferably further comprises at least one characteristic peak located at a diffraction angle (2θ) of 16.32±0.2°, 27.72±0.2°, 31.50±0.2°, 36.36±0.2° and 39.46±0.2°, such as 1, 2, 3, 4 or 5 characteristic peaks. In particular, the nepicastat maleate salt Form I has the XRPD characteristic peaks shown in Table 15: Table 15 In particular, the X-ray powder diffraction pattern of nepicastat maleate Form I is substantially as shown in Figure 56. Advantageously, the DSC spectrum of nepicastat maleate form I shows one endothermic peak at 210.0°C, more advantageously substantially as shown in FIG57 ; the TGA spectrum of nepicastat maleate form I shows a weight loss of 0.07% from room temperature to 120°C, more advantageously substantially as shown in FIG58 . In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat tartrate crystalline form I or nepicastat tartrate crystalline form II. The X-ray powder diffraction pattern of Nepicastat tartrate Form I comprises X-ray diffraction patterns at 14.28±0.2°, 19.08±0.2°, 23.66±0.2°, 24.58±0.2°, 26.34±0.2°, 26.98±0.2°, 28.58±0.2° and 31.34±0.2°. The present invention further comprises a characteristic peak at a diffraction angle (2θ) of 14.28±0.2°, 15.92±0.2°, 17.84±0.2°, 21.06±0.2° and 28.00±0.2°, for example, 1, 2, 3, 4 or 5 characteristic peaks; more preferably, the present invention further comprises a characteristic peak at a diffraction angle (2θ) of 33.44±0.2°, 37.34±0.2°, 40.34±0.2°, 42.26±0.2° and 46.82±0.2°, for example, 1, 2, 3, 4 or 5 characteristic peaks. In particular, the nepicastat tartrate crystal form I has the XRPD characteristic peaks shown in Table 16: Table 16 In particular, the X-ray powder diffraction pattern of Nepicastat tartrate Form I is substantially as shown in Figure 59. Advantageously, the DSC spectrum of nepicastat tartrate form I shows four endothermic peaks at 97.4°C, 184.6°C, 217.2°C and 250.7°C and one exothermic peak at 189.4°C, more advantageously substantially as shown in Figure 60; the TGA spectrum of nepicastat tartrate form I shows a weight loss of 4.28% from room temperature to 120°C, more advantageously substantially as shown in Figure 61. The X-ray powder diffraction pattern of the nepicastat tartrate crystal form II comprises characteristic peaks at diffraction angles (2θ) of 17.72±0.2°, 19.22±0.2°, 21.30±0.2°, 23.82±0.2°, 25.00±0.2°, 25.96±0.2°, 26.62±0.2° and 28.48±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 14.22±0.2°, 19.72±0.2°, 21.8 The invention relates to a novel nanostructured carbonyl crystal having a diffraction angle (2θ) of 4±0.2° and 22.42±0.2°, for example 1, 2, 3 or 4 characteristic peaks; more preferably, the nanostructured carbonyl crystal has a diffraction angle (2θ) of 13.00±0.2°, 15.20±0.2°, 31.50±0.2°, 33.60±0.2°, 36.08±0.2° and 37.42±0.2°, for example 1, 2, 3, 4, 5 or 6 characteristic peaks. In particular, Nepicastat tartrate crystal form II has the XRPD characteristic peaks shown in Table 17: Table 17 In particular, the X-ray powder diffraction pattern of nepicastat tartrate form II is substantially as shown in Figure 62. Advantageously, the DSC spectrum of nepicastat tartrate form II is shown at 182.7°C, 214.2°C and 246.0°C, more advantageously substantially as shown in Figure 63; the TGA spectrum of nepicastat tartrate form II shows a weight loss of 0.15% from room temperature to 120°C, more advantageously substantially as shown in Figure 64. In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat citrate Form I. The X-ray powder diffraction pattern of nepicastat citrate Form I comprises characteristic peaks at diffraction angles (2θ) of 12.98±0.2°, 14.30±0.2°, 16.36±0.2°, 17.64±0.2°, 19.38±0.2°, 22.68±0.2°, 25.10±0.2° and 26.34±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 22.28±0.2°, 30.26±0.2°, 40.26±0.2° and 40.86±0.2°, for example 1, 2, 3 or 4 characteristic peaks. In particular, Nepicastat citrate Form I has the XRPD characteristic peaks shown in Table 18: Table 18 In particular, the X-ray powder diffraction pattern of Nepicastat citrate Form I is substantially as shown in Figure 65. Advantageously, the DSC spectrum of nepicastat citrate form I shows one endothermic peak at 204.1°C, more advantageously substantially as shown in FIG66 ; the TGA spectrum of nepicastat citrate form I shows a weight loss of 0.85% from room temperature to 120°C, more advantageously substantially as shown in FIG67 . In some embodiments, the crystalline form of the nepicastat acid addition salt is nepicastat fumarate Form I. The X-ray powder diffraction pattern of the nepicastat fumarate crystalline form I comprises characteristic peaks at diffraction angles (2θ) of 13.58±0.2°, 14.12±0.2°, 15.56±0.2°, 17.18±0.2°, 21.86±0.2°, 23.22±0.2°, 23.98±0.2° and 26.40±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 16.20±0.2°, 24.66±0.2°, 25.00 ±0.2°, 27.92±0.2° and 28.60±0.2° diffraction angles (2θ) at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks; more preferably further comprising characteristic peaks at diffraction angles (2θ) of 10.78±0.2°, 18.22±0.2°, 19.96±0.2°, 30.32±0.2° and 33.06±0.2°, such as 1, 2, 3, 4 or 5 characteristic peaks. In particular, Nepicastat fumarate Form I has the XRPD characteristic peaks shown in Table 19: Table 19 In particular, the X-ray powder diffraction pattern of nepicastat fumarate Form I is substantially as shown in Figure 68. Advantageously, the DSC spectrum of nepicastat fumarate form I shows one endothermic peak at 216.0°C, more advantageously substantially as shown in Figure 69; the TGA spectrum of nepicastat fumarate form I shows a weight loss of 0.12% from room temperature to 120°C, more advantageously substantially as shown in Figure 70. The present invention also provides a method for preparing a crystalline form of nepicastat hydrochloride, which comprises: 1) Suspension beating method The nepicastat hydrochloride and an organic solvent are mixed under stirring, and the obtained suspension is centrifuged to collect solids; the organic solvent is selected from one or more of C1-C4 alcohols, C4-C6 ethers and C2-C6 nitriles; In particular, nepicastat hydrochloride and an organic solvent are mixed under stirring at room temperature to 50° C., preferably at 40° C. for 2-4 days, preferably 3 days, and the resulting suspension is centrifuged to collect solids, which are optionally further dried; the organic solvent is selected from one or more of ethanol, methyl tert-butyl ether, tetrahydrofuran and acetonitrile; advantageously, the ratio (W / V) of nepicastat hydrochloride to the organic solvent is 50:1; 2) Solvent evaporation method Dissolving nepicastat hydrochloride in a good solvent, allowing the solvent to evaporate naturally, and then collecting the solid; the good solvent is one or more of C1-C4 alcohol and C4-C6 ether or a mixed solvent thereof with water, preferably one or more of methanol, 50% isopropanol and 50% tetrahydrofuran; the ratio (W / V) of nepicastat hydrochloride to the good solvent is 50:1; 3) Anti-solvent method Dissolving nepicastat hydrochloride in a good solvent, adding an anti-solvent, and then collecting the solid; the good solvent is one or more of C1-C4 alcohol and C4-C6 ether or a mixed solvent thereof with water, preferably one or more of methanol, 50% isopropanol and 50% tetrahydrofuran; the anti-solvent is selected from one or more of C3-C6 ester, C4-C6 ether and C3-C6 ketone, preferably one or more of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane and 2-butanone; advantageously, the ratio (W / V) of nepicastat hydrochloride to the good solvent is 50:0.5-2, such as 50:1.5, 50:2 or 50:0.5; the volume ratio of the good solvent to the anti-solvent is 1:1 to 1:10, such as 1.5:4, 1.5:2 or 1:8; 4) mixing nepicastat hydrochloride, C1-C4 alcohol and water, heating the resulting suspension to 45-55° C., stirring until dissolved, cooling to 30-40° C., concentrating to remove part of the solvent, cooling the residue to 0-10° C., and collecting the solid by solid-liquid separation; In particular, nepicastat hydrochloride, C1-C4 alcohol and water are mixed, the resulting suspension is heated to 45-55°C, stirred until dissolved, cooled to 30-40°C and stirred for 1-3h, concentrated to remove part of the solvent, the residue is cooled to 0-10°C, solid is collected by solid-liquid separation, and the solid is optionally further dried; the C1-C4 alcohol is ethanol; advantageously, the ratio (W / W) of nepicastat hydrochloride to C1-C4 alcohol is 10:1 to 15:1, for example 12:1; the volume ratio of C1-C4 alcohol to water is 10:1 to 20:1, for example 16:1; 5) reflux (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, C1-C4 alcohol and concentrated hydrochloric acid with stirring, cool, solid precipitates, collect the solid by solid-liquid separation, add C1-C4 alcohol and water, heat until dissolved, concentrate to remove part of the solvent, cool the residue to 0-10° C., collect the solid by solid-liquid separation; In particular, (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, C1-C4 alcohol and 36% concentrated hydrochloric acid are refluxed with stirring for 5 hours, cooled to 20-30°C, solids are precipitated, and the solids are collected by solid-liquid separation. C1-C4 alcohol and water are added, heated to 65-70°C, stirred until dissolved, concentrated to remove part of the solvent, and the residue is cooled to 0-10°C, and the solids are collected by solid-liquid separation, and the solids are optionally further dried; the C1-C4 alcohol is isopropanol or methanol. The present invention also provides a method for preparing a crystalline form of nepicastatin acid addition salt, comprising: 1) mixing nepicastat and a C1-C4 alcohol, preferably ethanol, under stirring, and then adding an acid. If a large amount of precipitated solids is obtained, the solids are collected by centrifugation; if the obtained sample is a clear solution or a small amount of precipitated solids is obtained, the solvent is concentrated by nitrogen purging or natural evaporation, and the solids are precipitated and collected; the acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid and fumaric acid; Particularly, nepicastat and C1-C4 alcohol are stirred into a suspension at 40-60° C., preferably 50° C., and then an acid is added, cooled to room temperature and stirred overnight; the ratio (W / V) of nepicastat to C1-C4 alcohol is 50:1; the molar ratio of nepicastat to acid is 1:1.05 or 1:0.55; Alternatively, 2) mixing nepicastat and a C3-C6 ketone, preferably acetone, under stirring, then adding an acid, and if a large amount of precipitated solids is obtained, collecting the solids by centrifugation; if the obtained sample is a clear solution or a small amount of precipitated solids is obtained, concentrating the solvent by nitrogen purging or natural evaporation, and then adding an anti-solvent to precipitate and collect the solids; the acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid and fumaric acid; the anti-solvent is a C4-C6 ether, preferably methyl tert-butyl ether; Particularly, nepicastat and C3-C6 ketone are stirred at 40-60°C, preferably 50°C to form a solution, then an acid is added, cooled to room temperature and stirred overnight; the ratio (W / V) of nepicastat to C3-C6 ketone is 50:1; the molar ratio of nepicastat to acid is 1:1.05 or 1:0.55; the volume ratio of C3-C6 ketone to anti-solvent is 1:1 to 1:10, for example 1:5. The present invention also provides a pharmaceutical composition, which comprises a crystal form of a nepicastatin acid addition salt and an auxiliary material; the auxiliary material is preferably a pharmaceutically acceptable carrier, diluent or excipient. The present invention relates to use of a crystalline form of a nepicastatin acid addition salt or a pharmaceutical composition containing the crystalline form of a nepicastatin acid addition salt in preparing a drug for treating autoimmune diseases, post-traumatic stress disorder, congestive heart failure, hypertension, cancer or sepsis. The present invention relates to a crystalline form of a nepicastatin acid addition salt or a pharmaceutical composition containing the same, which is used for treating autoimmune diseases, post-traumatic stress disorder, congestive heart failure, hypertension, cancer or sepsis. The present invention also relates to a method for treating autoimmune diseases, post-traumatic stress disorder, congestive heart failure, hypertension, cancer or sepsis, comprising administering to a patient in need thereof an effective amount of nepicastatin plus A salt-forming crystal form or a pharmaceutical composition comprising the same. In some embodiments, the autoimmune disease is selected from autoimmune colitis, neuromyelitis optica, rheumatoid arthritis, scleroderma, psoriasis and uveitis, and further, the autoimmune colitis is Crohn's disease or ulcerative colitis. In some embodiments, the cancer is selected from colon cancer, breast cancer, liver cancer, melanoma, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, cervical cancer, renal cell carcinoma, bladder cancer, and gastric cancer. As used herein, "pharmaceutically acceptable" means that it is useful in preparing a pharmaceutical composition that is generally safe, non-biologically toxic, and non-undesirably toxic, and is acceptable for veterinary and human pharmaceutical use. As used herein, "carrier" refers to a diluent, adjuvant or excipient that is administered with a compound. Pharmaceutically acceptable carriers can be liquids, such as water and oils, including oils of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil, etc. Pharmaceutically acceptable carriers can also be physiological saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants, colorants, etc. can also be used. Those skilled in the art will appreciate that the pharmaceutical composition of the present invention can be formulated into various preparation forms well known in the art according to the specific mode of administration, such as oral dosage forms (powders, tablets, capsules, soft capsules, liquid medicines, syrups, elixirs, powders, capsules, granules), or topical preparations (creams, ointments, lotions, gels, balms, plasters, pastes, sprays, aerosols, etc.), or injection preparations (solutions, suspensions, emulsions). Among the pharmaceutical compositions of the present invention, those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration can be mentioned in particular, for example, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, skin gels, injectable preparations, drinkable suspensions, etc. The pharmaceutical composition according to the present invention may contain pharmaceutically acceptable carriers, adjuvants or diluents, such as fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, etc. Fillers such as starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; disintegrants such as starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinyl pyrrole, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc.; lubricants such as magnesium stearate, sodium lauryl sulfate, talc, silicon dioxide, etc.; suspending agents such as polyvinyl pyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc.; binders such as starch slurry, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, etc. The composition of the present invention can be prepared by any known method in the art so that the active ingredient can be quickly, persistently or slowly released after administration to the patient. The pharmaceutical compositions of the present invention are administered to individual animals such as mammals (rats, mice, domesticated animals or humans) by various routes, all of which are contemplated, for example, administration may be oral, topical, rectal, or by intravenous, intramuscular, transdermal, intrathecal, epidural or intraventricular injection. The dosage of the active ingredient of the present invention may vary according to the individual's condition and weight, the nature and severity of the disease, the drug form, the route of administration and the administration cycle, which may also be selected by those skilled in the art. The dosage may vary between 1-1500 mg / day, and may be administered once a day or in multiple doses per day. Administer medication. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a comparative XRPD spectrum of nepicastat hydrochloride forms I, II and III. From top to bottom in the figure are form III, form II, and form I. FIG. 2 is an XRPD pattern of nepicastat hydrochloride Form I. FIG3 is a DSC spectrum of nepicastat hydrochloride Form I. FIG. 4 is a TGA spectrum of nepicastat hydrochloride Form I. FIG5 is a PLM spectrum of nepicastat hydrochloride Form I. FIG6 is a DVS spectrum of Nepicastat hydrochloride Form I. Figure 7 is the XRPD spectrum before and after DVS of Nepicastat hydrochloride Form I. From top to bottom in the figure are the XRPD spectrum after DVS and the XRPD spectrum before DVS. Figure 8 is an XRPD pattern of nepicastat hydrochloride Form I after heating to 170°C. From top to bottom in the figure are the XRPD pattern of Form I after heating to 170°C and the XRPD pattern of the starting Form I. FIG. 9 is a TGA spectrum of Nepicastat hydrochloride Form I after heating to 170° C. FIG. 10 is an XRPD pattern of nepicastat hydrochloride Form II. FIG. 11 is a DSC spectrum of nepicastat hydrochloride Form II. FIG. 12 is a TGA spectrum of nepicastat hydrochloride Form II. FIG. 13 is a PLM spectrum of nepicastat hydrochloride Form II. FIG. 14 is a DVS spectrum of nepicastat hydrochloride Form II. Figure 15 is the XRPD spectrum of Nepicastat hydrochloride Form II before and after DVS. From top to bottom in the figure are the XRPD spectrum after DVS and the XRPD spectrum before DVS. FIG. 16 is an XRPD pattern of nepicastat hydrochloride Form III. FIG. 17 is a DSC spectrum of nepicastat hydrochloride Form III. FIG. 18 is a TGA spectrum of nepicastat hydrochloride Form III. FIG. 19 is an XRPD pattern of nepicastat hydrochloride Form IV. Figure 20 is a comparison of XRPD patterns of the suspension pulping method (40°C). From top to bottom in the figure are the XRPD patterns of the anhydrous ethanol pulping product, the XRPD patterns of the acetonitrile pulping product, the XRPD patterns of the methyl tert-butyl ether pulping product, the XRPD patterns of the tetrahydrofuran pulping product, and the XRPD patterns of the starting crystalline form I. Figure 21 is a comparison of XRPD patterns of the solvent evaporation method. From top to bottom in the figure are the XRPD patterns of the methanol evaporation product and the XRPD pattern of the starting crystalline form I. Figure 22 is a comparative XRPD spectrum of the anti-solvent method. From top to bottom in the figure are the XRPD spectrum of the product with 50% isopropanol as the good solvent 1,4-dioxane as the anti-solvent, the XRPD spectrum of the product with methanol as the good solvent methyl tert-butyl ether as the anti-solvent, the XRPD spectrum of the product with methanol as the good solvent 2-methyltetrahydrofuran as the anti-solvent, the XRPD spectrum of the product with methanol as the good solvent ethyl acetate as the anti-solvent, the XRPD spectrum of the product with 50% tetrahydrofuran as the good solvent 2-butanone as the anti-solvent, and the XRPD spectrum of the starting crystal form I. XRPD pattern. Figure 23 is a comparison of XRPD patterns of the products of the suspension of nepicastat hydrochloride Form I and Form II after 3 days of competition at room temperature. From top to bottom in the figure are the XRPD patterns of the product in 95% ethanol solution, the XRPD patterns of the product in 90% ethanol solution, the XRPD patterns of the product in 65% ethanol solution, the XRPD patterns of the product in 15% ethanol solution, the XRPD patterns of the product in water, the XRPD patterns of Form II, and the XRPD patterns of Form I. Figure 24 is an XRPD comparison spectrum of the salt form screening of nepicastat free base in the ethanol system. From top to bottom in the figure, there are XRPD spectra of fumarate salt form, citrate salt form, tartrate salt form II, hydrobromide salt form II, maleate salt form, p-toluenesulfonate salt form II, benzenesulfonate salt form, methanesulfonate salt form, phosphate salt form, sulfate (1:1) form III, sulfate (1:0.5) form II, blank ethanol, and nepicastat free base. Figure 25 is an XRPD comparison spectrum of the salt form screening of nepicastat free base in the acetone system. From top to bottom in the figure, there are XRPD spectra of fumarate salt form, citrate salt form, tartrate salt form I, hydrobromide salt form I, maleate salt form, p-toluenesulfonate salt form I, benzenesulfonate salt form, methanesulfonate salt form, phosphate salt form, sulfate (1:1) form III, sulfate (1:0.5) form I, blank acetone, and nepicastat free base. FIG. 26 is an XRPD pattern of nepicastat sulfate (1:0.5) Form I. FIG. 27 is a DSC spectrum of nepicastat sulfate (1:0.5) Form I. FIG. 28 is a TGA spectrum of nepicastat sulfate (1:0.5) Form I. FIG. 29 is an XRPD pattern of nepicastat sulfate (1:0.5) Form II. FIG30 is a DSC spectrum of nepicastat sulfate (1:0.5) Form II. FIG31 is a TGA spectrum of nepicastat sulfate (1:0.5) Form II. FIG. 32 is an XRPD pattern of nepicastat sulfate (1:1) Form III. FIG. 33 is a DSC spectrum of nepicastat sulfate (1:1) Form III. FIG. 34 is a TGA spectrum of nepicastat sulfate (1:1) Form III. FIG. 35 is an XRPD pattern of Nepicastat phosphate Form I. FIG. 36 is a DSC spectrum of Nepicastat phosphate Form I. FIG. 37 is a TGA spectrum of nepicastat phosphate form I. FIG. 38 is an XRPD pattern of nepicastat mesylate Form I. FIG. 39 is a DSC spectrum of nepicastat mesylate Form I. FIG. 40 is a TGA spectrum of nepicastat mesylate Form I. FIG. 41 is an XRPD pattern of nepicastat besylate Form I. FIG. 42 is a DSC spectrum of nepicastat besylate Form I. FIG. 43 is a TGA spectrum of nepicastat besylate Form I. Figure 44 is the XRPD pattern of nepicastat tosylate Form I. FIG. 45 is a DSC spectrum of nepicastat tosylate Form I. FIG. 46 is a TGA spectrum of nepicastat tosylate Form I. Figure 47 is the XRPD pattern of nepicastat tosylate Form II. FIG. 48 is a DSC spectrum of nepicastat tosylate Form II. FIG. 49 is a TGA spectrum of nepicastat tosylate Form II. Figure 50 is the XRPD pattern of Nepicastat hydrobromide Form I. FIG. 51 is a DSC spectrum of nepicastat hydrobromide Form I. FIG. 52 is a TGA spectrum of nepicastat hydrobromide Form I. FIG. 53 is an XRPD pattern of nepicastat hydrobromide Form II. FIG. 54 is a DSC spectrum of nepicastat hydrobromide Form II. FIG. 55 is a TGA spectrum of nepicastat hydrobromide Form II. Figure 56 is the XRPD pattern of Nepicastat maleate Form I. FIG. 57 is a DSC spectrum of Nepicastat maleate Form I. Figure 58 is the TGA spectrum of Nepicastat maleate Form I. Figure 59 is the XRPD pattern of Nepicastat tartrate Form I. Figure 60 is the DSC spectrum of Nepicastat tartrate Form I. Figure 61 is the TGA spectrum of Nepicastat tartrate Form I. Figure 62 is the XRPD pattern of Nepicastat tartrate Form II. FIG. 63 is a DSC spectrum of nepicastat tartrate Form II. FIG. 64 is a TGA spectrum of nepicastat tartrate Form II. Figure 65 is the XRPD pattern of Nepicastat citrate Form I. FIG. 66 is a DSC spectrum of Nepicastat citrate Form I. FIG. 67 is a TGA spectrum of nepicastat citrate Form I. Figure 68 is the XRPD pattern of Nepicastat fumarate Form I. FIG. 69 is a DSC spectrum of Nepicastat fumarate Form I. Figure 70 is the TGA spectrum of Nepicastat fumarate Form I. DETAILED DESCRIPTION The present invention will be described in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and are not intended to limit the essence and scope of the present invention. X-ray powder diffraction (XRPD) The instrument is Shimadzu's XRD-6000, and the sample is scanned according to the following parameters: Thermogravimetric analysis (TGA) The instrument is a Pyris1TGA from Platinum Elmer. About 5 mg of sample was weighed into a crucible, and the temperature was raised from 30°C to 350°C under nitrogen protection at a rate of 20°C / min, and maintained at 350°C for 1 min. Differential Scanning Calorimetry (DSC) The instrument is Mettler DSC3. About 0.5-5 mg of powder sample is weighed and placed in a closed aluminum crucible with a pinhole on the crucible cover. Under nitrogen protection, the temperature is raised from 30°C to 300°C for differential thermal scanning, and maintained at 300°C for 1 minute. The heating rate is 20°C / min. Polarized Light Microscopy (PLM) The instrument is XPV-203E from Shanghai Changfang Optical Instrument Co., Ltd. The sample is dispersed in a suitable medium, the sample is observed using an eyepiece and an objective lens, and the image is recorded using a camera computer system. Dynamic moisture sorption (DVS) The DVS curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). Test temperature: 25℃ Sample size: 10-20 mg dm / dt: 0.002% / min; RH range: 0%RH-95%RH-0%RH RH gradient: 10% Example 1 Nepicastat hydrochloride crystal form The inventors have discovered four polymorphs of nepicastat hydrochloride, which are named Form I, Form II, Form III and Form IV, respectively. The XRPD comparison patterns of Form I, Form II and Form III are shown in FIG1 . 1.1 Preparation method of crystal form I: Ethanol (59.4 kg), purified water (88.00 kg) and (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride anhydrous (5.00 kg, prepared according to Example 31 in CN1113874C) were added into the reaction kettle. The resulting suspension was heated to 45-55°C and stirred until dissolved, cooled to 30-40°C and stirred for 1-3h, and part of the solvent was concentrated in vacuo to a residual volume of about 14.0-16.0V (based on the weight of anhydrous API, as 1V). The residue was cooled to 0-10°C and centrifuged to obtain a wet product, which was dried in vacuo at 40-50°C to obtain 4.63kg of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride monohydrate with a yield of 52.4%, an HPLC purity of 99.8%, and a chiral purity of 99.8%, which was Form I. Its XRPD is shown in Figure 2. 1 H NMR (ppm): δ12.35(1H,S), δ8.65(3H,S), δ7.09(1H,s), δ7.02(1H,td,J=9.68,2.00Hz), δ6.90(1H,d,J=9.32Hz), δ4.65(1H,br s), δ4.11(3H,s), δ2.96(3H,m), δ2.77 (1H, M), δ 2.04 (1H, Brs). 1.2 Approximate solubility test At room temperature, a rough solubility test was conducted on Form I. Test method: Weigh about 4 mg of Form I, gradually add an appropriate volume of solvent, shake, observe whether it dissolves, and record the volume that can be completely dissolved and the volume of solvent that could not be completely dissolved last time. The total amount of solvent with very poor solubility does not exceed 4-5 mL. The rough solubility results are shown in Table 20. Table 20 Approximate solubility of Nepicastat hydrochloride Form I 1.3 Suspension beating method (40℃) The starting material is nepicastat hydrochloride form I, which has an off-white powder appearance. Its XRPD, DSC, TGA, PLM and DVS characterization results and heating experiment results are shown in Figures 2 to 9. Weigh approximately 50 mg of nepicastat hydrochloride Form I into a liquid phase vial, and then add 1 mL of the corresponding solvent. The sample is stirred at 40°C for 3 days, and the resulting suspension is centrifuged (12000 rpm, 10 min) to collect the wet solid; the collected solid is further dried in a vacuum oven at 40°C under reduced pressure for about 4 hours, and then the XRPD of the dried solid is measured. If the measured XRPD is different from the starting Form I, further DSC and TGA are tested to confirm the new form. The experimental results are summarized in Table 21 and Figure 20. At 40°C, the sample obtained by slurrying the nepicastat hydrochloride Form I in the methyl tert-butyl ether system and the tetrahydrofuran system for 3 days is Form I; the sample obtained by slurrying in the anhydrous ethanol system or the acetonitrile system for 3 days is Form II. Table 21 Nepicastat hydrochloride crystal form I suspension beating method (40°C) crystal screening 1.4 Solvent evaporation method Weigh approximately 50 mg of nepicastat hydrochloride Form I into a glass bottle, add a good solvent to completely dissolve the compound, filter using a 0.45 μm nylon filter membrane, cover the mouth of the sample bottle with aluminum foil with small holes, and place it in a fume hood to allow the solvent to evaporate naturally for about 1 to 3 weeks to collect the solid, and measure the XRPD of the solid. If the measured XRPD is different from the starting Form I, further study and test DSC and TGA to confirm the new form. The specific phenomena, treatment process and results are shown in Table 22 and Figure 21. The sample obtained by volatilization in a methanol system is crystal form II. Table 22 Nepicastat hydrochloride crystal form I volatile method crystal screening 1.5 Antisolvent method Weigh about 50 mg of nepicastat hydrochloride crystal form I into a glass vial, add an appropriate volume of good solvent (e.g., methanol) to completely dissolve it, and form a nearly saturated solution. Filter the filtrate using a 0.45 μm nylon filter membrane, and add different types of anti-solvents dropwise until a large amount of solid precipitates, and add an anti-solvent of up to 10 times the volume of the good solvent. For samples with solid precipitation, centrifuge at 12,000 rpm for 10 minutes and collect the wet solid; for samples without solid precipitation, place them in a fume hood and collect the solid by slowly evaporating the solvent. Dry the collected solid under reduced pressure at 40°C for about 4 hours, and measure the XRPD of the dried solid. The experimental results are summarized in Table 23 and Figure 22. By the anti-solvent method, the XRPD spectrum of the sample obtained in the 50% tetrahydrofuran / 2-butanone system of nepicastat hydrochloride Form I had no significant difference from that of the starting material, which was Form I; the samples obtained in the methanol / ethyl acetate system, the methanol / 2-methyltetrahydrofuran system and the methanol / methyl tert-butyl ether system were Form III; the sample obtained in the 50% isopropanol / 1,4-dioxane system had a lower crystallinity. Table 23 Nepicastat hydrochloride crystal form I anti-solvent method crystal screening 1.6 Preparation method of Form IV: Isopropanol (194.0 L), (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide (7.80 kg, DBH-7, prepared according to Example 30 of CN1113874C) and concentrated hydrochloric acid (10.2 kg) with a mass concentration of about 36% were added to the reaction kettle. After reflux and stirring for 5 hours, the reaction mixture was cooled to 20-30°C to precipitate solids, filtered, and the filter cake was washed with isopropanol (15.6 L) to obtain a wet product. Methanol (293.8 L) and water (22.5 L) were added. The reaction mixture was heated to 65-70° C. with stirring until dissolved, and concentrated in vacuo to about 18.0-20.0 V (wet product weight is 1 V), methanol (220.2 kg / time) was added to azeotropically remove water twice, and the residue (about 7.0-10.0 V) was cooled to 0-10° C., stirred for 5-7 hours, filtered, rinsed with 14.7 L of methanol, and dried in vacuo at 40-50° C. for 14 h to obtain (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (5.06 kg, yield 65.0%, HPLC purity 99.5%), which was tested by XRPD ( FIG. 19 ) and was found to be Form IV. 1.7 Nepicastat hydrochloride crystal form I The appearance of the Form I sample is an off-white powder. XRPD results show that Form I has obvious sharp diffraction peaks (Figure 2), and is a crystalline compound. DSC results (Figure 3) show four obvious endothermic peaks (100.3°C, 198.4°C, 227.8°C and 288.3°C) and one exothermic peak (208.64°C). TGA results (Figure 4) show a weight loss of 5.15% from 30°C to 160°C. PLM results (Figure 5) show birefringence under a polarized light microscope, with irregular granular crystal habit. DVS results show that the sample gains about 10% RH by moisture absorption from 0% RH to 80% RH. 1.036%, indicating that the sample is slightly hygroscopic ( FIG. 6 ). The crystal form of the sample remains unchanged before and after the DVS test ( FIG. 7 ). Through the heating experiment (the sample was heated to 170°C by TGA, exposed to air and cooled to room temperature, and then heated to 350°C after XRPD testing, and it was found that the second heating had the same weight loss of about 5% before 160°C), it can be known that the nepicastat hydrochloride form I is a hydrate and through the molecular weight of the nepicastat hydrochloride form I (Mw=349.8), it can be calculated that this compound is a monohydrate (see Figures 1 and 9). The stability test of Form I was conducted, and the results are shown in Tables 24 and 25 below (inner packaging material: double-layer polyethylene bag). The results show that under accelerated conditions (40°C / 75%RH) and long-term conditions (25°C / 60%RH), the test results did not change significantly, no new impurities were generated, and the stability was good. In addition, stability studies were conducted on Form I (60°C, 60°C / 75%RH) and Form II (40°C, 40°C / 75%RH, 60°C, 60°C / 75%RH) under relatively harsh conditions. The results showed that: The Form I solid was placed at 60°C and 60°C / 75% RH for 15 days without any obvious degradation impurities being produced, and was more stable than Form II. Form I was placed at 60°C and 60°C / 75% RH for 15 days and its crystal form was stable (judged by XRPD spectrum). Form II, at 40°C and 60°C, changes into Form III (judged by XRPD pattern). However, when placed at 40°C / 75%RH and 60°C / 75%RH for 15 days, the form does not change. Based on the above chemical and crystal stability studies on the two crystal forms of the hydrochloride salt, Form I is more stable than Form II. 1.8 Nepicastat hydrochloride crystal form II Form II can be obtained by slurrying the suspension of Form I in anhydrous ethanol or acetonitrile at 40°C for 3 days or volatilizing in methanol. The specific preparation method can be found in Table 20 and Table 21. The XRPD, DSC, TGA and DVS characterization results of Form II samples are shown in Figures 10 to 15. The appearance of the Form II sample is an off-white powder. The results of X-ray powder diffraction measurement show that the sample has multiple obvious characteristic diffraction peaks (Figure 10), which is crystalline. Thermal analysis (DSC, Figure 11 and TGA, Figure 12) shows that the initial melting point of the Form II sample is 247.22°C, and melting is accompanied by degradation; the weight loss is 0.4048% from 25.63°C to 120°C. The PLM results (Figure 13) show a granular crystal habit. The DVS results (Figure 14) show that the sample absorbs moisture from 0%RH to 80%RH and gains weight by about 0.453%, indicating that the sample is slightly hygroscopic, and the crystal form of the sample remains unchanged before and after the DVS test (Figure 15). In addition, the approximate solubility of Form II in water was also tested, which was 7.9-10.5 mg / mL, close to the solubility of Form I in water. 1.9 Nepicastat hydrochloride form III Form III can be obtained by adding an antisolvent (ethyl acetate, 2-methyltetrahydrofuran or methyl tert-butyl ether) to Form I in methanol. The specific preparation method can be found in Table 22. The XRPD, DSD and TGA characterization results of Form III samples are shown in Figures 16 to 19. The appearance of the Form III sample is an off-white powder. The X-ray powder diffraction measurement results show that the sample has multiple obvious characteristic diffraction peaks (Figure 16), which is crystalline. Thermal analysis (DSC, Figure 13 and TGA, Figure 18) shows that the initial melting point of the Form III sample is 235.39°C, and melting is accompanied by degradation; the weight loss from 30.35°C to 120°C is 2.1661%. 1.10 Investigation of stable crystal form - competition experiment of adding seed crystals In order to confirm the stability of the crystalline form at room temperature, the following competition experiments were carried out for crystalline form I and crystalline form II: Take 5 portions of Form II, add pure water, 15% ethanol solution, 65% ethanol solution, 90% ethanol solution and 95% ethanol solution respectively, ultrasonicate for 1 minute to obtain 5 portions of suspension containing Form II, stir at room temperature for 24 hours, each system has solid residue, centrifuge, take the supernatant, and then add Form I (20 mg) and Form II (20 mg) to each supernatant to form a suspension containing Form I and Form II, ultrasonicate for 1 minute, stir at room temperature for 3 days, take samples, and detect the crystal form. The results showed (Table 26 and Figure 23): the solid crystal form obtained after 3 days of competition at room temperature in pure water turned into Form I; in 15% ethanol solution, the solid crystal form obtained after 3 days of competition at room temperature was a mixed crystal of Form I and Form II; the solid obtained after 3 days of competition at room temperature in 65% ethanol solution, 90% ethanol solution and 95% ethanol solution was Form II. Table 26 Competition test results of different water activities *The proportions of mixed solvents are all in volume percentage. The results of the competition experiment between Form I and Form II show that in pure water, Form II is less stable than Form I; in an ethanol-water mixed solution with a low water activity (0.291-0.750), Form II can exist stably; in a 15% ethanol solution with a water activity of 0.945, mixed crystals of Form I and Form II are obtained. Example 2 Other crystalline forms of nepicastatin acid addition salts Nepicastat free base is prepared according to the specification of CN106983747A.

[0190] It was prepared by the method described in the previous section. 2.1 Approximate solubility test In order to select a suitable method for salt screening, the compound was tested for approximate solubility. The test method is: weigh about 4 mg of nepicastat free base, gradually add appropriate volume of solvent, shake, observe whether it dissolves, and record the volume that can be completely dissolved and the volume of solvent that could not be completely dissolved last time. The total amount of solvent with very poor solubility does not exceed 4 mL. Calculate its approximate solubility. According to the approximate solubility results shown in Table 27, nepicastat free base has greater solubility in dichloromethane:methanol (1:1, V:V), methanol, acetone and ethanol. Table 27 Approximate solubility of nepicastat free base 2.2 Preliminary screening of salt forms of nepicastat free base in ethanol system According to the approximate solubility results, the ethanol system was selected for the salt-forming experiment. Approximately 50 mg of nepicastat free base (i.e., API in Table 28 and Table 29) was weighed into each vial, 1 mL of anhydrous ethanol was added, and stirred at 50°C to form an off-white suspension, and then the counterion was slowly added dropwise to the reaction solution at a molar ratio of 1:1.05 or 1:0.55. Finally, after magnetic stirring at 50°C for 2 hours, it was naturally cooled to room temperature and stirred overnight (about 20 hours). After stirring overnight, if the sample in the vial is a suspension and the amount of solids is large, the solids are collected by centrifugation (12000 rpm, centrifugation for 10 minutes); if the sample in the vial is a clear solution or the amount of solids is small, nitrogen purging or natural evaporation is used to concentrate the solvent, precipitate and collect the solids. The collected solids were centrifuged at 40°C. The dried solids were dried under reduced pressure and vacuum for 4 h, and X-ray powder diffraction was performed on the dried solids. See Figure 24 and Table 28 for details. If the XRPD pattern of the dried solids was inconsistent with the XRPD pattern of the starting free base, the dried solids were further characterized, including DSC, TGA, etc. 2.3 Preliminary screening of salt forms of nepicastat free base in acetone system Weigh approximately 50 mg of nepicastat free base into each vial, add 1 mL of acetone solution, and stir at 50°C to form a solution. Then slowly add the counterion to the reaction solution at a molar ratio of 1:1.05 or 1:0.55. Finally, after stirring at 50°C for 2 hours, cool the sample naturally to room temperature and stir magnetically overnight (about 20 hours). After stirring overnight, if the sample in the vial is a suspension and the amount of solids is large, centrifugation (12000 rpm, centrifugation for 10 minutes) is used to collect the solid; if the sample in the vial is a clear solution or the amount of solids is small, the solvent is concentrated by natural evaporation and the anti-solvent MTBE is added to precipitate and collect the solid. The collected solid is dried under reduced pressure and vacuum at 40°C for 4 hours, and the dried solid is tested by X-ray powder diffraction. See Figure 25 and Table 29 for details. If the XRPD pattern of the dried solids was inconsistent with the XRPD pattern of the starting free base, the dried solids were further characterized, including TGA, DSC, etc. 2.4 Characterization of salt forms The nepicastat sulfate (1:0.5), sulfate (1:1), phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate and fumarate obtained in the preliminary screening were characterized by XRPD, DSC, TGA, etc. The XRPD, DSC and TGA spectra of nepicastat sulfate (1:0.5) Form I are shown in Figures 26, 27 and 28, respectively. The XRPD, DSC and TGA spectra of nepicastat sulfate (1:0.5) Form II are shown in Figures 29, 30 and 31, respectively. The XRPD, DSC and TGA spectra of nepicastat sulfate (1:1) Form III are shown in Figures 32, 33 and 34, respectively. The XRPD, DSC and TGA spectra of nepicastat phosphate form I are shown in Figures 35, 36 and 37, respectively. The XRPD, DSC and TGA spectra of nepicastat mesylate Form I are shown in Figures 38, 39 and 40, respectively. The XRPD, DSC and TGA spectra of nepicastat besylate Form I are shown in Figures 41, 42 and 43, respectively. The XRPD, DSC and TGA spectra of nepicastat tosylate Form I are shown in Figures 44, 45 and 46, respectively. The XRPD, DSC and TGA spectra of nepicastat tosylate Form II are shown in Figures 47, 48 and 49, respectively. The XRPD, DSC and TGA spectra of nepicastat hydrobromide Form I are shown in Figures 50, 51 and 52, respectively. The XRPD, DSC and TGA spectra of nepicastat hydrobromide Form II are shown in Figures 53, 54 and 55, respectively. The XRPD, DSC and TGA spectra of Nepicastat maleate Form I are shown in Figures 56, 57 and 58, respectively. The XRPD, DSC and TGA spectra of Nepicastat tartrate Form I are shown in Figures 59, 60 and 61, respectively. The XRPD, DSC and TGA spectra of Nepicastat tartrate Form II are shown in Figures 62, 63 and 64, respectively. The XRPD, DSC and TGA spectra of Nepicastat citrate Form I are shown in Figures 65, 66 and 67, respectively. The XRPD, DSC and TGA spectra of Nepicastat fumarate Form I are shown in Figures 68, 69 and 70, respectively. 2.5 Approximate solubility test of crystalline forms of nepicastatin acid addition salt in water Weigh about 4 mg of the compound shown in the table below, gradually add appropriate volume of purified water at room temperature, shake ultrasonically, observe whether it dissolves, and record the volume that can be completely dissolved and the volume of solvent that could not be completely dissolved last time. The results are shown in Table 31. Table 31 Approximate solubility test results of some crystalline forms of nepicastatin acid addition salts in water (room temperature) *: The approximate solubility in water of the crystalline form of nepicastatin acid addition salt is calculated as salt. From the test results of the approximate solubility of the candidate salt forms in water, it can be seen that the solubility of the maleate salt in pure water is slightly higher than that of the other candidate salt forms, but still lower than that of nepicastat hydrochloride in pure water (7.4 mg / mL). 2.6 Stability test of the crystalline form of nepicastatin acid addition salt The crystalline form of nepicastatin acid addition salt in Table 31 was subjected to high temperature test (60±2°C) and accelerated test (40°C±2°C / 75%RH±5%RH) for 4 weeks. The results showed that: The sulfate (1:0.5) crystal form II is stable under accelerated conditions, but impurities increase under high temperature conditions; The sulfate (1:1) form III is stable under accelerated conditions, but impurities increase under high temperature conditions; Phosphate Form I is stable under accelerated conditions, and impurities increase slightly under high temperature conditions; The mesylate salt Form I is stable under accelerated and high temperature conditions; The maleate salt form I is stable under accelerated and high temperature conditions; The citrate salt form I is stable under accelerated conditions, but impurities increase under high temperature conditions; The fumarate salt form I is stable under accelerated conditions, but the impurities increase under high temperature conditions. Example 3 Bioavailability Test Nepicastat hydrochloride crystal form I, crystal form II and other nepicastat acid addition salts in Table 31 were intravenously and orally administered to mice, respectively, wherein: The prescription for intravenous (IV) administration was: 5% (v / v) DMSO + 10% (v / v) Solutol HS 15 + 85% (v / v) normal saline; The prescription for oral (PO) administration is: 0.5% (w / v) MC4000 aqueous solution (MC is methylcellulose). The specific dosing conditions are as follows: Test: Each prescription was tested in parallel on 3 mice; Weight: about 30g Dosage form: IV; PO Dosage: IV—15 mg / kg; PO—30 mg / kg; Before administration: Do not eat or drink for 12 hours before administration; After administration: Water is not forbidden after administration, and food can be taken after 2 hours; Blood collection site: hind leg vein Blood collection time: IV---0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h; PO---0.25, 0.5, 1, 2, 4, 6, 8, 24h. Since the solubility of nepicastat hydrochloride form I and form II in water is very similar, it was found in the experiment that both obtained clear solutions when preparing the dosing samples, so only nepicastat hydrochloride form I was tested subsequently. The experimental results show that the oral bioavailability of hydrochloride crystal form I is greater than 70%. The bioavailability of the other acid addition salts is 0.9 to 1.3 times that of hydrochloride crystal form I. The bioavailability of each acid addition salt is good. The bioavailability results of each acid addition salt relative to hydrochloride crystal form I are shown in Table 32 below. T 1 / 2 and AUC 0→t In addition to the T of the mesylate form I and the fumarate form I max Less than 2h, T of other acid addition salts max All are within the range of 2 to 4 hours. Table 32 Relative bioavailability

Claims

1. The crystal form of nepicastatin acid addition salt, in, The acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate and fumarate, preferably hydrochloride.

2. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat hydrochloride crystalline form I, nepicastat hydrochloride crystalline form II, nepicastat hydrochloride crystalline form III or nepicastat hydrochloride crystalline form IV; In particular, The nepicastat hydrochloride crystal form I is a monohydrate, and its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 15.48±0.2°, 20.66±0.2°, 22.64±0.2°, 25.60±0.2°, 27.06±0.2°, 29.70±0.2°, 31.84±0.2° and 41.94±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 17.04±0.2°, 23.82±0.2°, 25.08±0.2°, 34.34±0.2°, 36.78±0.2°, 43.88±0.2° and 44.1 2±0.2° diffraction angle (2θ) at least one characteristic peak; more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 5.12±0.2°, 12.98±0.2°, 27.68±0.2°, 28.20±0.2° and 39.94±0.2°; advantageously, the DSC spectrum of the nepicastat hydrochloride form I shows four endothermic peaks at 130.8°C, 205.5°C, 251.8°C and 296.9°C and one exothermic peak at 210.9°C; the TGA spectrum of the nepicastat hydrochloride form I shows a weight loss of 5.15% from room temperature to 120°C; The nepicastat hydrochloride crystal form II is an anhydrous substance, and its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 20.62±0.2°, 21.90±0.2°, 25.04±0.2°, 28.28±0.2°, 30.05±0.2° and 31.46±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 10.88±0.2°, 13.60±0.2°, 14.84±0.2°, 17.96±0.2° and 27.32±0. 2° at least one characteristic peak at a diffraction angle (2θ); more preferably further comprising at least one characteristic peak at a diffraction angle (2θ) of 7.12±0.2°, 16.74±0.2°, 18.57±0.2°, 23.01±0.2°, 24.64±0.2°, 34.54±0.2°, 40.17±0.2° and 45.56±0.2°; advantageously, the DSC spectrum of nepicastat hydrochloride form II shows an endothermic peak at 266.2°C; Nepicastat hydrochloride form III, whose X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 13.58±0.2°, 20.22±0.2°, 22.32±0.2°, 24.54±0.2°, 26.16±0.2°, 30.14±0.2° and 31.26±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 6.86±0.2°, 7.62±0.2°, 10.26±0.2°, 11.14±0.2°, 13.03±0.2° and 40.76±0.2°; advantageously, the DSC spectrum of nepicastat hydrochloride form III shows an endothermic peak at 267.1°C; The nepicastat hydrochloride form IV has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles (2θ) of 13.60±0.2°, 20.70±0.2°, 21.94±0.2°, 24.99±0.2° and 25.64±0.2°; preferably further comprising characteristic peaks at diffraction angles (2θ) of 15.56±0.2°, 16.78±0.2°, 22.68±0.2°, 24.99±0.2° and 25.64±0.2°; preferably further comprising characteristic peaks at diffraction angles (2θ) of 15.56±0.2°, 16.78±0.2°, 22.68±0.2° and 25.64±0.2°. At least one characteristic peak at a diffraction angle (2θ) of 10.95±0.2°, 13.06±0.2°, 14.84±0.2°, 17.93±0.2° and 29.95±0.2°; more preferably, at least one characteristic peak at a diffraction angle (2θ) of 10.95±0.2°, 13.06±0.2°, 14.84±0.2°, 17.93±0.2° and 29.95±0.2°. At least one characteristic peak, even more preferably further comprises at least one characteristic peak located at a diffraction angle (2θ) of 5.23±0.2°, 7.12±0.2°, 23.80±0.2°, 34.52±0.2°, 33.16±0.2° and 38.48±0.2°.

3. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat sulfate (1:0.5) crystalline form I, nepicastat sulfate (1:0.5) crystalline form II or nepicastat sulfate (1:1) crystalline form III; In particular, The X-ray powder diffraction pattern of nepicastat sulfate (1:0.5) Form I comprises characteristic peaks at diffraction angles (2θ) of 9.90±0.2°, 14.78±0.2°, 16.72±0.2°, 19.82±0.2°, 22.08±0.2°, 22.40±0.2° and 24.86±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 25.56±0.2°, 26.19±0.2°, 28.42±0.2°, 29.80±0.2°, 30.90±0.2°, 31.30±0.2°, 33.70±0.2°, 34.91±0.2°, 36.90±0.2°, 38.70±0.2°, 39.91±0.2°, 40.91±0.2°, 41.91±0.2°, 42.91±0.2°, 43.91±0.2°, 44.91±0.2°, 47.91±0.2°, 48.91±0.2°, 49.91±0.2°, 50.91±0.2°, 51.91±0.2°, 52.91±0.2°, 53.91±0.2°, 54.91±0.2°, 55.91±0.2°, 56.91±0.2°, 57.91±0.2°, 5 and at least one characteristic peak at a diffraction angle (2θ) of 30.68±0.2°; more preferably further comprising at least one characteristic peak at a diffraction angle (2θ) of 35.16±0.2°, 35.80±0.2° and 40.26±0.2°; advantageously, the DSC spectrum of nepicastat sulfate (1:0.5) Form I shows three endothermic peaks at 112.6°C, 127.3°C and 187.2°C and one exothermic peak at 207.3°C; The X-ray powder diffraction pattern of nepicastat sulfate (1:0.5) Form II comprises characteristic peaks at diffraction angles (2θ) of 4.56±0.2°, 8.24±0.2°, 9.02±0.2°, 16.08±0.2°, 16.58±0.2°, 17.90±0.2°, 22.01±0.2° and 25.12±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 19.48±0.2°, 23.68±0.2° and 27.14±0.2°; advantageously, the DSC spectrum of nepicastat sulfate (1:0.5) Form II shows an endothermic peak at 252.1°C; The X-ray powder diffraction pattern of nepicastat sulfate (1:1) form III comprises characteristic peaks at diffraction angles (2θ) of 9.92±0.2°, 16.82±0.2°, 19.84±0.2°, 22.10±0.2°, 22.44±0.2°, 25.18±0.2° and 28.42±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 12.40±0.2°, 14.26±0.2°, 24.06±0.2°, 30.68±0.2°, 31.00±0.2° and 35.28±0.2°; advantageously, the DSC spectrum of nepicastat sulfate (1:1) form III shows two endothermic peaks at 101.5°C and 201.3°C.

4. The crystalline form of the nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat phosphate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 5.24±0.2°, 10.48±0.2°, 21.14±0.2°, 22.76±0.2°, 23.74±0.2°, 25.54±0.2°, 26.52±0.2° and 29.74±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 12.50±0.2°, 16.92 ±0.2°, 21.92±0.2° and 27.34±0.2° at least one characteristic peak at diffraction angles (2θ); more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 13.58±0.2°, 15.48±0.2°, 19.40±0.2°, 20.68±0.2°, 34.66±0.2°, 37.62±0.2° and 39.90±0.2°; advantageously, the DSC spectrum of the nepicastat phosphate form I shows an endothermic peak at 227.1°C.

5. The crystalline form of nepicastatin acid addition salt according to claim 1, wherein the crystalline form is nepicastatin mesylate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 17.52±0.2°, 19.74±0.2°, 20.38±0.2°, 20.10±0.2°, 25.00±0.2° and 27.36±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 7.90±0.2°, 13.48±0.2°, 14.80±0.2°, 16.70±0.2°, 18.60±0.2°, 20.70±0.2°, 21.90±0.2°, 23.10±0.2°, 24.30±0.2°, 25.40±0.2°, 26.90±0.2°, 27.30±0.2°, 28.70±0.2°, 29.90±0.2°, 30.90±0.2°, 31.70±0.2°, 33.70±0.2°, 34.70±0.2°, 36.70±0.2°, 37.70±0.2°, 38. , 15.06±0.2°, 22.88±0.2° and 23.28±0.2° at least one characteristic peak at diffraction angles (2θ); more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 28.50±0.2°, 29.08±0.2°, 31.42±0.2°, 32.94±0.2° and 36.36±0.2°; advantageously, the DSC spectrum of nepicastat mesylate form I shows an endothermic peak at 280.7°C.

6. The crystalline form of nepicastatin acid addition salt according to claim 1, wherein the crystalline form is nepicastatin besylate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 14.00±0.2°, 16.62±0.2°, 17.96±0.2°, 22.70±0.2°, 24.66±0.2° and 26.86±0.2°; preferably further comprises a peak at 7.38±0.2° , 8.06±0.2°, 11.84±0.2° and 20.42±0.2° diffraction angles (2θ) at least one characteristic peak; more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 19.34±0.2°, 21.62±0.2°, 28.50±0.2° and 30.42±0.2°; advantageously, the DSC spectrum of nepicastat besylate form I shows an endothermic peak at 229.9°C.

7. The crystalline form of nepicastatin acid addition salt according to claim 1, wherein the crystalline form is nepicastatin tosylate crystalline form I or nepicastatin tosylate crystalline form II; In particular, The X-ray powder diffraction pattern of the crystalline form I of nepicastat toluenesulfonate comprises characteristic peaks at diffraction angles (2θ) of 13.40±0.2°, 15.52±0.2°, 19.38±0.2°, 19.78±0.2°, 23.52±0.2° and 28.74±0.2°; advantageously, the DSC spectrum of the crystalline form I of nepicastat toluenesulfonate shows three endothermic peaks at 182.7°C, 215.2°C and 230.0°C and one exothermic peak at 238.0°C; The X-ray powder diffraction pattern of the crystalline form II of nepicastat toluenesulfonate comprises characteristic peaks at diffraction angles (2θ) of 4.80±0.2°, 16.62±0.2°, 17.04±0.2°, 17.54±0.2°, 19.34±0.2° and 20.14±0.2°; preferably further comprises at least one peak at diffraction angles (2θ) of 9.44±0.2°, 15.46±0.2° and 21.46±0.2°. A characteristic peak; more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 24.78±0.2°, 25.10±0.2°, 26.34±0.2° and 29.20±0.2°; Advantageously, the DSC spectrum of nepicastat tosylate form II shows 5 endothermic peaks at 68.2°C, 175.3°C, 205.2°C, 212.2°C and 225.2°C and 1 exothermic peak at 233.6°C.

8. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat hydrobromide crystalline form I or nepicastat hydrobromide crystalline form II; In particular, The X-ray powder diffraction pattern of the nepicastat hydrobromide salt form I comprises characteristic peaks at diffraction angles (2θ) of 13.88±0.2°, 14.60±0.2°, 17.74±0.2°, 18.14±0.2°, 22.84±0.2° and 25.76±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 20.34±0.2°, 24.14±0.2° and 26.52±0.2°. More preferably, it further comprises at least one characteristic peak at diffraction angles (2θ) of 15.64±0.2°, 16.12±0.2°, 27.14±0.2° and 28.18±0.2°; Advantageously, the DSC spectrum of the crystalline form I of nepicastat hydrobromide shows three endothermic peaks at 98.2°C, 149.5°C and 184.5°C; The X-ray powder diffraction pattern of the nepicastat hydrobromide form II comprises characteristic peaks at diffraction angles (2θ) of 16.50±0.2°, 18.34±0.2°, 21.60±0.2°, 22.16±0.2°, 23.96±0.2°, 24.82±0.2°, 29.90±0.2° and 31.18±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 20.60±0.2°, 26.02±0.2°, 27.10±0.2°, 28.87±0.2°, 29.90±0.2° and 31.18±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 20.60±0.2°, 26.02±0.2°, 28.87±0.2°, 29.90±0.2° and 31.18±0.2°. At least one characteristic peak at diffraction angles (2θ) of 26.42±0.2° and 27.30±0.2°; more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 7.34±0.2°, 14.74±0.2°, 28.20±0.2°, 34.98±0.2° and 37.16±0.2°; advantageously, the DSC spectrum of nepicastat hydrobromide form II shows an endothermic peak at 273.2°C.

9. The crystalline form of nepicastatin acid addition salt according to claim 1, wherein the crystalline form is nepicastatin maleate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 12.81±0.2°, 16.76±0.2°, 23.96±0.2°, 24.58±0.2°, 25.02±0.2°, 25.94±0.2°, 26.34±0.2° and 28.38±0.2°; preferably further comprises a peak at 14.98±0.2°. , 18.64±0.2°, 19.36±0.2°, 20.56±0.2° and 21.92±0.2° diffraction angles (2θ) at least one characteristic peak; more preferably further comprising at least one characteristic peak at diffraction angles (2θ) of 16.32±0.2°, 27.72±0.2°, 31.50±0.2°, 36.36±0.2° and 39.46±0.2°; advantageously, the DSC spectrum of nepicastat maleate form I shows 1 endothermic peak at 210.0°C.

10. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat tartrate crystalline form I or nepicastat tartrate crystalline form II; In particular, The X-ray powder diffraction pattern of the nepicastat tartrate crystalline form I comprises characteristic peaks at diffraction angles (2θ) of 14.28±0.2°, 19.08±0.2°, 23.66±0.2°, 24.58±0.2°, 26.34±0.2°, 26.98±0.2°, 28.58±0.2° and 31.34±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 14.28±0.2°, 15.92±0.2°, 17.84±0.2°, 21.06±0.2° and at least one characteristic peak at a diffraction angle (2θ) of 28.00±0.2°; more preferably further comprising characteristic peaks at diffraction angles (2θ) of 33.44±0.2°, 37.34±0.2°, 40.34±0.2°, 42.26±0.2° and 46.82±0.2°; advantageously, the DSC spectrum of the nepicastat tartrate form I shows four endothermic peaks at 97.4°C, 184.6°C, 217.2°C and 250.7°C and one exothermic peak at 189.4°C; The X-ray powder diffraction pattern of the nepicastat tartrate crystal form II comprises characteristic peaks at diffraction angles (2θ) of 17.72±0.2°, 19.22±0.2°, 21.30±0.2°, 23.82±0.2°, 25.00±0.2°, 25.96±0.2°, 26.62±0.2° and 28.48±0.2°; preferably further comprises characteristic peaks at diffraction angles (2θ) of 14.22±0.2°, 19.72±0.2°, At least one characteristic peak at a diffraction angle (2θ) of 21.84±0.2° and 22.42±0.2°; more preferably further comprising characteristic peaks at diffraction angles (2θ) of 13.00±0.2°, 15.20±0.2°, 31.50±0.2°, 33.60±0.2°, 36.08±0.2° and 37.42±0.2°; advantageously, the DSC spectrum of the nepicastat tartrate form II shows a peak at 182.7°C, There are three endothermic peaks at 214.2℃ and 246.0℃.

11. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat citrate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 12.98±0.2°, 14.30±0.2°, 16.36±0.2°, 17.64±0.2°, 19.38±0.2°, 22.68±0.2°, 25.10±0.2° and 26.34±0.2°; preferably further comprises at least one characteristic peak at diffraction angles (2θ) of 22.28±0.2°, 30.26±0.2°, 40.26±0.2° and 40.86±0.2°; advantageously, the DSC spectrum of nepicastat citrate crystalline form I shows one endothermic peak at 204.1°C.

12. The crystalline form of nepicastat acid addition salt according to claim 1, wherein the crystalline form is nepicastat fumarate crystalline form I; in particular, its X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles (2θ) of 13.58±0.2°, 14.12±0.2°, 15.56±0.2°, 17.18±0.2°, 21.86±0.2°, 23.22±0.2°, 23.98±0.2° and 26.40±0.2°; preferably further comprises a peak at 16.20±0 .2°, 24.66±0.2°, 25.00±0.2°, 27.92±0.2° and 28.60±0.2° at least one characteristic peak at diffraction angles (2θ); more preferably further comprising characteristic peaks at diffraction angles (2θ) of 10.78±0.2°, 18.22±0.2°, 19.96±0.2°, 30.32±0.2° and 33.06±0.2°; advantageously, the DSC spectrum of nepicastat fumarate form I shows 1 endothermic peak at 216.0°C.

13. A method for preparing the nepicastat hydrochloride crystalline form according to claim 2, wherein include: 1) Suspension beating method Nepicastat hydrochloride and an organic solvent are mixed, and the obtained suspension is separated into solid and liquid to collect the solid; the organic solvent is selected from C 1 -C 4 Alcohol, C 4 -C 6 Ether and C 2 -C 6 One or more of nitriles; In particular, nepicastat hydrochloride and an organic solvent are mixed under stirring at room temperature to 50° C., preferably at 40° C. for 2-4 days, preferably 3 days, and the resulting suspension is separated into solid and liquid to collect the solid, which is optionally further dried; the organic solvent is selected from one or more of ethanol, methyl tert-butyl ether, tetrahydrofuran and acetonitrile; advantageously, the ratio (W / V) of nepicastat hydrochloride to the organic solvent is 50:1; 2) Solvent evaporation method Dissolve nepicastat hydrochloride in a good solvent, allow the solvent to evaporate naturally, and then collect the solid; the good solvent is C 1 -C 4 Alcohol and C 4 -C 6 One or more of ether or a mixed solvent thereof with water, preferably one or more of methanol, 50% isopropanol and 50% tetrahydrofuran; the ratio (W / V) of nepicastat hydrochloride to the good solvent is 50:1; 3) Anti-solvent method Dissolve nepicastat hydrochloride in a good solvent, add an anti-solvent, and then collect the solid; the good solvent is C 1 -C 4 Alcohol and C 4 -C 6 One or more of ether or a mixed solvent thereof with water, preferably one or more of methanol, 50% isopropanol and 50% tetrahydrofuran; the anti-solvent is selected from C 3 -C 6 Ester, C 4 -C 6 Ether and C 3 -C 6 One or more of ketones, preferably ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane Advantageously, the ratio (W / V) of nepicastat hydrochloride to the good solvent is 50:0.5-2, such as 50:1.5, 50:2 or 50:0.5; the volume ratio of the good solvent to the anti-solvent is 1:1 to 1:10, such as 1.5:4, 1.5:2 or 1:8; 4) Nepicastat hydrochloride, C 1 -C 4 Mix alcohol and water, heat the resulting suspension to 45-55°C, stir until dissolved, cool to 30-40°C, concentrate to remove part of the solvent, cool the residue to 0-10°C, and collect the solid by solid-liquid separation; In particular, nepicastat hydrochloride, C 1 -C 4 The alcohol and water are mixed, the resulting suspension is heated to 45-55°C, stirred until dissolved, cooled to 30-40°C and stirred for 1-3h, concentrated to remove part of the solvent, the residue is cooled to 0-10°C, solid-liquid separation is performed to collect the solid, and the solid is optionally further dried; the C 1 -C 4 The alcohol is ethanol; advantageously, nepicastat hydrochloride and C 1 -C 4 The ratio of alcohol (W / W) is 10:1 to 15:1, for example 12:1; C 1 -C 4 The volume ratio of alcohol to water is 10:1 to 20:1, for example 16:1; 5) (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, C 1 -C 4 The alcohol and concentrated hydrochloric acid were refluxed and stirred, cooled, and solids were precipitated. The solids were collected by solid-liquid separation, and C 1 -C 4 Alcohol and water, heated until dissolved, concentrated to remove part of the solvent, the residue was cooled to 0-10°C, and the solid was collected by solid-liquid separation; In particular, (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, C 1 -C 4 The alcohol and 36% concentrated hydrochloric acid were refluxed and stirred for 5 h, cooled to 20-30 ° C, solid precipitated, solid was collected by solid-liquid separation, and C 1 -C 4 alcohol and water, heated to 65-70°C, stirred until dissolved, concentrated to remove part of the solvent, the residue was cooled to 0-10°C, solid-liquid separation was performed to collect the solid, and the solid was optionally further dried; C 1 -C 4 The alcohol is isopropanol or methanol.

14. A method for preparing a crystalline form of a nepicastatin acid addition salt according to any one of claims 1 and 3-12, wherein include: 1) Nepicastat and C 1 -C 4 alcohol, preferably ethanol, is mixed under stirring, and then an acid is added. If a large amount of precipitated solids is obtained, the solids are collected by centrifugation; if the obtained sample is a clear solution or a small amount of precipitated solids is obtained, the solvent is concentrated by nitrogen purging or natural evaporation, and the solids are precipitated and collected; the acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid and fumaric acid; In particular, nepicastat and C 1 -C 4 The alcohol is stirred at 40-60°C, preferably 50°C to form a suspension, and then the acid is added, cooled to room temperature and stirred overnight; Nepicastat and C 1 -C 4 The ratio (W / V) of alcohol is 50:1; the molar ratio of nepicastat to acid is 1:1.05 or 1:0.55; Alternatively, 2) Nepicastat and C 3 -C 6 A ketone, preferably acetone, is mixed under stirring, and then an acid is added. If a large amount of precipitated solids is obtained, the solids are collected by centrifugation; if the obtained sample is a clear solution or a small amount of precipitated solids is obtained, the solvent is concentrated by nitrogen purging or natural evaporation, and then an anti-solvent is added to precipitate and collect the solids; the acid is selected from sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid and fumaric acid; the anti-solvent is C 4 -C 6 Ether, preferably methyl tert-butyl ether; In particular, nepicastat and C 3 -C 6 The ketone is stirred at 40-60°C, preferably 50°C to form a solution, and then the acid is added, cooled to room temperature and stirred overnight; Nepicastat and C 3 -C 6 The ratio of ketone (W / V) is 50:1; the molar ratio of nepicastat to acid is 1:1.05 or 1:0.55; C 3 -C 6 The volume ratio of ketone to anti-solvent is 1:1 to 1:10, for example 1:

5.

15. A pharmaceutical composition comprising the crystalline form of the nepicastatin acid addition salt according to any one of claims 1 to 12 and an auxiliary material; the auxiliary material is preferably a pharmaceutically acceptable carrier, diluent or excipient.

16. Use of the crystalline form of nepicastatin acid addition salt according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating autoimmune diseases, post-traumatic stress disorder, congestive heart failure, hypertension, cancer or sepsis, preferably, the cancer is selected from colon cancer, breast cancer, liver cancer, melanoma, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, cervical cancer, renal cell carcinoma, bladder cancer and gastric cancer, preferably, the autoimmune disease is selected from autoimmune colitis, neuromyelitis optica, rheumatoid arthritis, scleroderma, psoriasis and uveitis, and further, the autoimmune colitis is Crohn's disease or ulcerative colitis.

Images