Polymorphic forms of nepicastat acid addition salts, methods for their preparation and uses

Abstract

The present invention relates to polymorphic forms of nepicastat acid addition salts, their preparation methods, and uses. The acid addition salts are selected from the group consisting of hydrochloride, sulfate, phosphate, mesylate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate, and fumarate, with hydrochloride being preferred. Nepicastat acid addition salts have high polymorphic stability, high solubility, high plasma concentration, high bioavailability, and excellent pharmacological activity, making them suitable for pharmaceutical preparations.

Description

[Technical Field]

[0001] The present invention relates to polymorphic acid addition salts of nepicastat, and methods for their preparation and use. The acid addition salts are selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate, and fumarate, with hydrochloride being preferred. [Background technology]

[0002] Anxiety disorders are the most common mental illnesses with a significant economic burden. In addition to generalized anxiety disorder, anxiety disorders include post-traumatic stress disorder (PTSD), panic disorder, obsessive-compulsive disorder, social disorders, and other phobias.

[0003] Post-traumatic stress disorder can be severe and chronic, with some studies indicating a lifetime incidence rate of 1.3% to 7.8% in the general population. Post-traumatic stress disorder typically accompanies a psychologically distressing traumatic event. These events may include, for example, attacks, terrorist incidents, physical assaults, sexual assaults, car accidents, and natural disasters. Responses to such events may include intense anxiety, helplessness, or fear. Most people recover from traumatic events over time and return to normal life. In contrast, in patients with post-traumatic stress disorder, symptoms persist and possibly worsen over time, preventing a return to normal life.

[0004] Nepicastat, also known as SYN117 and RS-25560-197, is a highly selective inhibitor of dopamine beta-hydroxylase (DBH), having the following structural formula, and can effectively treat PTSD.

[0005] [ka]

[0006] Additionally, nepicastat is being investigated as a potential treatment for congestive heart failure. Nepicastat and its analogs (e.g., etamicastat) share potential applications in the treatment of hypertension, cancer, and other conditions. Nepicastat has also been reported to effectively reduce the mortality rate of sepsis and to alleviate sepsis-induced functional damage to multiple organs (e.g., heart, lungs, liver, intestine, etc.). Furthermore, nepicastat has been reported to be capable of treating autoimmune diseases.

[0007] Drug polymorphism has become an essential and important part of drug research and development and drug quality control. Research on drug polymorphism can facilitate the selection of biological activity of drug compounds, and help improve drug stability, solubility and other properties, which in turn is beneficial to the development of drug preparations, drug storage, and the improvement of drug manufacturing quality. It can also improve the bioavailability of compounds and enhance clinical efficacy.

[0008] However, there are no relevant reports of polymorphism of acid addition salts of nepicastat in the prior art. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] CN1113874C [Patent Document 2] CN106983747A Summary of the Invention [Problem to be solved by the invention]

[0010] The technical problem solved by the present invention is to provide polymorphic forms of acid addition salts of nepicastat, as well as methods for preparing and using the same. After extensive experimental studies, the inventors discovered a method for preparing polymorphic forms of acid addition salts of nepicastat, and performed detection and stability studies on the resulting polymorphic forms using X-ray powder diffraction, TGA, DSC, etc. As a result, a crystalline form of the acid addition salt of nepicastat with good stability was found. [Means for solving the problem]

[0011] The present invention solves the above technical problems through the following technical solutions.

[0012] The present invention provides a crystalline form of an acid addition salt of nepicastat, wherein 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. The crystalline form of the acid addition salt may be anhydrous, hydrated, or solvated.

[0013] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the hydrochloride salt of nepicastat, crystalline Form II of the hydrochloride salt of nepicastat, crystalline Form III of the hydrochloride salt of nepicastat, or crystalline Form IV of the hydrochloride salt of nepicastat.

[0014] Crystalline Form I of the hydrochloride salt of nepicastat is a monohydrate and its X-ray powder diffraction pattern contains 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°, and preferably at 17.04±0.2°, 23.82±0.2°, 25.08±0.2°, 34.34±0.2°, 36.7±0.2°, and 41.94±0.2°. and 44.12±0.2°, more preferably at least one characteristic peak, such as 1, 2, 3, 4, 5, 6 or 7 characteristic peaks, 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°.

[0015] Specifically, crystalline Form I of the hydrochloride salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 1.

[0016] [Table 1]

[0017] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the hydrochloride salt of nepicastat is substantially as shown in FIGS.

[0018] Advantageously, the DSC spectrum of crystalline Form I of the hydrochloride salt of nepicastat exhibits 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 Figure 3, and the TGA spectrum of crystalline Form I of the hydrochloride salt of nepicastat exhibits a mass loss of 5.15% from room temperature to 120°C, more advantageously substantially as shown in Figure 4.

[0019] Crystalline Form II of the hydrochloride salt of nepicastat is an anhydrous form, and its X-ray powder diffraction pattern contains 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 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°. It may further comprise at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, and more preferably at least one characteristic peak, such as 1, 2, 3, 4, 5, 6, 7 or 8 characteristic peaks, at diffraction angles (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°.

[0020] Specifically, crystalline Form II of the hydrochloride salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 2.

[0021] [Table 2]

[0022] More specifically, the X-ray powder diffraction pattern for crystalline Form II of the hydrochloride salt of nepicastat is substantially as shown in FIGS.

[0023] Advantageously, the DSC spectrum of crystalline Form II of the hydrochloride salt of nepicastat exhibits a single endothermic peak at 266.2°C, more advantageously substantially as shown in Figure 11, and the TGA spectrum of crystalline Form II of the hydrochloride salt of nepicastat exhibits a mass loss of 0.40% from room temperature to 120°C, more advantageously substantially as shown in Figure 12.

[0024] Crystalline Form III of the hydrochloride salt of nepicastat is characterized by an X-ray powder diffraction pattern containing 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°, and preferably further containing at least one characteristic peak, e.g., 1, 2, 3, 4, 5, or 6 characteristic peaks, 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°.

[0025] Specifically, crystalline Form III of the hydrochloride salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 3.

[0026] [Table 3]

[0027] More specifically, the X-ray powder diffraction pattern for crystalline Form III of the hydrochloride salt of nepicastat is substantially as shown in FIGS.

[0028] Advantageously, the DSC spectrum of crystalline Form III of the hydrochloride salt of nepicastat exhibits a single endothermic peak at 267.1°C, more advantageously substantially as shown in Figure 17, and the TGA spectrum of crystalline Form III of the hydrochloride salt of nepicastat exhibits a mass loss of 2.17% from room temperature to 120°C, more advantageously substantially as shown in Figure 18.

[0029] Crystalline Form IV of the hydrochloride salt of nepicastat contains 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°, and preferably further contains at least one characteristic peak, e.g., 1, 2, 3, 4, 5, 6, or 7 characteristic peaks, 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°, and more preferably 10.95±0.2°. and 29.95±0.2°, and even more preferably further comprising at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, at diffraction angles (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°.

[0030] Specifically, crystalline Form IV of the hydrochloride salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 4.

[0031] [Table 4]

[0032] More specifically, the X-ray powder diffraction pattern for crystalline Form IV of the hydrochloride salt of nepicastat is substantially as shown in FIG.

[0033] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the sulfate salt (1:0.5), crystalline Form II of the sulfate salt (1:0.5), or crystalline Form III of the sulfate salt (1:1). It can be understood that compounds corresponding to crystalline Form I of the sulfate salt (1:0.5) of nepicastat and crystalline Form II of the sulfate salt (1:0.5) of nepicastat are the sulfate salt of nepicastat, while compounds corresponding to crystalline Form III of the sulfate salt (1:1) of nepicastat are the bisulfate salt of nepicastat.

[0034] The X-ray powder diffraction pattern for crystalline Form I of the sulfate salt of nepicastat (1:0.5) contains 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°, and preferably at 25.56±0.2°, 26.19±0.2°, 27.19±0.2°, and 28.16±0.2°. It further comprises at least one characteristic peak, for example one, two, three or four characteristic peaks, at diffraction angles (2θ) of 8.42±0.2° and 30.68±0.2°, more preferably at least one characteristic peak, for example one, two or three characteristic peaks, at diffraction angles (2θ) of 35.16±0.2°, 35.80±0.2° and 40.26±0.2°.

[0035] Specifically, crystalline Form I of the sulfate salt of nepicastat (1:0.5) is characterized by the characteristic XRPD peaks shown in Table 5.

[0036] [Table 5]

[0037] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the sulfate salt (1:0.5) of nepicastat is substantially as shown in FIG.

[0038] Advantageously, the DSC spectrum of crystalline Form I of the sulfate salt (1:0.5) of nepicastat exhibits 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 Figure 27, and the TGA spectrum of crystalline Form I of the sulfate salt (1:0.5) of nepicastat exhibits a mass loss of 6.51% from room temperature to 120°C, more advantageously substantially as shown in Figure 28.

[0039] The X-ray powder diffraction pattern of crystalline Form II of the sulfate salt of nepicastat (1:0.5) contains 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°, and preferably further contains at least one characteristic peak, e.g., one, two, or three characteristic peaks, at diffraction angles (2θ) of 19.48±0.2°, 23.68±0.2°, and 27.14±0.2°.

[0040] Specifically, crystalline Form II of the sulfate salt of nepicastat (1:0.5) is characterized by the characteristic XRPD peaks shown in Table 6.

[0041] [Table 6]

[0042] More specifically, the X-ray powder diffraction pattern for crystalline Form II of the sulfate salt (1:0.5) of nepicastat is substantially as shown in FIG.

[0043] Advantageously, the DSC spectrum of crystalline Form II of the sulfate salt (1:0.5) of nepicastat exhibits a single endothermic peak at 252.1°C, more advantageously substantially as shown in Figure 30, and the TGA spectrum of crystalline Form II of the sulfate salt (1:0.5) of nepicastat exhibits a mass loss of 0.07% from room temperature to 120°C, more advantageously substantially as shown in Figure 31.

[0044] The X-ray powder diffraction pattern of crystalline Form III of the sulfate salt (1:1) of nepicastat contains 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°, and preferably further contains at least one characteristic peak, e.g., 1, 2, 3, 4, 5, or 6 characteristic peaks, 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°.

[0045] Specifically, crystalline Form III of the sulfate salt (1:1) of nepicastat is characterized by the characteristic XRPD peaks shown in Table 7.

[0046] [Table 7]

[0047] More specifically, the X-ray powder diffraction pattern for crystalline Form III of the sulfate salt (1:1) of nepicastat is substantially as shown in FIG.

[0048] Advantageously, the DSC spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat exhibits two endothermic peaks at 101.5°C and 201.3°C, more advantageously substantially as shown in Figure 33, and the TGA spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat exhibits a mass loss of 4.51% from room temperature to 120°C, more advantageously substantially as shown in Figure 34.

[0049] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the phosphate salt of nepicastat.

[0050] The X-ray powder diffraction pattern of crystalline Form I of the phosphate salt of nepicastat contains 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°, and preferably at diffraction angles of 12.50±0.2°, 16.92±0.2°, 21.92±0.2°, and 27.34±0.2°. and more preferably at least one characteristic peak, such as 1, 2, 3, 4, 5, 6, or 7 characteristic peaks, 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°.

[0051] Specifically, crystalline Form I of the phosphate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 8.

[0052] [Table 8]

[0053] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the phosphate salt of nepicastat is substantially as shown in FIG.

[0054] Advantageously, the DSC spectrum of crystalline Form I of the phosphate salt of nepicastat exhibits a single endothermic peak at 227.1°C, more advantageously substantially as shown in Figure 36, and the TGA spectrum of crystalline Form I of the phosphate salt of nepicastat exhibits a mass loss of 0.12% from room temperature to 120°C, more advantageously substantially as shown in Figure 37.

[0055] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the methanesulfonate salt of nepicastat.

[0056] The X-ray powder diffraction pattern for crystalline Form I of the methanesulfonate salt of nepicastat contains 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°, and preferably at 7.90±0.2°, 13.48±0.2°, 15.06±0.2°, 22.88±0.2°, and 23.2 It further comprises at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, at a diffraction angle (2θ) of 8±0.2°, more preferably at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, 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°.

[0057] Specifically, crystalline Form I of the methanesulfonate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 9.

[0058] [Table 9]

[0059] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the methanesulfonate salt of nepicastat is substantially as shown in FIG.

[0060] Advantageously, the DSC spectrum of crystalline Form I of the methanesulfonate salt of nepicastat exhibits a single endothermic peak at 280.7°C, more advantageously substantially as shown in Figure 39, and the TGA spectrum of crystalline Form I of the methanesulfonate salt of nepicastat exhibits a mass loss of 0.06% from room temperature to 120°C, more advantageously substantially as shown in Figure 40.

[0061] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the benzenesulfonate salt of nepicastat.

[0062] The X-ray powder diffraction pattern for crystalline Form I of the benzenesulfonate salt of nepicastat contains 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°, and preferably at 7.38±0.2°, 8.06±0.2°, 11.84±0.2°, and 20. and more preferably, at least one characteristic peak, e.g., one, two, three or four characteristic peaks, at diffraction angles (2θ) of 19.34±0.2°, 21.62±0.2°, 28.50±0.2° and 30.42±0.2°.

[0063] Specifically, crystalline Form I of the benzenesulfonate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 10.

[0064] [Table 10]

[0065] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the benzenesulfonate salt of nepicastat is substantially as shown in FIG.

[0066] Advantageously, the DSC spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat exhibits a single endothermic peak at 229.9°C, more advantageously substantially as shown in Figure 42, and the TGA spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat exhibits a mass loss of 0.35% from room temperature to 120°C, more advantageously substantially as shown in Figure 43.

[0067] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the p-toluenesulfonate salt of nepicastat or crystalline Form II of the p-toluenesulfonate salt of nepicastat.

[0068] The X-ray powder diffraction pattern for crystalline Form I of the p-toluenesulfonate salt of nepicastat contains 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°.

[0069] Specifically, crystalline Form I of the p-toluenesulfonate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 11.

[0070] [Table 11]

[0071] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the p-toluenesulfonate salt of nepicastat is substantially as shown in FIG.

[0072] Advantageously, the DSC spectrum of crystalline Form I of the p-toluenesulfonate salt of nepicastat exhibits 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, and the TGA spectrum of crystalline Form I of the p-toluenesulfonate salt of nepicastat exhibits a mass loss of 2.38% from room temperature to 120°C, more advantageously substantially as shown in Figure 46.

[0073] The X-ray powder diffraction pattern of crystalline Form II of the p-toluenesulfonate salt of nepicastat contains 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°, and preferably further contains at least one characteristic peak, e.g., one, two, or three characteristic peaks, at diffraction angles (2θ) of 9.44±0.2°, 15.46±0.2°, and 21.46±0.2°, and more preferably further contains at least one characteristic peak, e.g., one, two, three, or four characteristic peaks, at diffraction angles (2θ) of 24.78±0.2°, 25.10±0.2°, 26.34±0.2°, and 29.20±0.2°.

[0074] Specifically, crystalline Form II of the p-toluenesulfonate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 12.

[0075] [Table 12]

[0076] More specifically, the X-ray powder diffraction pattern for crystalline Form II of the p-toluenesulfonate salt of nepicastat is substantially as shown in FIG.

[0077] Advantageously, the DSC spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat exhibits 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, and the TGA spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat exhibits a mass loss of 0.39% from room temperature to 120°C, more advantageously substantially as shown in Figure 49.

[0078] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the hydrobromide salt of nepicastat or crystalline Form II of the hydrobromide salt of nepicastat.

[0079] The X-ray powder diffraction pattern of crystalline Form I of the hydrobromide salt of nepicastat contains 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°, and preferably further contains at least one characteristic peak, e.g., one, two, or three characteristic peaks, at diffraction angles (2θ) of 20.34±0.2°, 24.14±0.2°, and 26.52±0.2°, and more preferably further contains at least one characteristic peak, e.g., one, two, three, or four characteristic peaks, at diffraction angles (2θ) of 15.64±0.2°, 16.12±0.2°, 27.14±0.2°, and 28.18±0.2°.

[0080] Specifically, crystalline Form I of the hydrobromide salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 13.

[0081] [Table 13]

[0082] More specifically, the X-ray powder diffraction pattern for crystalline Form I of the hydrobromide salt of nepicastat is substantially as shown in FIG.

[0083] Advantageously, the DSC spectrum of crystalline Form I of the hydrobromide salt of nepicastat exhibits three endothermic peaks at 98.2°C, 149.5°C, and 184.5°C, more advantageously substantially as shown in Figure 51, and the TGA spectrum of crystalline Form I of the hydrobromide salt of nepicastat exhibits a mass loss of 2.84% from room temperature to 120°C, more advantageously substantially as shown in Figure 52.

[0084] The X-ray powder diffraction pattern of crystalline Form II of the hydrobromide salt of nepicastat contains 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°, and preferably at 20.60±0.2°, 26.02±0.2°, 26.42±0.2°, and 31.18±0.2°. and 27.30±0.2°, more preferably at least one characteristic peak, such as 1, 2, 3, or 4 characteristic peaks, 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°.

[0085] Specifically, crystalline Form II of the hydrobromide salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 14.

[0086] [Table 14]

[0087] More specifically, the X-ray powder diffraction pattern for crystalline Form II of the hydrobromide salt of nepicastat is substantially as shown in FIG.

[0088] Advantageously, the DSC spectrum of crystalline Form II of the hydrobromide salt of nepicastat exhibits a single endothermic peak at 273.2°C, more advantageously substantially as shown in Figure 54, and the TGA spectrum of crystalline Form II of the hydrobromide salt of nepicastat exhibits a mass loss of 0.04% from room temperature to 120°C, more advantageously substantially as shown in Figure 55.

[0089] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the maleate salt of nepicastat.

[0090] The X-ray powder diffraction pattern for crystalline Form I of the maleate salt of nepicastat contains 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°, and preferably at 14.98±0.2°, 18.64±0.2°, 19.36±0.2°, 20.56±0.2°, 21.66±0.2°, 22.46±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°. The optically active material may further comprise at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, at diffraction angles (2θ) of 0.2° and 21.92±0.2°, more preferably at least one characteristic peak, such as 1, 2, 3, 4 or 5 characteristic peaks, 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°.

[0091] Specifically, crystalline Form I of the maleate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 15.

[0092] [Table 15]

[0093] Specifically, the X-ray powder diffraction pattern for crystalline Form I of the maleate salt of nepicastat is substantially as shown in FIG.

[0094] Advantageously, the DSC spectrum of crystalline Form I of the maleate salt of nepicastat exhibits a single endothermic peak at 210.0°C, more advantageously substantially as shown in Figure 57, and the TGA spectrum of crystalline Form I of the maleate salt of nepicastat exhibits a mass loss of 0.07% from room temperature to 120°C, more advantageously substantially as shown in Figure 58.

[0095] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the tartrate salt of nepicastat or crystalline Form II of the tartrate salt of nepicastat.

[0096] The X-ray powder diffraction pattern of crystalline Form I of the tartrate salt of nepicastat contains 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°, and preferably at 14.28±0.2°, 15.92±0.2°, 17.84±0.2°, 21.84±0.2°, and 22.84±0.2°. and 28.00±0.2°, and more preferably further comprising characteristic peaks, such as 1, 2, 3, 4 or 5 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°.

[0097] Specifically, crystalline Form I of the tartrate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 16.

[0098] [Table 16]

[0099] Specifically, the X-ray powder diffraction pattern for crystalline Form I of the tartrate salt of nepicastat is substantially as shown in FIG.

[0100] Advantageously, the DSC spectrum of crystalline Form I of the tartrate salt of nepicastat exhibits 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, and the TGA spectrum of crystalline Form I of the tartrate salt of nepicastat exhibits a mass loss of 4.28% from room temperature to 120°C, more advantageously substantially as shown in Figure 61.

[0101] The X-ray powder diffraction pattern of crystalline Form II of the tartrate salt of nepicastat contains 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°, and preferably at 14.22±0.2°, 19.72±0.2°, 21.84±0.2°, and 2 It further comprises at least one characteristic peak, such as 1, 2, 3 or 4 characteristic peaks, at a diffraction angle (2θ) of 2.42±0.2°, more preferably further comprises characteristic peaks, such as 1, 2, 3, 4, 5 or 6 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°.

[0102] Specifically, crystalline Form II of the tartrate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 17.

[0103] [Table 17]

[0104] Specifically, the X-ray powder diffraction pattern for crystalline Form II of the tartrate salt of nepicastat is substantially as shown in FIG.

[0105] Advantageously, the DSC spectrum of crystalline Form II of the tartrate salt of nepicastat exhibits endothermic peaks at 182.7°C, 214.2°C, and 246.0°C, and more advantageously is substantially as shown in Figure 63, and the TGA spectrum of crystalline Form II of the tartrate salt of nepicastat exhibits a mass loss of 0.15% from room temperature to 120°C, and more advantageously is substantially as shown in Figure 64.

[0106] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the citrate salt of nepicastat.

[0107] The X-ray powder diffraction pattern of crystalline Form I of the citrate salt of nepicastat contains 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°, and preferably further contains at least one characteristic peak, e.g., one, two, three, or four characteristic peaks, at diffraction angles (2θ) of 22.28±0.2°, 30.26±0.2°, 40.26±0.2°, and 40.86±0.2°.

[0108] Specifically, crystalline Form I of the citrate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 18.

[0109] [Table 18]

[0110] Specifically, the X-ray powder diffraction pattern for crystalline Form I of the citrate salt of nepicastat is substantially as shown in FIG.

[0111] Advantageously, the DSC spectrum of crystalline Form I of the citrate salt of nepicastat exhibits a single endothermic peak at 204.1°C, more advantageously substantially as shown in Figure 66, and the TGA spectrum of crystalline Form I of the citrate salt of nepicastat exhibits a mass loss of 0.85% from room temperature to 120°C, more advantageously substantially as shown in Figure 67.

[0112] In some embodiments, the crystalline form of the acid addition salt of nepicastat is crystalline Form I of the fumarate salt of nepicastat.

[0113] The X-ray powder diffraction pattern for crystalline Form I of the fumarate salt of nepicastat contains 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°, and preferably at 16.20±0.2°, 24.66±0.2°, 25.00±0.2°, 27.00±0.2°, and 28.00±0.2°. and 28.60±0.2°, and more preferably further comprising characteristic peaks, such as 1, 2, 3, 4 or 5 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°.

[0114] Specifically, crystalline Form I of the fumarate salt of nepicastat is characterized by the characteristic XRPD peaks shown in Table 19.

[0115] [Table 19]

[0116] Specifically, the X-ray powder diffraction pattern for crystalline Form I of the fumarate salt of nepicastat is substantially as shown in FIG.

[0117] Advantageously, the DSC spectrum of crystalline Form I of the fumarate salt of nepicastat exhibits a single endothermic peak at 216.0°C, more advantageously substantially as shown in Figure 69, and the TGA spectrum of crystalline Form I of the fumarate salt of nepicastat exhibits a mass loss of 0.12% from room temperature to 120°C, more advantageously substantially as shown in Figure 70.

[0118] The present invention provides a process for preparing a crystalline form of the hydrochloride salt of nepicastat, comprising: 1) Suspension-pulverization method mixing nepicastat hydrochloride with an organic solvent under stirring and centrifuging the resulting suspension to collect the solid, wherein the organic solvent is selected from one or more of C1-C4 alcohols, C4-C6 ethers, and C2-C6 nitriles; Specifically, the process comprises the steps of: mixing nepicastat hydrochloride with an organic solvent under stirring at a temperature ranging from room temperature to 50°C, preferably at 40°C, for 2 to 4 days, preferably 3 days; centrifuging the resulting suspension to collect the solid; and optionally further drying the solid; wherein the organic solvent is one or more selected from the group consisting of ethanol, methyl tert-butyl ether, tetrahydrofuran, and acetonitrile, and preferably at a ratio of nepicastat hydrochloride to organic solvent (w / v) of 50:1; 2) Solvent evaporation method dissolving nepicastat hydrochloride in a good solvent, allowing the solvent to evaporate, and then collecting the solid, wherein the good solvent is one or more of a C1-C4 alcohol and a C4-C6 ether, or a mixture thereof with water, preferably one or more of methanol, 50% isopropanol, and 50% tetrahydrofuran, in a ratio (w / v) of nepicastat hydrochloride to the good solvent of 50:1; 3) Antisolvent method dissolving nepicastat hydrochloride in a good solvent, adding an anti-solvent, and then collecting the solid, wherein the good solvent is one or more of a C1-C4 alcohol and a C4-C6 ether, or a mixture thereof with water, preferably one or more of methanol, 50% isopropanol, and 50% tetrahydrofuran; and the anti-solvent is one or more selected from C3-C6 esters, C4-C6 ethers, and C3-C6 ketones, 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, e.g., 50:1.5, 50:2, or 50:0.5, and the volume ratio of the good solvent to the anti-solvent is 1:1-1:10, e.g., 1.5:4, 1.5:2, or 1:8; 4) combining nepicastat hydrochloride with a C1-C4 alcohol and water, heating the resulting suspension to 45-55°C and stirring until dissolved, cooling to 30-40°C, concentrating to remove a portion of the solvent, cooling the residue to 0-10°C, and collecting the solid after solid-liquid separation; Specifically, the process comprises mixing nepicastat hydrochloride, a C1-C4 alcohol, and water, heating the resulting suspension to 45-55°C and stirring until dissolved, cooling to 30-40°C, stirring for 1-3 hours, concentrating to remove a portion of the solvent, cooling the residue to 0-10°C, and collecting the solid after solid-liquid separation, optionally further drying the solid; wherein the C1-C4 alcohol is ethanol, and preferably the ratio (w / w) of nepicastat hydrochloride to the C1-C4 alcohol is 10:1-15:1, e.g., 12:1, and the volume ratio of the C1-C4 alcohol to water is 10:1-20:1, e.g., 16:1; 5) stirring (S)—N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, a C1-C4 alcohol, and concentrated hydrochloric acid under reflux, cooling to precipitate a solid, collecting the solid after solid-liquid separation, adding a C1-C4 alcohol and water, heating until dissolved, concentrating to remove a portion of the solvent, cooling the residue to 0-10° C., and collecting the solid after solid-liquid separation; Specifically, (S)—N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide, a C1-C4 alcohol, and 36% concentrated hydrochloric acid are stirred under reflux for 5 hours, cooled to 20-30° C. to precipitate a solid, the solid is collected after solid-liquid separation, a C1-C4 alcohol and water are added, heated to 65-70° C., stirred until dissolved, concentrated to remove a portion of the solvent, cooled to 0-10° C., the solid is collected after solid-liquid separation, and optionally further dried, wherein the C1-C4 alcohol is isopropanol or methanol. Also provided is a method comprising:

[0119] The present invention provides a process for preparing a crystalline form of an acid addition salt of nepicastat, comprising: 1) mixing nepicastat with a C1-C4 alcohol, preferably ethanol, under stirring, followed by addition of an acid, whereby if a large amount of solids precipitates, the solids are collected by centrifugation or a sample is obtained as a clear solution, or if a small amount of solids precipitates, the solvent is concentrated by nitrogen purging or natural evaporation, whereby the solids precipitate and are collected; wherein the acid is selected from the group consisting of sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid, and fumaric acid; Specifically, the method comprises the steps of: mixing nepicastat and a C1-C4 alcohol with stirring at 40-60°C, preferably 50°C, to form a suspension; adding an acid; cooling to room temperature; and stirring overnight; wherein the ratio of nepicastat to the C1-C4 alcohol (w / v) is 50:1, and the molar ratio of nepicastat to the acid is 1:1.05 or 1:0.55; or 2) mixing nepicastat and a C3-C6 ketone, preferably acetone, under stirring, then adding an acid, and if a large amount of solids precipitates, collecting the solids by centrifugation or obtaining a clear solution, or if a small amount of solids precipitates, concentrating the solvent by nitrogen purging or natural evaporation, then adding an anti-solvent, precipitating and collecting the solids; wherein the acid is selected from the group consisting of sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid, and fumaric acid, and the anti-solvent is a C4-C6 ether, preferably methyl tert-butyl ether; Specifically, the process involves mixing nepicastat and a C3-C6 ketone under stirring at 40-60°C, preferably 50°C, to prepare a solution, adding an acid, cooling to room temperature, and stirring overnight, wherein the ratio of nepicastat to the C3-C6 ketone (w / v) is 50:1, the molar ratio of nepicastat to the acid is 1:1.05 or 1:0.55, and the volume ratio of the C3-C6 ketone to the anti-solvent is 1:1 to 1:10, e.g., 1:5. Also provided is a method comprising:

[0120] The present invention also provides a pharmaceutical composition comprising a crystalline form of an acid addition salt of nepicastat and an auxiliary material, preferably a pharmaceutically acceptable carrier, diluent, or excipient.

[0121] The present invention relates to the use of a crystalline form of an acid addition salt of nepicastat, or a pharmaceutical composition comprising same, in the preparation of a medicament for the treatment of autoimmune disease, post-traumatic stress disorder, congestive heart failure, hypertension, cancer, or sepsis.

[0122] The present invention relates to a crystalline form of an acid addition salt of nepicastat or a pharmaceutical composition comprising the same for use in the treatment of autoimmune diseases, post-traumatic stress disorder, congestive heart failure, hypertension, cancer, or sepsis.

[0123] 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 a crystalline form of an acid addition salt of nepicastat or a pharmaceutical composition comprising same.

[0124] In some embodiments, the autoimmune disease is selected from the group consisting of autoimmune colitis, neuromyelitis optica, rheumatoid arthritis, scleroderma, psoriasis, and uveitis, and further, the autoimmune colitis is Crohn's disease or ulcerative colitis.

[0125] In some embodiments, the cancer is selected from the group consisting of 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.

[0126] As used herein, the expression "pharmaceutically acceptable" refers to substances useful for preparing pharmaceutical compositions that are generally safe, have no biological or other undesirable toxicities, and are acceptable for veterinary and human pharmaceutical use.

[0127] The term "carrier" as used herein 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 those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, rapeseed oil, etc. Pharmaceutically acceptable carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, silica gel, urea, etc. In addition, acids, stabilizers, thickeners, lubricants, coloring agents, etc. can also be used.

[0128] Those skilled in the art will understand that the pharmaceutical compositions of the present invention may be formulated into various formulations well known in the art according to the particular route of administration, for example, oral preparations (powders, tablets, capsules, soft capsules, liquids, syrups, elixirs, powders, sachets, granules), or preparations for topical administration (creams, ointments, lotions, gels, balms, salves, pastes, sprays, aerosols, etc.), or injectable preparations (solutions, suspensions, emulsions). Of the pharmaceutical compositions of the present invention, particular mention may be made of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, for example, tablets or dragees, sublingual tablets, gelatin capsules, troches, suppositories, creams, ointments, skin gels, injections, drinkable suspensions, etc.

[0129] 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, matrices, etc. Fillers include, for example, starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc. Disintegrants include, for example, starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrole, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc. Lubricants include, for example, magnesium stearate, sodium lauryl sulfate, talc, silicon dioxide, etc. Suspending agents include, for example, polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc. Binders include, for example, starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc. The compositions of the invention may be formulated by any method known in the art so as to provide quick, sustained or slow release of the active ingredient after administration to the patient.

[0130] The pharmaceutical compositions of the present invention may be administered to an individual animal, such as a mammal (rat, mouse, livestock, or human) by a variety of routes, and all routes of administration are contemplated, for example, the route of administration may be oral, topical, rectal administration, or intravenous, intramuscular, transdermal, intrathecal, epidural, or intracerebroventricular injection.

[0131] The dosage of the active ingredient of the present invention may vary depending on the condition and weight of the individual, the nature and severity of the disease, the drug form, the administration route, and the administration period, and can be selected by those skilled in the art. The dosage may vary from 1 to 1500 mg / day, and the drug may be administered daily in a single dose or in divided doses. [Brief explanation of the drawings]

[0132] [Figure 1] 1 shows comparative XRPD patterns of crystalline Forms I, II, and III of the hydrochloride salt of nepicastat. From top to bottom, the XRPD patterns are Form III, Form II, and Form I. [Figure 2] 1 is an XRPD pattern of crystalline Form I of the hydrochloride salt of nepicastat. [Figure 3] 1 is a DSC spectrum of crystalline Form I of the hydrochloride salt of nepicastat. [Figure 4] 1 is a TGA spectrum of crystalline Form I of the hydrochloride salt of nepicastat. [Figure 5] 1 is a PLM spectrum of crystalline Form I of the hydrochloride salt of nepicastat. [Figure 6] 1 is a DVS spectrum of crystalline Form I of the hydrochloride salt of nepicastat. [Figure 7] 1 shows XRPD patterns of crystalline Form I of the hydrochloride salt of nepicastat before and after DVS. From top to bottom, the XRPD pattern is after DVS and the XRPD pattern is before DVS. [Figure 8] 1 shows the XRPD pattern of crystalline Form I of the hydrochloride salt of nepicastat after heating to 170° C. From top to bottom, the XRPD pattern of crystalline Form I after heating to 170° C. and the XRPD pattern of initial crystalline Form I. [Figure 9]1 is a TGA spectrum of crystalline Form I of the hydrochloride salt of nepicastat after heating to 170° C. [Figure 10] 1 is an XRPD pattern of crystalline Form II of the hydrochloride salt of nepicastat. [Figure 11] 1 is a DSC spectrum of crystalline Form II of the hydrochloride salt of nepicastat. [Figure 12] 1 is a TGA spectrum of crystalline Form II of the hydrochloride salt of nepicastat. [Figure 13] 1 is a PLM spectrum of crystalline Form II of the hydrochloride salt of nepicastat. [Figure 14] 1 is a DVS spectrum of crystalline Form II of the hydrochloride salt of nepicastat. [Figure 15] 1 shows XRPD patterns of crystalline Form II of the hydrochloride salt of nepicastat before and after DVS. From top to bottom, the XRPD pattern is after DVS and the XRPD pattern is before DVS. [Figure 16] 1 is an XRPD pattern of crystalline Form III of the hydrochloride salt of nepicastat. [Figure 17] 1 is a DSC spectrum of crystalline Form III of the hydrochloride salt of nepicastat. [Figure 18] 1 is a TGA spectrum of crystalline Form III of the hydrochloride salt of nepicastat. [Figure 19] 1 is an XRPD pattern of crystalline Form IV of the hydrochloride salt of nepicastat. [Figure 20] Comparative XRPD patterns for the suspension-grinding method (40° C.) are, from top to bottom, the XRPD pattern of the product obtained by grinding with absolute ethanol, the XRPD pattern of the product obtained by grinding with acetonitrile, the XRPD pattern of the product obtained by grinding with methyl tert-butyl ether, the XRPD pattern of the product obtained by grinding with tetrahydrofuran, and the XRPD pattern of the initial crystalline Form I. [Figure 21] 1 shows comparative XRPD patterns for the solvent evaporation method, from top to bottom, the XRPD pattern of the product obtained by methanol evaporation and the XRPD pattern of the initial crystalline form I. [Figure 22] 1 shows comparative XRPD patterns for the anti-solvent method. From top to bottom, the figure shows the XRPD pattern of the product obtained by using 50% isopropanol as a good solvent and 1,4-dioxane as an anti-solvent, the XRPD pattern of the product obtained by using methanol as a good solvent and methyl tert-butyl ether as an anti-solvent, the XRPD pattern of the product obtained by using methanol as a good solvent and 2-methyltetrahydrofuran as an anti-solvent, the XRPD pattern of the product obtained by using methanol as a good solvent and ethyl acetate as an anti-solvent, the XRPD pattern of the product obtained by using 50% tetrahydrofuran as a good solvent and 2-butanone as an anti-solvent, and the XRPD pattern of the initial crystalline Form I. [Figure 23] Figure 1 shows comparative XRPD patterns of suspensions of crystalline Forms I and II of nepicastat hydrochloride salt after a 3-day competition at room temperature. From top to bottom, the patterns are: the XRPD pattern of the product in 95% ethanol solution, the XRPD pattern of the product in 90% ethanol solution, the XRPD pattern of the product in 65% ethanol solution, the XRPD pattern of the product in 15% ethanol solution, the XRPD pattern of the product in water, the XRPD pattern of crystalline Form II, and the XRPD pattern of crystalline Form I. [Figure 24] 1 shows comparative XRPD patterns for screening salt forms of nepicastat free base in ethanol systems. From top to bottom, the XRPD patterns are for the fumarate crystalline form, the citrate crystalline form, the tartrate crystalline form II, the hydrobromide crystalline form II, the maleate crystalline form, the p-toluenesulfonate crystalline form II, the benzenesulfonate crystalline form, the methanesulfonate crystalline form, the phosphate crystalline form, the sulfate (1:1) crystalline form III, the sulfate (1:0.5) crystalline form II, blank ethanol, and the free base of nepicastat. [Figure 25]1 shows comparative XRPD patterns for screening salt forms of nepicastat free base in acetone systems. From top to bottom, the XRPD patterns are for the fumarate crystalline form, the citrate crystalline form, the tartrate crystalline form I, the hydrobromide crystalline form I, the maleate crystalline form, the p-toluenesulfonate crystalline form I, the benzenesulfonate crystalline form, the methanesulfonate crystalline form, the phosphate crystalline form, the sulfate (1:1) crystalline form III, the sulfate (1:0.5) crystalline form I, blank acetone, and the free base of nepicastat. [Figure 26] 1 is an XRPD pattern for crystalline Form I of the sulfate salt of nepicastat (1:0.5). [Figure 27] 1 is a DSC spectrum of crystalline Form I of the sulfate salt of nepicastat (1:0.5). [Figure 28] 1 is a TGA spectrum of crystalline Form I of the sulfate salt of nepicastat (1:0.5). [Figure 29] 1 is an XRPD pattern for crystalline Form II of the sulfate salt of nepicastat (1:0.5). [Figure 30] 1 is a DSC spectrum of crystalline Form II of the sulfate salt of nepicastat (1:0.5). [Figure 31] 1 is a TGA spectrum of crystalline Form II of the sulfate salt of nepicastat (1:0.5). [Figure 32] 1 is an XRPD pattern for crystalline Form III of the sulfate salt (1:1) of nepicastat. [Figure 33] 1 is a DSC spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat. [Figure 34] 1 is a TGA spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat. [Figure 35] 1 is an XRPD pattern for crystalline Form I of the phosphate salt of nepicastat. [Figure 36] 1 is a DSC spectrum of crystalline Form I of the phosphate salt of nepicastat. [Figure 37] 1 is a TGA spectrum of crystalline Form I of the phosphate salt of nepicastat. [Figure 38] 1 is an XRPD pattern for crystalline Form I of the methanesulfonate salt of nepicastat. [Figure 39] 1 is a DSC spectrum of crystalline Form I of the methanesulfonate salt of nepicastat. [Figure 40] 1 is a TGA spectrum of crystalline Form I of the methanesulfonate salt of nepicastat. [Figure 41] 1 is an XRPD pattern for crystalline Form I of the benzenesulfonate salt of nepicastat. [Figure 42] 1 is a DSC spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat. [Figure 43] 1 is a TGA spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat. [Figure 44] 1 is an XRPD pattern for crystalline Form I of the p-toluenesulfonate salt of nepicastat. [Figure 45] 1 is a DSC spectrum of crystalline Form I of the p-toluenesulfonate salt of nepicastat. [Figure 46] 1 is a TGA spectrum of crystalline Form I of the p-toluenesulfonate salt of nepicastat. [Figure 47] 1 is an XRPD pattern of crystalline Form II of the p-toluenesulfonate salt of nepicastat. [Figure 48] 1 is a DSC spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat. [Figure 49] 1 is a TGA spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat. [Figure 50] 1 is an XRPD pattern for crystalline Form I of the hydrobromide salt of nepicastat. [Figure 51] 1 is a DSC spectrum of crystalline Form I of the hydrobromide salt of nepicastat. [Figure 52] 1 is a TGA spectrum of crystalline Form I of the hydrobromide salt of nepicastat. [Figure 53] 1 is an XRPD pattern of crystalline Form II of the hydrobromide salt of nepicastat. [Figure 54] 1 is a DSC spectrum of crystalline Form II of the hydrobromide salt of nepicastat. [Figure 55] 1 is a TGA spectrum of crystalline Form II of the hydrobromide salt of nepicastat. [Figure 56] 1 is an XRPD pattern of crystalline Form I of the maleate salt of nepicastat. [Figure 57] 1 is a DSC spectrum of crystalline Form I of the maleate salt of nepicastat. [Figure 58] 1 is a TGA spectrum of crystalline Form I of the maleate salt of nepicastat. [Figure 59] 1 is an XRPD pattern for crystalline Form I of the tartrate salt of nepicastat. [Figure 60] 1 is a DSC spectrum of crystalline Form I of the tartrate salt of nepicastat. [Figure 61] 1 is a TGA spectrum of crystalline Form I of the tartrate salt of nepicastat. [Figure 62] 1 is an XRPD pattern for crystalline Form II of the tartrate salt of nepicastat. [Figure 63] 1 is a DSC spectrum of crystalline Form II of the tartrate salt of nepicastat. [Figure 64] 1 is a TGA spectrum of crystalline Form II of the tartrate salt of nepicastat. [Figure 65] 1 is an XRPD pattern of crystalline Form I of the citrate salt of nepicastat. [Figure 66] 1 is a DSC spectrum of crystalline Form I of the citrate salt of nepicastat. [Figure 67] 1 is a TGA spectrum of crystalline Form I of the citrate salt of nepicastat. [Figure 68] 1 is an XRPD pattern for crystalline Form I of the fumarate salt of nepicastat. [Figure 69] 1 is a DSC spectrum of crystalline Form I of the fumarate salt of nepicastat. [Figure 70] 1 is a TGA spectrum of crystalline Form I of the fumarate salt of nepicastat. DETAILED DESCRIPTION OF THE INVENTION

[0133] The present invention will be described in more detail by the following examples, which are only intended to describe the technical solutions of the present invention and should not be considered as limiting the spirit and scope of the present invention.

[0134] X-ray powder diffraction (XRPD) The instrument is a Shimadzu XRD-6000, and the sample is scanned according to the following parameters:

[0135] [Table 20]

[0136] Thermogravimetric analysis (TGA) The instrument is a Pyris1 TGA manufactured by PerkinElmer Co. Approximately 5 mg of sample is weighed and placed in a crucible, and under nitrogen protection, the temperature is increased from 30°C to 350°C at a heating rate of 20°C / min, and maintained at 350°C for 1 minute.

[0137] Differential scanning calorimetry (DSC) The instrument used was a Mettler DSC3. Approximately 0.5–5 mg of powder sample was weighed and placed in a covered aluminum crucible with a pinhole in the lid. Under nitrogen protection, a differential calorimetry scan was performed by increasing the temperature from 30°C to 300°C and maintaining it at 300°C for 1 minute. The heating rate was 20°C / min.

[0138] [Table 21]

[0139] Polarized Light Microscope (PLM) The instrument is XPV-203E manufactured by Shanghai Changfang Optical Instrument Co., Ltd. The sample is dispersed in a suitable medium and observed using an eyepiece and an objective lens. The image is recorded using a camera computer system.

[0140] Dynamic Vapor Sorption (DVS) The DVS curve is obtained using DVS Intrinsic manufactured by SMS (Surface Measurement Systems). Test temperature: 25℃ Sample amount: 10-20 mg dm / dt:0.002% / min RH range: 0%RH~95%RH~0%RH RH gradient: 10% [Example]

[0141] Crystalline Forms of the Hydrochloride Salt of Nepicastat The present inventors have discovered four polymorphs of the hydrochloride salt of nepicastat, designated Form I, Form II, Form III, and Form IV. Comparative XRPD patterns of Form I, Form II, Form III, and Form IV are shown in Figure 1.

[0142] 1.1 Method for preparing crystalline form I: Ethanol (59.4 kg), purified water (88.00 kg), and anhydrous (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (5.00 kg, prepared according to Example 31 of CN1113874C) were added to a reaction kettle. The resulting suspension was heated to 45-55 °C and stirred until dissolved, cooled to 30-40 °C, and stirred for 1-3 hours. The resulting mixture was concentrated under vacuum to remove some of the solvent until a residue of approximately 14.0-16.0 V (based on the mass of the anhydrous API as 1 V) was obtained. The residue was cooled to 0-10 °C and centrifuged to obtain the wet product. The wet product was dried under vacuum at 40-50 °C to give 4.63 kg of (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride monohydrate in 52.4% yield, 99.8% HPLC purity, and 99.8% chiral purity as crystalline form I. Its XRPD is shown in Figure 2. 1 H NMR (ppm): δ12.35 (1 H, S), δ8.65 (3 H, S), δ7.09 (1 H, s), δ7.02 (1 H, td, J=9.68, 2.00Hz), δ6.90 (1 H, d, J=9.32 Hz), δ4.65 (1 H, br s), δ4.11 (3H, s), δ2.96 (3H, m), δ2.77 (1H, M), δ2.04 (1H, Brs).

[0143] 1.2 Approximate solubility test An approximate solubility test was performed on crystalline form I at room temperature. The test method was as follows: weigh out approximately 4 mg of crystalline form I, slowly add an appropriate volume of solvent to it, shake, and observe whether crystalline form I was dissolved, and record the volume of solvent, including the volume that allowed complete dissolution and the previous volume of solvent that could not completely dissolve crystalline form I. For insufficient solubility, the total amount of solvent added was 4-5 mL or less. The results of the approximate solubility are shown in Table 20.

[0144] [Table 22]

[0145] 1.3 Suspension-grinding method (40°C) The starting material was crystalline Form I of the hydrochloride salt of nepicastat, which appeared as an off-white powder. The results of its XRPD, DSC, TGA, PLM, and DVS characterization, as well as the results of the heating experiments, are shown in Figures 2-9.

[0146] Approximately 50 mg of crystalline Form I of the hydrochloride salt of nepicastat was weighed and placed in a liquid vial, and then 1 mL of the corresponding solvent was added thereto. The sample was stirred at 40°C for 3 days, and the resulting suspension was centrifuged to collect the wet solid (12,000 rpm, 10 minutes). The collected solid was further subjected to vacuum drying in a vacuum drying oven under reduced pressure at 40°C for approximately 4 hours. The XRPD of the dried solid was then determined. If the determined XRPD was different from that of the initial crystalline Form I, further studies were performed by DSC and TGA to confirm the new crystalline form.

[0147] The experimental results are summarized in Table 21 and Figure 20. At 40°C, the samples obtained were Form I of nepicastat hydrochloride after grinding in methyl tert-butyl ether and tetrahydrofuran systems for 3 days, and the samples obtained were Form II of nepicastat hydrochloride after grinding in absolute ethanol or acetonitrile systems for 3 days.

[0148] [Table 23]

[0149] 1.4 Solvent evaporation method Approximately 50 mg of crystalline Form I of nepicastat hydrochloride was weighed and placed in a glass vial. A good solvent was added to completely dissolve the compound. After filtration using a 0.45 μm nylon filter membrane, the vial was capped with aluminum foil with small holes and placed in a fume hood. After approximately 1-3 weeks of natural evaporation of the solvent, the solid was collected and its XRPD was determined. If the determined XRPD differed from that of the initial crystalline Form I, further studies were performed using DSC and TGA to confirm the new crystalline form.

[0150] The specific phenomena, processing procedures, and results are shown in Table 22 and Figure 21. The obtained sample is crystalline form II by evaporation in a methanol system.

[0151] [Table 24]

[0152] 1.5 Antisolvent method Approximately 50 mg of crystalline Form I of nepicastat hydrochloride was weighed into a glass vial, and an appropriate volume of a good solvent (e.g., methanol) was added to completely dissolve it and form a nearly saturated solution. After filtration using a 0.45 μm nylon membrane, different anti-solvents were added dropwise to the filtrate until a large amount of solid precipitated. The anti-solvent was added in a volume at most 10 times the volume of the good solvent. For samples with precipitated solids, the wet solids were collected by centrifugation at 12,000 rpm for 10 minutes. For samples without precipitated solids, the solids were collected by slowly evaporating the solvent in a fume hood. The collected solids were then vacuum-dried at 40°C under reduced pressure for approximately 4 hours, and the XRPD of the dried solids was determined.

[0153] The experimental results are summarized in Table 23 and Figure 22. Antisolvent analysis of crystalline Form I of the hydrochloride salt of nepicastat revealed that there were no significant differences in the XRPD patterns between the sample obtained in 50% tetrahydrofuran / 2-butanone system and the starting material, indicating that the sample was crystalline Form I; the samples obtained in methanol / ethyl acetate, methanol / 2-methyltetrahydrofuran, and methanol / methyl tert-butyl ether systems were crystalline Form III; and the sample obtained in 50% isopropanol / 1,4-dioxane system showed relatively low crystallinity.

[0154] [Table 25]

[0155] 1.6 Method for preparing crystalline 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 approximately 36% were added to a reaction kettle. After stirring under reflux for 5 hours, the reaction mixture was cooled to 20-30°C to precipitate a solid, which was then filtered. 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 under stirring until dissolved, and then concentrated under vacuum to approximately 18.0-20.0 V (where 1 V is the mass of the wet product). Methanol (220.2 kg / portion) was added to it and azeotropically distilled twice to remove water. The residue (approximately 7.0-10.0 V) was cooled to 0-10°C, stirred for an additional 5-7 hours, filtered, and rinsed with 14.7 L of methanol. The resulting product was dried under vacuum at 40-50°C for 14 hours to give (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (5.06 kg, 65.0% yield, 99.5% HPLC purity), which was determined to be crystalline Form IV by XRPD (Figure 19).

[0156] 1.7 Crystalline Form I of the Hydrochloride Salt of Nepicastat The sample of crystalline form I appeared as an off-white powder. XRPD results indicated that crystalline form I had clear sharp diffraction peaks (Figure 2) and was a crystalline compound. DSC results (Figure 3) showed four clear 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) showed a mass loss of 5.15% from 30 °C to 160 °C. PLM results (Figure 5) showed birefringence under polarized light microscopy and an irregular granular crystal habit. DVS results showed that the mass gain due to hygroscopicity of the sample was approximately 1.036% from 0% RH to 80% RH, indicating the sample's slight hygroscopicity (Figure 6). The crystalline morphology of the sample remained unchanged before and after the DVS test (Figure 7).

[0157] Form I of the hydrochloride salt of nepicastat was determined to be a hydrate by heating experiments (a sample was heated to 170°C by TGA, exposed to air, cooled to room temperature, an XRPD was determined, and the sample was then heated again to 350°C, finding the same mass loss of approximately 5% during the second heating period before 160°C), and the compound was determined to be a monohydrate by calculation of the molecular weight of Form I of the hydrochloride salt of nepicastat (Mw = 349.8) (see Figures 1 and 9).

[0158] Stability experiments were conducted on crystalline Form I, with the results shown in Tables 24 and 25 (inner packaging: double-layer polyethylene bag). The results showed that there were no significant changes in the detection results and no new impurities were generated under accelerated conditions (40°C / 75%RH) and long-term conditions (25°C / 60%RH), indicating good stability.

[0159] In addition, stability studies were conducted on crystalline form I (60°C, 60°C / 75%RH) and crystalline form II (40°C, 40°C / 75%RH, 60°C, 60°C / 75%RH) under relatively harsh conditions, and the results showed that:

[0160] After the solid crystalline form I was left under conditions of 60°C and 60°C / 75%RH for 15 days, it did not produce significant impurities due to decomposition, and crystalline form I was more stable than crystalline form II.

[0161] After standing at 60°C and 60°C / 75% RH for 15 days, crystalline Form I was stable (as determined by the XRPD pattern).

[0162] Under the conditions of 40°C and 60°C, crystalline form II was transformed into crystalline form III (determined by XRPD pattern), but the crystalline form did not change after standing for 15 days under the conditions of 40°C / 75% RH and 60°C / 75% RH.

[0163] Based on the above chemical and crystalline stability studies for the two crystalline forms of the hydrochloride salt, crystalline Form I is more stable than crystalline Form II.

[0164] [Table 26]

[0165] [Table 27]

[0166] 1.8 Crystalline Form II of the Hydrochloride Salt of Nepicastat Crystalline Form II can be obtained by grinding a suspension of crystalline Form I in absolute ethanol or acetonitrile at 40°C for 3 days, or by evaporation in methanol, and the specific preparation methods are shown in Tables 20 and 21. The XRPD, DSC, TGA, PLM, and DVS characterization results for a sample of crystalline Form II are shown in Figures 10 to 15.

[0167] The sample of crystalline Form II appeared as an off-white powder. X-ray powder diffraction (XRD) determined the sample had several distinct characteristic diffraction peaks (Figure 10), indicating its crystalline nature. Thermal analysis (DSC, Figure 11 and TGA, Figure 12) showed that the sample of crystalline Form II had an initial melting point of 247.22°C, its melting was accompanied by decomposition, and the mass loss from 25.63°C to 120°C was 0.4048%. PLM results (Figure 13) indicated a granular crystal habit. DVS results (Figure 14) showed that the sample's hygroscopic mass gain was approximately 0.453% from 0% RH to 80% RH, indicating the sample's slight hygroscopicity. The crystalline morphology of the sample remained unchanged before and after the DVS test (Figure 15).

[0168] In addition, the estimated solubility of crystalline Form II in water was determined to be 7.9-10.5 mg / mL, which was similar to the solubility of crystalline Form I in water.

[0169] 1.9 Crystalline Form III of the Hydrochloride Salt of Nepicastat Crystalline Form III can be obtained by adding an antisolvent (ethyl acetate, 2-methyltetrahydrofuran, or methyl tert-butyl ether) to crystalline Form I in methanol, and its specific preparation method is shown in Table 22. The XRPD, DSC, and TGA characterization results for a sample of crystalline Form III are shown in Figures 16 to 19.

[0170] The sample of crystalline Form III appeared as an off-white powder. X-ray powder diffraction determination showed that the sample was crystalline, with several clear characteristic diffraction peaks (Figure 16). Thermal analysis (DSC, Figure 13 and TGA, Figure 18) showed that the sample of crystalline Form III had an initial melting point of 235.39°C, its melting was accompanied by decomposition, and its mass loss from 30.35°C to 120°C was 2.1661%.

[0171] 1.10 Investigation of stable crystal forms - competition experiments by adding seed crystals To confirm the stability of the crystalline forms at room temperature, the following competition experiments were performed on crystalline forms I and II.

[0172] Five portions of crystalline Form II were taken, and purified water, 15% ethanol solution, 65% ethanol solution, 90% ethanol solution, and 95% ethanol solution were added thereto, respectively, and sonicated for 1 minute to obtain five suspensions containing crystalline Form II. The suspensions were stirred at room temperature for 24 hours, and all systems had solid residues. All systems were centrifuged, and the supernatants were collected. Then, crystalline Form I (20 mg) and crystalline Form II (20 mg) were added to each supernatant to obtain suspensions containing crystalline Form I and II. The resulting suspensions were sonicated for 1 minute, stirred at room temperature for 3 days, and sampled to detect the crystalline forms.

[0173] The results (Table 26 and Figure 23) showed that the solid crystalline form obtained after competition in purified water at room temperature for 3 days was converted to crystalline form I, the solid crystalline form obtained after competition in 15% ethanol solution at room temperature for 3 days was a mixed crystal of crystalline form I and crystalline form II, and the solids obtained after competition in 65%, 90%, and 95% ethanol solutions at room temperature for 3 days were crystalline form II.

[0174] [Table 28]

[0175] The results of the competition experiment between crystalline forms I and II showed that the stability of crystalline form II in purified water was not as good as that of crystalline form I, but that crystalline form II could exist stably in ethanol-water mixed solutions with lower water activities (0.291-0.750), and that a mixed crystal of crystalline forms I and II was obtained in a 15% ethanol solution with a water activity of 0.945. [Example]

[0176] Crystalline Forms of Other Acid Addition Salts of Nepicastat Nepicastat free base was prepared according to the method described in paragraph

[0190] of the specification of CN106983747A.

[0177] 2.1 Approximate solubility test To select an appropriate method for salt form screening, an approximate solubility test was performed on the compound. The test method was as follows: approximately 4 mg of nepicastat free base was weighed, and an appropriate volume of solvent was slowly added thereto, shaken, and observed to see if the free base dissolved. The volume of solvent, including the volume that allowed complete dissolution and the previous volume of solvent that did not completely dissolve the free base, was recorded. For insufficient solubility, the total volume of solvent added was 4 mL or less. The approximate solubility was calculated.

[0178] According to the estimated solubility results shown in Table 27, nepicastat free base has higher solubility in dichloromethane:methanol (1:1, V:V), methanol, acetone, and ethanol.

[0179] [Table 29]

[0180] Preliminary Screening of Nepicastat Free Base Salt Forms in a 2.2 Ethanol System Based on the estimated solubility results, an ethanol system was selected for the salt formation experiments. Approximately 50 mg of nepicastat free base (i.e., API listed in Tables 28 and 29) was weighed into each vial, and 1 mL of absolute ethanol was added. The mixture was stirred at 50°C to form an off-white suspension. The counterion was then slowly added dropwise to the reaction solution in a molar ratio of 1:1.05 or 1:0.55. Finally, after magnetic stirring at 50°C for 2 hours, the reaction solution was allowed to cool to room temperature and stirred overnight (approximately 20 hours). After overnight stirring, if the sample in the vial was a suspension with a large amount of solids, the solids were collected by centrifugation (12,000 rpm, centrifugation for 10 minutes). Alternatively, if the sample in the vial was a clear solution or contained a small amount of solids, the solvent was concentrated by nitrogen purging or natural evaporation, and the solids were precipitated and collected. The collected solids were subjected to vacuum drying under reduced pressure at 40°C for 4 hours, and X-ray powder diffraction detection of the dried solids was performed. For details, see Figure 24 and Table 28. If the XRPD pattern of the dried solids did not match that of the starting free base, these dried solids were subjected to further characterization including DSC, TGA, etc.

[0181] [Table 30A]

[0182] [Table 30B]

[0183] Preliminary screening of nepicastat free base salt forms in a 2.3 acetone system. Approximately 50 mg of nepicastat free base was weighed into each vial, and 1 mL of acetone solution was added thereto and stirred at 50°C to form a solution. Then, counterions were slowly added dropwise to the reaction solution in a molar ratio of 1:1.05 or 1:0.55. Finally, after stirring at 50°C for 2 hours, the samples were allowed to cool to room temperature and then magnetically stirred overnight (approximately 20 hours). After overnight stirring, if the sample in the vial was a suspension with a large amount of solids, the solids were collected by centrifugation (12,000 rpm, centrifugation for 10 minutes). Alternatively, if the sample in the vial was a clear solution or had a small amount of solids, the solvent was concentrated by natural evaporation, followed by the addition of MTBE as an anti-solvent to precipitate and collect the solids. The collected solids were vacuum-dried under reduced pressure at 40°C for 4 hours, and X-ray powder diffraction analysis of the dried solids was performed. See Figure 25 and Table 29 for details. If the XRPD patterns of the dried solids did not match that of the starting free base, these dried solids were subjected to further characterization including TGA, DSC, and the like.

[0184] [Table 31A]

[0185] [Table 31B]

[0186] 2.4 Salt Form Characterization Nepicastat sulfate (1:0.5), sulfate (1:1), phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydrobromide, maleate, tartrate, citrate, and fumarate salts obtained from the preliminary screening were characterized by XRPD, DSC, TGA, etc.

[0187] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the sulfate salt of nepicastat (1:0.5) are shown in Figures 26, 27, and 28, respectively.

[0188] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form II of the sulfate salt of nepicastat (1:0.5) are shown in Figures 29, 30, and 31, respectively.

[0189] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat are shown in Figures 32, 33, and 34, respectively.

[0190] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the phosphate salt of nepicastat are shown in Figures 35, 36, and 37, respectively.

[0191] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the methanesulfonate salt of nepicastat are shown in Figures 38, 39, and 40, respectively.

[0192] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat are shown in Figures 41, 42, and 43, respectively.

[0193] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the p-toluenesulfonate salt of nepicastat are shown in Figures 44, 45, and 46, respectively.

[0194] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat are shown in Figures 47, 48, and 49, respectively.

[0195] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the hydrobromide salt of nepicastat are shown in Figures 50, 51, and 52, respectively.

[0196] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form II of the hydrobromide salt of nepicastat are shown in Figures 53, 54, and 55, respectively.

[0197] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the maleate salt of nepicastat are shown in Figures 56, 57, and 58, respectively.

[0198] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the tartrate salt of nepicastat are shown in Figures 59, 60, and 61, respectively.

[0199] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form II of the tartrate salt of nepicastat are shown in Figures 62, 63, and 64, respectively.

[0200] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the citrate salt of nepicastat are shown in Figures 65, 66, and 67, respectively.

[0201] The XRPD pattern, DSC spectrum, and TGA spectrum of crystalline Form I of the fumarate salt of nepicastat are shown in Figures 68, 69, and 70, respectively.

[0202] [Table 32A]

[0203] [Table 32B]

[0204] 2.5 Estimated Solubility Tests for Some Crystalline Forms of the Acid Addition Salt of Nepicastat in Water. Approximately 4 mg of the compound shown in the following table was weighed, and an appropriate volume of purified water was slowly added thereto at room temperature, and the mixture was ultrasonically shaken to observe whether the compound was dissolved, and the volume of the solvent, including the volume that allowed complete dissolution and the previous volume of the solvent that could not completely dissolve the compound, was recorded. The results are shown in Table 31.

[0205] [Table 33]

[0206] Estimated solubility testing of the candidate salt forms in water indicates that the solubility of the maleate salt in purified water is slightly higher than that of the other candidate salt forms, but is still not as good as that of the hydrochloride salt of nepicastat in purified water (7.4 mg / mL).

[0207] 2.6 Stability Studies of Some Crystalline Forms of Acid Addition Salts of Nepicastat The crystalline forms of the acid addition salt of nepicastat listed in Table 31 were subjected to high temperature testing (60±2°C) and accelerated testing (40±2°C / 75%RH±5%RH) for a total of 4 weeks. The results were: The crystalline form II of the sulfate salt (1:0.5) is stable under accelerated conditions, and impurities increase under high temperature conditions. The crystalline form III of the sulfate salt (1:1) is stable under accelerated conditions, and impurities increase under high temperature conditions. The crystalline form I of the phosphate salt is stable under accelerated conditions, and impurities increase slightly under high temperature conditions; Crystalline Form I of the methanesulfonate salt is stable under accelerated and elevated temperature conditions; that crystalline Form I of the maleate salt is stable under accelerated and elevated temperature conditions; Crystalline Form I of the Citrate Salt is stable under accelerated conditions, and impurities increase under elevated temperature conditions; Crystalline Form I of the fumarate salt is stable under accelerated conditions, and impurities increase under high temperature conditions. showed. [Example]

[0208] Bioavailability Testing Crystalline Forms I and II of nepicastat hydrochloride and the other crystalline forms of nepicastat acid addition salts listed in Table 31 were administered intravenously and orally to mice, respectively. The formulation for intravenous (IV) administration is 5% (v / v) DMSO + 10% (v / v) Solutol HS 15 + 85% (v / v) saline; The formulation for oral (PO) administration was a 0.5% (v / v) aqueous solution of MC4000 (MC: methylcellulose).

[0209] The specific administration was as follows: Experiment: Three mice were tested in parallel for each formulation. Weight: approx. 30g Route of administration: IV, PO Doses administered: IV-15mg / kg, PO-30mg / kg Pre-administration: Fast for 12 hours before administration and allow mice to drink water. Post-administration: Allow mice to drink water and feed within 2 hours after administration Blood collection site: hind leg vein Blood collection time: IV---0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours PO---0.25, 0.5, 1, 2, 4, 6, 8, 24 hours.

[0210] Due to the very similar solubilities of crystalline Forms I and II of the hydrochloride salt of nepicastat in water, it was found in experiments that both would yield clear solutions when preparing dosing samples. Therefore, further testing was performed only on crystalline Form I of the hydrochloride salt of nepicastat.

[0211] The experimental results showed that the oral bioavailability of crystalline form I of the hydrochloride was over 70%. The bioavailability of each of the other acid addition salts was 0.9 to 1.3 times that of crystalline form I of the hydrochloride, which was good. The relative bioavailability of each of the acid addition salts to crystalline form I of the hydrochloride is shown in Table 32 (Table 34). 1 / 2 and AUC 0→t The T for crystalline Form I of the methanesulfonate salt and crystalline Form I of the fumarate salt are relatively similar. max Except for other acid addition salts, T max is in the range of 2 to 4 hours.

[0212] [Table 34]

Claims

1. A crystalline form of an acid addition salt of nepicastat, wherein 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 is nepicastat hydrochloride crystalline Form I, nepicastat hydrochloride crystalline Form II, nepicastat hydrochloride crystalline Form III, or nepicastat hydrochloride crystalline Form IV; in particular, Crystalline Form I of the hydrochloride salt of nepicastat is a monohydrate and has an X-ray powder diffraction pattern containing 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°, and preferably at least one peak 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°. and more preferably 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 crystalline Form I of the hydrochloride salt of nepicastat exhibits 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 crystalline Form I of the hydrochloride salt of nepicastat exhibits a mass loss of 5.15% from room temperature to 120°C. Crystalline Form II of the hydrochloride salt of nepicastat is an anhydrous form and has an X-ray powder diffraction pattern containing 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 at least 10.88±0.2°, 13.60±0.2°, 14.84±0.2°, 17.96±0.2°, and 27.32±0.2°. and preferably at least one characteristic peak at diffraction angles (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 crystalline Form II of the hydrochloride salt of nepicastat exhibits a single endothermic peak at 266.2°C. Crystalline Form III of the hydrochloride salt of nepicastat is characterized by an X-ray powder diffraction pattern containing 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°, and preferably further containing 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°; and advantageously, the DSC spectrum of crystalline Form III of the hydrochloride salt of nepicastat exhibits a single endothermic peak at 267.1°C. Crystalline Form IV of the hydrochloride salt of nepicastat contains 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°, and preferably further contains 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°, and more preferably at 10.95±0.2°.

2. The crystalline form of an acid addition salt of nepicastat according to claim 1, characterized by an X-ray powder diffraction pattern further comprising at least one characteristic peak at diffraction angles (2θ) of 13.06±0.2°, 14.84±0.2°, 17.93±0.2°, and 29.95±0.2°, and even more preferably at least one characteristic peak at diffraction angles (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 is nepicastat sulfate salt (1:0.5) crystalline Form I, nepicastat sulfate salt (1:0.5) crystalline Form II, or nepicastat sulfate salt (1:1) crystalline Form III; in particular, The X-ray powder diffraction pattern of crystalline Form I of the sulfate salt of nepicastat (1:0.5) contains 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°, and preferably at diffraction angles of 25.56±0.2°, 26.19±0.2°, 28.42±0.2°, and 30.68±0.2°. and more preferably at least one characteristic peak at diffraction angles (2θ) of 35.16±0.2°, 35.80±0.2°, and 40.26±0.2°. Advantageously, the DSC spectrum of crystalline Form I of the sulfate salt (1:0.5) of nepicastat exhibits 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 crystalline Form II of nepicastat sulfate salt (1:0.5) contains 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°, and preferably further contains 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 crystalline Form II of nepicastat sulfate salt (1:0.5) exhibits a single endothermic peak at 252.1°C. The X-ray powder diffraction pattern of crystalline Form III of nepicastat sulfate salt (1:1) contains 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 12.40±0.2°, 14.26±0.2°, 24.26±0.2°, and 26.26±0.2°.

2. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises at least one characteristic peak at diffraction angles (2θ) of 0.06±0.2°, 30.68±0.2°, 31.00±0.2°, and 35.28±0.2°, and advantageously, the DSC spectrum of crystalline Form III of the sulfate salt (1:1) of nepicastat exhibits two endothermic peaks at 101.5°C and 201.3°C.

4. The crystalline form is Form I of the phosphate salt of nepicastat, specifically, its X-ray powder diffraction pattern contains 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°, and preferably at diffraction angles (2θ) of 12.50±0.2°, 16.92±0.2°, 21.92±0.2°, and 27.34±0.2°.

10. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises at least one characteristic peak, more preferably 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°, and advantageously, the DSC spectrum of crystalline Form I of the phosphate salt of nepicastat exhibits a single endothermic peak at 227.1°C.

5. The crystalline form is crystalline Form I of the methanesulfonate salt of nepicastat, specifically, its X-ray powder diffraction pattern contains 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°, and preferably at diffraction angles of 7.90±0.2°, 13.48±0.2°, 15.06±0.2°, 22.88±0.2°, and 23.28±0.2°.

2. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises at least one characteristic peak at diffraction angles (2θ), more preferably 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°, and advantageously, the DSC spectrum of crystalline Form I of the methanesulfonate salt of nepicastat exhibits a single endothermic peak at 280.7°C.

6. The crystalline form is crystalline Form I of the benzenesulfonate salt of nepicastat, specifically, its X-ray powder diffraction pattern contains 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°, and preferably at diffraction angles of 7.38±0.2°, 8.06±0.2°, 11.84±0.2°, and 20.42±0.2°.

2. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises at least one characteristic peak at diffraction angles (2θ), more preferably 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°, and advantageously, the DSC spectrum of crystalline Form I of the benzenesulfonate salt of nepicastat exhibits a single endothermic peak at 229.9°C.

7. the crystalline form is crystalline Form I of the p-toluenesulfonate salt of nepicastat or crystalline Form II of the p-toluenesulfonate salt of nepicastat; in particular, The X-ray powder diffraction pattern of crystalline Form I of the p-toluenesulfonate salt of nepicastat contains 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 crystalline Form I of the p-toluenesulfonate salt of nepicastat exhibits 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 crystalline Form II of the p-toluenesulfonate salt of nepicastat contains 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°, and preferably further contains at least one characteristic peak at diffraction angles (2θ) of 9.44±0.2°, 15.46±0.2°, and 21.46±0.2°, and more preferably at least one characteristic peak at diffraction angles (2θ) of 24.

2. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises at least one characteristic peak at diffraction angles (2θ) of 0.78±0.2°, 25.10±0.2°, 26.34±0.2°, and 29.20±0.2°, and advantageously, the DSC spectrum of crystalline Form II of the p-toluenesulfonate salt of nepicastat exhibits 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.

8. the crystalline form is crystalline Form I of the hydrobromide salt of nepicastat or crystalline Form II of the hydrobromide salt of nepicastat; in particular, Crystalline Form I of the hydrobromide salt of nepicastat has an X-ray powder diffraction pattern containing 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°, and preferably at least at diffraction angles (2θ) of 20.34±0.2°, 24.14±0.2°, and 26.52±0.2°. and preferably 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 crystalline Form I of the hydrobromide salt of nepicastat exhibits three endothermic peaks at 98.2°C, 149.5°C, and 184.5°C. The X-ray powder diffraction pattern of crystalline Form II of the hydrobromide salt of nepicastat contains 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°, and preferably at diffraction angles (2θ) of 20.60±0.2°, 26.02±0.2°, 26.42±0.2°, and 27.30±0.2°. 2θ), more preferably 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°; and advantageously, the DSC spectrum of crystalline Form II of the hydrobromide salt of nepicastat exhibits a single endothermic peak at 273.2°C.

9. The crystalline form is crystalline Form I of the maleate salt of nepicastat, specifically, its X-ray powder diffraction pattern contains 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°, and preferably 14.98±0.2°, 18.64±0.2°, 19.36±0.2°, 20.56±0.2°, and 21.

2. The crystalline form of the acid addition salt of nepicastat according to claim 1, further comprising at least one characteristic peak at a diffraction angle (2θ) of 92±0.2°, more preferably at least one characteristic peak 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°, and advantageously, the DSC spectrum of crystalline Form I of the maleate salt of nepicastat exhibits a single endothermic peak at 210.0°C.

10. the crystalline form is crystalline Form I of the tartrate salt of nepicastat or crystalline Form II of the tartrate salt of nepicastat; in particular, The X-ray powder diffraction pattern of crystalline Form I of the tartrate salt of nepicastat contains 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°, and preferably at diffraction angles of 14.28±0.2°, 15.92±0.2°, 17.84±0.2°, 21.06±0.2°, and 28.00±0.2°. and preferably at least one characteristic peak 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 crystalline Form I of the tartrate salt of nepicastat exhibits 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. Crystalline Form II of the tartrate salt of nepicastat has an X-ray powder diffraction pattern containing 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°, and preferably at least one peak at diffraction angles (2θ) of 14.22±0.2°, 19.72±0.2°, 21.84±0.2°, and 22.42±0.2°.

2. The crystalline form of the acid addition salt of nepicastat of claim 1 further comprises three 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°, and advantageously, the DSC spectrum of crystalline Form II of the tartrate salt of nepicastat exhibits three endothermic peaks at 182.7°C, 214.2°C, and 246.0°C.

11. 2. The crystalline form of an acid addition salt of nepicastat according to claim 1, wherein the crystalline form is crystalline Form I of the citrate salt of nepicastat, specifically, the X-ray powder diffraction pattern thereof contains 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°, and preferably further contains 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°, and advantageously, the DSC spectrum of crystalline Form I of the citrate salt of nepicastat exhibits a single endothermic peak at 204.1°C.

12. The crystalline form is crystalline Form I of the fumarate salt of nepicastat, specifically, its X-ray powder diffraction pattern contains 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°, and preferably at 16.20±0.2°, 24.66±0.2°, 25.00±0.2°, 27.92±0.2°, and and 28.60±0.2°, more preferably 10.78±0.2°, 18.22±0.2°, 19.96±0.2°, 30.32±0.2°, and 33.06±0.2° 2θ, and advantageously, the DSC spectrum of crystalline Form I of the fumarate salt of nepicastat exhibits a single endothermic peak at 216.0°C.

13. 10. A process for preparing the crystalline form of nepicastat hydrochloride salt of claim 2, comprising: 1) Suspension-pulverization method mixing nepicastat hydrochloride with an organic solvent and subjecting the resulting suspension to solid-liquid separation to collect the solid, wherein the organic solvent is 1 ~C 4 Alcohol, C 4 ~C 6 Ether and C 2 ~C 6 nitriles, Specifically, the method comprises the steps of: mixing nepicastat hydrochloride with an organic solvent under stirring at a temperature ranging from room temperature to 50°C, preferably at 40°C, for 2 to 4 days, preferably 3 days; subjecting the resulting suspension to solid-liquid separation to collect the solid; and optionally further drying the solid; wherein the organic solvent is one or more selected from the group consisting of ethanol, methyl tert-butyl ether, tetrahydrofuran, and acetonitrile; and preferably, the ratio of nepicastat hydrochloride to organic solvent (w / v) is 50:1; 2) Solvent evaporation method dissolving nepicastat hydrochloride in a good solvent, allowing the solvent to evaporate, and then collecting the solid, wherein the good solvent is 1 ~C 4 Alcohol and C 4 ~C 6 one or more ethers or mixtures thereof with water, preferably one or more of methanol, 50% isopropanol, and 50% tetrahydrofuran, in a ratio (w / v) of nepicastat hydrochloride to the good solvent of 50:1; 3) Antisolvent method dissolving nepicastat hydrochloride in a good solvent, adding an anti-solvent, and then collecting the solid, wherein the good solvent is 1 ~C 4 Alcohol and C 4 ~C 6 one or more of ethers or their mixtures with water, preferably one or more of methanol, 50% isopropanol and 50% tetrahydrofuran, and the anti-solvent is C 3 ~C 6 Estelle, C 4 ~C 6 Ether, and C 3 ~C 6 one or more ketones selected from the group consisting of ethyl acetate, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and 2-butanone, preferably in a ratio (w / v) of nepicastat hydrochloride to the good solvent of 50:0.5 to 2, e.g., 50:1.5, 50:2, or 50:0.5, and a volume ratio of the good solvent to the anti-solvent of 1:1 to 1:10, e.g., 1.5:4, 1.5:2, or 1:8; 4) Nepicastat hydrochloride, C 1 ~C 4 mixing the alcohol and water, heating the resulting suspension to 45-55°C and stirring until dissolved, cooling to 30-40°C, concentrating to remove some of the solvent, cooling the residue to 0-10°C and collecting the solid after solid-liquid separation; Specifically, nepicastat hydrochloride, C 1 ~C 4 mixing alcohol and water, heating the resulting suspension to 45-55°C and stirring until dissolved, cooling to 30-40°C, stirring for 1-3 hours, concentrating to remove some of the solvent, cooling the residue to 0-10°C, collecting the solid after solid-liquid separation, and optionally further drying the solid, comprising: 1 ~C 4 Advantageously, the alcohol is ethanol and the C of the hydrochloride salt of nepicastat is 1 ~C 4 the ratio (W / W) of the alcohol to the alcohol is 10:1 to 15:1, for example 12:1, 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 are stirred under reflux, cooled to precipitate a solid, and the solid is collected after solid-liquid separation. 1 ~C 4 adding alcohol and water, heating until dissolved, concentrating to remove some of the solvent, cooling the residue to 0-10°C and collecting the solid after solid-liquid separation; Specifically, (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 stirred under reflux for 5 hours, cooled to 20-30°C, and the solid was precipitated. After solid-liquid separation, the solid was collected and C 1 ~C 4 adding alcohol and water, heating to 65-70°C, stirring until dissolved, concentrating to remove some of the solvent, cooling the residue to 0-10°C, collecting the solid after solid-liquid separation, and optionally further drying the solid; 1 ~C 4 the alcohol is isopropanol or methanol A method comprising:

14. 13. A process for preparing a crystalline form of the acid addition salt of nepicastat according to any one of claims 1 and 3-12, comprising: 1) Nepicastat and C 1 ~C 4 mixing an alcohol, preferably ethanol, under stirring, then adding an acid, and if a large amount of solids precipitates, collecting the solids by centrifugation or obtaining a sample as a clear solution, or if a small amount of solids precipitates, concentrating the solvent by nitrogen purging or natural evaporation, precipitating and collecting the solids, wherein the acid is selected from the group consisting of sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid, and fumaric acid; Specifically, nepicastat and C 1 ~C 4 nepicastat C. 1 ~C 4 the ratio (w / v) of nepicastat to alcohol is 50:1 and the molar ratio of nepicastat to acid is 1:1.05 or 1:0.55; or 2) nepicastat and C 3 ~C 6 2. A process for precipitating a ketone, preferably acetone, under stirring, followed by adding an acid, whereby if a large amount of solid is precipitated, the solid is collected by centrifugation or the sample is obtained as a clear solution, or if a small amount of solid is precipitated, the solvent is concentrated by nitrogen purging or natural evaporation, followed by adding an anti-solvent, whereby the solid is precipitated and collected, wherein the acid is selected from the group consisting of sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, maleic acid, tartaric acid, citric acid, and fumaric acid, and the anti-solvent is C 4 ~C 6 ether, preferably methyl tert-butyl ether, Specifically, nepicastat and C 3 ~C 6 ketone with stirring at 40-60°C, preferably 50°C, to form a solution, followed by addition of acid, cooling to room temperature, and stirring overnight; 3 ~C 6 the molar ratio of nepicastat to the acid (w / v) is 50:1, and the molar ratio of nepicastat to the acid is 1:1.05 or 1:0.55; 3 ~C 6 the volume ratio of ketone to antisolvent is 1:1 to 1:10, for example 1:5; A method comprising:

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

16. 19. Use of a crystalline form of an acid addition salt of nepicastat as defined in any one of claims 1-12 or the pharmaceutical composition of claim 15 in the preparation of a medicament for treating an autoimmune disease, post-traumatic stress disorder, congestive heart failure, hypertension, cancer, or sepsis, wherein the cancer is preferably selected from the group consisting of 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, and the autoimmune disease is preferably selected from the group consisting of autoimmune colitis, neuromyelitis optica, rheumatoid arthritis, scleroderma, psoriasis, and uveitis, and the autoimmune colitis is Crohn's disease or ulcerative colitis.

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