Crystals of compound X7 hydrochloride, its preparation method and use

Abstract

The present invention relates to a crystalline compound X7 hydrochloride of formula (I), its preparation method and use, wherein the crystalline compound X7 hydrochloride has a characteristic diffraction peak at 5°-35° in the powder X-ray diffraction pattern where the diffraction angle is 2θ, and the crystalline compound X7 hydrochloride has excellent physicochemical properties. [Formula 1] TIFF2023542816000034.tif44170

Description

[Technical Field]

[0001] The present invention relates to the technical field of medicinal chemistry, in particular to the crystal of compound X7 hydrochloride, its preparation method and use. [Background technology]

[0002] Compound X7 hydrochloride has a strong vasodilatory effect, a reliable antihypertensive effect, a rapid onset of action, a mild heart rate reduction while lowering blood pressure, no effect on the cardiac conduction system, a favorable hemodynamic effect, and long-term use of the drug has the advantage of protecting against organ damage caused by hypertension. The crystalline structure of a pharmaceutical active ingredient often affects the chemical and physical stability of the drug, and differences in crystallization and storage conditions can change the crystalline structure of a compound, sometimes resulting in the formation of a different crystalline form. Therefore, more in-depth research is needed to find crystals with better physicochemical properties. Summary of the Invention [Problem to be solved by the invention]

[0003] In light of this, the present invention aims to provide a crystalline form of compound X7 hydrochloride, as well as a preparation method and use thereof, and the crystalline form of compound X7 hydrochloride has excellent physicochemical properties. [Means for solving the problem]

[0004] In accordance with the above object, one aspect of the present invention provides a crystal of compound X7 hydrochloride, wherein the powder X-ray diffraction pattern of the crystal of compound X7 hydrochloride, where the diffraction angle is expressed as 2θ, has a characteristic diffraction peak at 5° to 35°, and the structural formula of compound X7 hydrochloride is as shown in formula (I). [ka]

[0005] In a preferred embodiment of the present invention, the crystals of compound X7 hydrochloride include crystalline form A, and the powder X-ray diffraction pattern of crystalline form A, where the diffraction angle is expressed as 2θ, has characteristic diffraction peaks at 15.12±0.2°, 11.57±0.2°, and 21.03±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form A, expressed in terms of diffraction angles 2θ, has characteristic diffraction peaks simultaneously at 26.01±0.2°, 17.92±0.2° and 27.89±0.2°. More preferably, the powder X-ray diffraction pattern of crystalline form A, expressed in terms of diffraction angles 2θ, has characteristic diffraction peaks simultaneously at 25.34±0.2°, 19.96±0.2°, 12.49±0.2°, 30.64±0.2°, 7.57±0.2°, 31.11±0.2° and 9.99±0.2°. In a preferred embodiment of the present invention, the thermogravimetric analysis graph of crystalline form A has a weight loss of 0.8±0.5% in the range of 30.0 to 155.0°C; and / or the differential scanning calorimetry graph of crystalline form A has an endothermic peak in the range of 210.0 to 220.0°C; and / or, Form A is an anhydrous crystalline form.

[0006] In a preferred embodiment of the present invention, the crystals of compound X7 hydrochloride include crystalline form B, and the powder X-ray diffraction pattern of crystalline form B, where the diffraction angle is expressed as 2θ, has characteristic diffraction peaks at 7.38±0.2°, 13.19±0.2°, and 16.99±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form B, expressed in terms of diffraction angles 2θ, has characteristic diffraction peaks simultaneously at 25.57±0.2°, 14.48±0.2° and 25.05±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form B in 2θ has characteristic diffraction peaks at 19.86±0.2°, 23.08±0.2° and 21.38±0.2° simultaneously.

[0007] In a preferred embodiment of the present invention, the thermogravimetric analysis graph of crystalline form B has a weight loss of 8.0-12.0% in the range of 29.0-72.0°C; and / or the differential scanning calorimetry graph of crystalline form B has endothermic peaks in both the ranges of 60.0 to 80.0°C and 195.0 to 215.0°C, and an exothermic peak in the range of 125.0 to 145.0°C; and / or crystalline form B is a hydrate.

[0008] In a preferred embodiment of the present invention, the crystals of compound X7 hydrochloride include crystalline form C, and the powder X-ray diffraction pattern of crystalline form C, where the diffraction angle is expressed as 2θ, has characteristic diffraction peaks at 8.26±0.2°, 15.68±0.2°, and 14.03±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form C in 2θ simultaneously has characteristic diffraction peaks at 21.25±0.2°, 25.30±0.2° and 13.43±0.2°. More preferably, the powder X-ray diffraction pattern of crystalline Form C in degrees 2θ has characteristic diffraction peaks simultaneously at 15.91±0.2°, 20.59±0.2°, 23.64±0.2°, 28.70±0.2°, 16.59±0.2°, 21.73±0.2°, 19.28±0.2°, 27.13±0.2°, 38.46±0.2°, 33.57±0.2°, 25.78±0.2°, 30.31±0.2° and 34.30±0.2°.

[0009] In a preferred embodiment of the present invention, the thermogravimetric analysis graph of crystalline form C has a weight loss of 1.5-2.5% in the range of 27.0-190.0°C; and / or the differential scanning calorimetry graph of crystalline form C has an exothermic peak in the range of 128.0 to 160.0°C and an endothermic peak in the range of 201.0 to 210.0°C; and / or crystalline form C is an anhydrous crystalline form.

[0010] In a preferred embodiment of the present invention, the crystals of compound X7 hydrochloride include crystalline form D, and the powder X-ray diffraction pattern of crystalline form D, where the diffraction angle is expressed as 2θ, has characteristic diffraction peaks at 15.69±0.2°, 24.98±0.2°, and 8.69±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form D in degrees 2θ has characteristic diffraction peaks simultaneously at 15.12±0.2°, 12.67±0.2° and 22.11±0.2°. More preferably, the powder X-ray diffraction pattern of crystalline form D in degrees 2θ has characteristic diffraction peaks simultaneously at 21.40±0.2°, 25.62±0.2°, 27.89±0.2°, 19.39±0.2°, 18.38±0.2°, 6.28±0.2°, 13.85±0.2°, 27.39±0.2°, 28.94±0.2°, 18.88±0.2°, 35.84±0.2°, 33.36±0.2°, 31.68±0.2° and 30.65±0.2°.

[0011] In a preferred embodiment of the present invention, the thermogravimetric analysis graph of crystalline form D has a weight loss of 2.0-2.5% in the range of 30.0-190.0°C; and / or the differential scanning calorimetry graph of crystalline form D has an endothermic peak in the range of 200.0 to 210.0°C; and / or crystalline form D is an anhydrous crystalline form.

[0012] In a preferred embodiment of the present invention, the crystalline form of compound X7 hydrochloride comprises crystalline form E, which has characteristic diffraction peaks at 23.08±0.2°, 19.05±0.2°, and 13.01±0.2° in its powder X-ray diffraction pattern (2θ). More preferably, the powder X-ray diffraction pattern of said crystalline form E in degrees 2θ has characteristic diffraction peaks simultaneously at 26.12±0.2°, 21.56±0.2° and 11.81±0.2°. More preferably, the powder X-ray diffraction pattern of said crystalline form E in 2θ has characteristic diffraction peaks simultaneously at 15.36±0.2°, 23.83±0.2° and 24.75±0.2°. More preferably, the powder X-ray diffraction pattern of crystalline Form E, expressed in terms of diffraction angles 2θ, has characteristic diffraction peaks simultaneously at 18.75±0.2°, 9.57±0.2°, 9.81±0.2°, 22.71±0.2°, 24.28±0.2°, 16.76±0.2°, 28.19±0.2°, 19.72±0.2°, 20.77±0.2° and 16.40±0.2°.

[0013] In a preferred embodiment of the present invention, the crystals of compound X7 hydrochloride include crystalline form F, and the powder X-ray diffraction pattern of crystalline form F, where the diffraction angle is expressed as 2θ, has characteristic diffraction peaks at 11.74±0.2°, 5.77±0.2°, and 15.66±0.2°. More preferably, the powder X-ray diffraction pattern of crystalline form E, expressed in terms of diffraction angles 2θ, has characteristic diffraction peaks simultaneously at 23.79±0.2°, 26.51±0.2°, 13.81±0.2°, 28.49±0.2°, 30.11±0.2°, 20.25±0.2°, 17.74±0.2°, 8.82±0.2°, 18.79±0.2° and 33.04±0.2°.

[0014] In a preferred embodiment of the present invention, the thermogravimetric analysis graph of crystalline form F has a weight loss of 8.0-8.5% in the range of 25.0-90.0°C; and / or the differential scanning calorimetry graph of crystalline form F has simultaneous endothermic peaks in the ranges of 50.0 to 80.0°C, 195.0 to 205.0°C, and 206.0 to 215.0°C; and / or crystalline form F is a hydrate.

[0015] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, wherein (a) the method for preparing crystalline form A comprises the following steps: Compound X7 hydrochloride is dissolved in a first good solvent, and the first poor solvent is added dropwise thereto, and the precipitated solid is collected to obtain the crystalline form A; Preferably, the first good solvent is selected from any of methanol, trichloromethane, dimethyl sulfoxide, or N-methylpyrrolidone; And / or preferably, the first anti-solvent is selected from any of acetone, isopropyl acetate, 2-methyltetrahydrofuran, methyl isobutyl ketone, toluene, isopropanol, methyl tert-butyl ether, acetonitrile or ethyl acetate. Or (b) a process for preparing crystalline form A, comprising the steps of: The open container containing the compound X7 hydrochloride is placed in a closed container containing the first solvent, and the container is allowed to stand to collect the solid, thereby obtaining the crystalline form A; Preferably, the first solvent is selected from any of water, methylene chloride, ethanol, methanol, acetonitrile, tetrahydrofuran, trichloromethane, acetone, dimethyl sulfoxide, ethyl acetate, 1,4 dioxane or isopropanol; Preferably, the standing is carried out at room temperature for 6 to 10 days. Or (c) a process for preparing crystalline form A, comprising the steps of: Compound X7 hydrochloride is placed in a container, and a second solvent is added to dissolve compound X7 hydrochloride in the second solvent to prepare a clear solution, which is then slowly evaporated, and the solid is collected to obtain the crystalline form A; Preferably, the second solvent is selected from the group consisting of methanol, ethanol, methylene chloride, trichloromethane, a mixed solvent of methanol and acetone in a volume ratio of (0.5 to 1.5):1, a mixed solvent of ethanol and acetonitrile in a volume ratio of (3.5 to 4.5):1, and a mixed solvent of methylene chloride and tetrahydrofuran in a volume ratio of (3.5 to 4.5):1. Or (d) a process for preparing crystalline form A, comprising the steps of: Compound X7 hydrochloride is dissolved in a third solvent, the solution is clarified by heating, and then filtered. The filtrate is slowly cooled and the precipitated solid is collected to obtain the crystalline form A; Preferably, the third solvent is selected from the group consisting of methanol, trichloromethane, acetonitrile, a mixed solvent of methanol and isopropyl acetate in a volume ratio of (0.5-1.5):1, a mixed solvent of ethanol and methyl tert-butyl ether in a volume ratio of (3.5-4.5):1, and a mixed solvent of trichloromethane and acetonitrile in a volume ratio of (0.5-1.5):1; and / or preferably, the heating is performed at 40 to 60°C for 1.5 to 2.5 hours; And / or, preferably, the gradual cooling is performed by cooling the filtrate from 40 to 60°C to 3 to 8°C at a cooling rate of 0.05 to 0.1°C / min. Or, (e) a process for preparing crystalline form A, comprising the steps of: Adding a fourth solvent to compound X7 hydrochloride to obtain a suspension, stirring the suspension, and then centrifuging the solid to obtain the crystalline form A; Preferably, the fourth solvent is ethanol, methyl isobutyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, a mixed solvent of ethanol and 1,4-dioxane in a volume ratio of (0.5 to 1.5):1, a mixed solvent of methyl isobutyl ketone and n-heptane in a volume ratio of (0.5 to 1.5):1, a mixed solvent of isopropyl acetate and dichloromethane in a volume ratio of (3.5 to 4.5):1, a mixed solvent of tetrahydrofuran and acetonitrile in a volume ratio of (0.5 to 1.5):1, a mixed solvent of acetone and N-methylpyrrolidone in a volume ratio of (3.5 to 4.5):1, a mixed solvent of isopropanol, methanol and ethyl acetate in a volume ratio of (0.5 to 1.5):1, a mixed solvent of methanol and methyl tert-butyl ether in a volume ratio of (0.5 to 1.5):1, a mixed solvent of 2-methyltetrahydrofuran and trichloromethane in a volume ratio of (3.5 to 4.5):1, methyl isobutyl a mixed solvent of ketone and dimethyl sulfoxide in a volume ratio of (3.5-4.5):1, or a mixed solvent of ethanol and water in a volume ratio of (70-97):(3-30); And / or, preferably, the suspension is stirred at room temperature for 3 to 5 days. Or (f) A process for preparing crystalline form A, comprising the steps of: The fifth solvent is added to the compound X7 hydrochloride to obtain a turbid solution, and the turbid solution is stirred at 45 to 55°C, and the solid is collected by centrifugation to obtain the crystalline form A; Preferably, the fifth solvent is selected from the group consisting of ethanol, isopropanol, acetone, isopropyl acetate, 1,4-dioxane, acetonitrile, n-heptane, a mixed solvent of isopropanol and 2-methyltetrahydrofuran in a volume ratio of 0.5 to 1.5:1, a mixed solvent of methyl isobutyl ketone and ethyl acetate in a volume ratio of 0.5 to 1.5:1, a mixed solvent of chloroform and n-heptane in a volume ratio of 3.5 to 4.5:1, a mixed solvent of ethanol and acetone in a volume ratio of 0.5 to 1.5:1, a mixed solvent of acetonitrile and water in a volume ratio of 0.5 to 1.5:1, and a mixed solvent of isopropyl acetate and N,N-dimethylacetamide in a volume ratio of 8.5 to 1.5. a mixed solvent of methyl tert-butyl ether and N-methylpyrrolidone in a volume ratio of (8.5 to 9.5):1, a mixed solvent of acetone and acetonitrile in a volume ratio of (0.5 to 1.5):1, or a mixed solvent of 2-methyltetrahydrofuran and toluene in a volume ratio of (0.5 to 1.5):1: And / or, preferably, the suspension is stirred at 45 to 55°C for 3 to 5 days. Or, (g) a process for preparing crystalline form A, comprising the steps of: Dissolving compound X7 hydrochloride in a second good solvent to prepare a clear solution, opening the container containing the clear solution and placing it in a sealed container containing a second poor solvent, and recovering the precipitated solid to obtain the crystalline form A; Preferably, the second good solvent is selected from any of methanol, methylene chloride, or chloroform; And / or preferably, the second anti-solvent is selected from any of ethyl acetate, 1,4-dioxane, isopropyl acetate, toluene, methyl isobutyl ketone, acetonitrile, 2-methyltetrahydrofuran, n-heptane, isopropanol, ethyl acetate or methyl tert-butyl ether. Or (h) A process for preparing crystalline form A, comprising the steps of: Compound X7 hydrochloride is dissolved in a sixth solvent, a polymeric material is added, and the mixture is slowly evaporated, and the solid is collected to obtain the crystalline form A; Preferably, the sixth solvent is selected from the group consisting of methanol, methylene chloride, a mixed solvent of acetonitrile and trichloromethane in a volume ratio of (0.5-1.5):1, trichloromethane, a mixed solvent of acetone and methylene chloride in a volume ratio of 1:(1-3), or a mixed solvent of ethanol and water in a volume ratio of (0.5-1.5):1; And / or preferably, the polymer material comprises a mixed polymer material A and a mixed polymer material B, the mixed polymer material comprising an equal mass mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose, and the mixed polymer material B comprising an equal mass mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, or hydroxyethyl cellulose.

[0016] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, (1) the method for preparing crystalline form B includes the following steps: Compound X7 hydrochloride is placed in a container, and a mixed solvent of acetonitrile and water in a volume ratio of (0.5-1.5):1 is added to dissolve Compound X7 hydrochloride in the mixed solvent to prepare a clear solution, which is then slowly evaporated to recover the solid, thereby obtaining the crystalline form B. Or (2) A method for preparing crystalline form B, comprising the steps of: Dissolve compound X7 hydrochloride in a third solvent, heat to clarify the solution, filter, slowly cool the filtrate, collect the precipitated solid, and dry it at room temperature and humidity to obtain the crystalline form B; Preferably, the stirring is carried out at 40 to 60°C for 0.5 to 1.5 days; And / or, preferably, the gradual cooling is performed by cooling the filtrate from 40 to 60°C to 3 to 8°C at a cooling rate of 0.05 to 0.1°C / min. Or (3) A method for preparing crystalline form B, comprising the steps of: Adding water to compound X7 hydrochloride to obtain a turbid solution, stirring the turbid solution, and collecting the solid by centrifugation to obtain the crystalline form B; Preferably, the suspension is stirred at room temperature for 3 to 5 days.

[0017] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, wherein the method for preparing crystalline form C comprises the following steps: Compound X7 hydrochloride is dissolved in water, stirred and filtered, the filtrate is slowly cooled, the precipitated solid is collected, and dried under vacuum at room temperature to obtain the crystalline form C; Preferably, the stirring is performed at 40 to 60°C for 2 to 4 hours; And / or preferably, the slow cooling is performed by cooling the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C / min; And / or preferably, the vacuum drying time is 0.5 to 1.5 days.

[0018] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, (i) the method for preparing crystalline form D, comprising the steps of: Compound X7 hydrochloride is placed in a container, and a mixed solvent of chloroform and n-heptane in a volume ratio of (0.5-1.5):1 is added to dissolve Compound X7 hydrochloride in the mixed solvent to prepare a clear solution. The solution is then slowly evaporated to recover the solid, thereby obtaining the crystalline form D. Or (ii) a process for preparing crystalline form D, comprising the steps of: Compound X7 hydrochloride is dissolved in a second good solvent to prepare a clear solution, and the container containing the clear solution is opened and placed in a sealed container containing a second poor solvent. The precipitated solid is collected to obtain the crystalline form D.

[0019] Based on the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, wherein the method for preparing crystalline form E comprises the following steps: Compound X7 hydrochloride is dissolved in water, heated to clarify the solution, filtered, and the filtrate is slowly cooled to collect the precipitated solid to obtain the crystalline form E; Preferably, the heating is performed at 40 to 60°C for 1.5 to 2.5 hours; And / or preferably, the slow cooling is performed by cooling the filtrate from 40 to 60°C to 3 to 8°C at a cooling rate of 0.05 to 0.1°C / min.

[0020] According to the same inventive concept, another aspect of the present invention provides a method for preparing the crystal of compound X7 hydrochloride, crystalline form F, comprising the steps of: Compound X7 hydrochloride is dissolved in a mixed solvent of ethanol and water in a volume ratio of (4-6):2, and the solution is subjected to ultrasonic treatment and filtration. The filtrate is evaporated at room temperature to obtain the crystalline form F; Preferably, the ultrasonic treatment time is 20 to 40 seconds.

[0021] In a preferred embodiment of the present invention, crystalline form F is dissolved in water and stirred at room temperature, after which it transforms into crystalline form B; Alternatively, crystalline form C is transformed into crystalline form D by heating it to 155-165°C and cooling it to room temperature; Alternatively, crystalline form D or crystalline form C is transformed into crystalline form A by stirring in at least one solvent selected from ethanol and trichloromethane for 2 to 4 days; preferably, the stirring temperature is room temperature or 45 to 55°C; Alternatively, crystalline form B or crystalline form F is transformed into crystalline form A by stirring in acetone or a mixed solvent of acetone and water at room temperature, and preferably, the water activity of the mixed solvent of acetone and water is w ≦0.8.

[0022] Based on the same inventive concept, another aspect of the present invention provides a pharmaceutical composition comprising a crystal of compound X7 hydrochloride and a pharmaceutically acceptable carrier or excipient.

[0023] Based on the same inventive concept, another aspect of the present invention provides the use of the crystals of compound X7 hydrochloride or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment and delay of hypertension, hypertension-induced target organ damage and hypertension-related diseases. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 shows the polymorphic transition relationship of the compound X7 hydrochloride of the present invention. [Figure 2a] FIG. 2a is an XRPD diagram of crystalline form A of the present invention. [Figure 2b] FIG. 2b is a TGA / DSC diagram of crystalline form A of the present invention, where curve A represents the TGA diagram of crystalline form A and curve B represents the DSC diagram of crystalline form A. [Figure 2c] FIG. 2c is a 1H NMR diagram of crystalline form A of the present invention. [Figure 3a] FIG. 3a is an XRPD diagram of crystalline form B of the present invention. [Figure 3b] FIG. 3b is a TGA / DSC diagram of crystalline form B of the present invention, where curve A represents the TGA diagram of crystalline form B and curve B represents the DSC diagram of crystalline form B. [Figure 3c] FIG. 3c is a 1H NMR diagram of crystalline form B of the present invention. [Figure 4a] FIG. 4a is an XRPD diagram of crystalline form C of the present invention. [Figure 4b] FIG. 4b is a TGA / DSC diagram of crystalline form C of the present invention, where curve A represents the TGA diagram of crystalline form C and curve B represents the DSC diagram of crystalline form C. [Figure 5a] FIG. 5a is an XRPD diagram of crystalline form D of the present invention. [Figure 5b] FIG. 5b is a TGA / DSC diagram of crystalline form D of the present invention, where curve A represents the TGA diagram of crystalline form D and curve B represents the DSC diagram of crystalline form D. [Figure 6] FIG. 6 is an XRPD diagram of crystalline form E of the present invention. [Figure 7a] FIG. 7a is an XRPD diagram of crystalline form F of the present invention. [Figure 7b] FIG. 7b is a TGA / DSC diagram of crystalline form F of the present invention, where curve A represents the TGA diagram of crystalline form F and curve B represents the DSC diagram of crystalline form F. [Figure 7c] FIG. 7c is a H NMR diagram of crystalline form F of the present invention. [Figure 8]

number

[0025] It should be noted that technical or scientific terms used in one or more embodiments herein have the ordinary meaning as understood by a person skilled in the art to which this disclosure belongs, unless otherwise defined. In the present invention, all operations are carried out at room temperature and atmospheric pressure unless otherwise specified. In the present invention, "room temperature" refers to (25±2)° C., and "room humidity" refers to a relative air humidity of 30 to 80%. In the present invention, relative humidity is represented by RH, and represents the ratio of the amount of water vapor (water vapor pressure) contained in a gas (usually air) to the amount of water vapor saturated under the same conditions as the air (saturated water vapor pressure). In the present invention, the water activity is a w It is expressed as σ and is defined as the volume of free water currently available in the sample, and ranges from 0 (absolute dryness) to 1 (100% relative humidity).

[0026] The abbreviations of the solvents and their corresponding Chinese names for the following embodiments are shown in Table 1 below. [Table 1] The reagents in Table 1 can be purchased from Sinopharm Group Chemical Reagents Co., Ltd.

[0027] As mentioned in the Background Art section, the crystalline structure of a pharmaceutical active ingredient often affects the chemical and physical stability of the pharmaceutical. Differences in crystallization and storage conditions can easily cause changes in the crystalline structure of the compound, sometimes resulting in the formation of other crystalline forms. Therefore, further research is needed to find crystals with better physicochemical properties. The present invention aims to screen for crystalline polymorphs of compound X7 hydrochloride, identify and evaluate the identified crystalline polymorphs, and recommend those with better physical and chemical properties for further research and development. In the present invention, starting from compound X7 hydrochloride as the initial sample, over 100 polymorph screening tests were conducted using methods such as antisolvent addition, gas-solid permeation, gas-liquid permeation, room temperature / 50°C suspension stirring, room temperature evaporation, slow cooling, and polymer induction, and six new crystalline forms of the hydrochloride salt were identified, designated as forms A, B, C, D, E, and F. The specific test methods and results are summarized in Table 2.

[0028] [Table 2]

[0029] Representative samples of the resulting new crystalline forms were then characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and high-performance liquid chromatography / ion chromatography (HPLC / IC). Specific characterization results are summarized in Table 3.

[0030] [Table 3]

[0031] In the present invention, the structural formula of compound X7 hydrochloride is as shown in formula (I). [ka]

[0032] The chemical name of compound X7 hydrochloride is 3-(4-(1H-benzotriazol-1-yl)butyl)piperazin-1-yl)benzisothiazole hydrochloride, and the molecular formula is C 21 H 24 SN6-HCl has a molecular weight of 428.98 and appears as a white powder.

[0033] In this study, the interconversion relationship between the various crystalline forms obtained in the screening test was investigated, and the results are summarized in Figure 1. To clarify the stability relationship between the anhydrous crystalline forms and the hydrates, a mixed suspension competition test was conducted on the relevant crystalline forms. The results showed that (1) when a physical mixture of anhydrous crystalline forms A, C, and D was suspended and stirred in EtOH and CHCl3 for 3 days at room temperature (25 ± 2°C) and 50°C, it transitioned to crystalline form A. (2) When a physical mixture of anhydrous crystalline form A and hydrate crystalline forms B and F was suspended and stirred in acetone / H2O at room temperature, it transitioned to crystalline form A, and when suspended and stirred in water, it transitioned to crystalline form B (aw = 1). Overall, these results indicated that crystalline form A is the thermodynamically stable anhydrous crystalline form at room temperature and 50°C and at a water activity of aw ≤ 0.8, while crystalline form B is a more stable hydrate at room temperature and a water activity of aw = 1. The results of the mixed suspension competition test are summarized in Table 4.

[0034] [Table 4]

[0035] Based on the above characterization results, anhydrous crystalline form A and hydrate crystalline form B were selected and evaluated for moisture adsorption capacity, solid stability, equilibrium solubility in water, crystal morphology, etc. 1) The results of the dynamic moisture sorption (DVS) test showed that at 25°C / 80% RH (relative humidity), crystalline form A absorbed 0.08% water and was not hygroscopic (see the Chinese Pharmacopoeia 2015 Edition (Guideline for Drug Moisture Absorption Test)); crystalline form B showed a rapid change in water absorption at 80%-95% RH during the adsorption process and at 50%-30% RH during desorption, indicating a transition between the anhydrous crystalline form and the hydrate. 2) Crystalline forms A and B were stored at 80°C for one day, then left open for one week at 25°C / 60% RH and 40°C / 75% RH to measure their physical and chemical stability. The test results showed that crystal form A did not undergo polymorphic transformation or a decrease in chemical purity under the three conditions, while crystal form B did not experience a decrease in chemical purity and maintained its crystalline form even after one week at 25°C / 60% RH. 3) The 24-hour equilibrium solubilities of crystalline forms A and B in H2O were 3.8 and 3.4 mg / mL, respectively, and neither crystalline form changed after the solubility test. 4) PLM results showed that form A was a needle-like crystal, while form B was a granular crystal with a particle size of <20 μm. Stability tests showed that form A had good physical and chemical stability. Based on the stability relationships between the crystalline forms and the evaluation of the solid-state properties, anhydrous crystalline form A is recommended as the preferred crystalline form for further development.

[0036] The molecular weights of the polymeric materials used in the present invention are weight-average molecular weights, measured by gel permeation chromatography (GPC) in accordance with the National Standard of the People's Republic of China GB / T 21863-2008 (corresponding to the German Standard DIN 55672-1:2007 "Gel Permeation Chromatography (GPC) Part 1: Tetrahydrofuran (THF) as Eluting Solvent"). Specifically, the weight-average molecular weight of polyvinylpyrrolidone is 8,000 to 700,000, that of polyvinyl alcohol is 16,000 to 20,000, that of polyvinyl chloride is 50,000 to 110,000, that of polyvinyl acetate is 20,000 to 30,000, that of hydroxypropylmethylcellulose is 400,000 to 675,000, and that of methylcellulose is 18,000 to 20,000. The weight-average molecular weight of polycaprolactone is 50,000-70,000, the weight-average molecular weight of polyethylene glycol is 200-600, the weight-average molecular weight of polymethyl methacrylate is 80,000-200,000, the weight-average molecular weight of alginic acid is 300,000-400,000, and the weight-average molecular weight of hydroxyethyl cellulose is 700,000-800,000, all of which can be purchased from Ashland Chemical (Nanjing) Co., Ltd.

[0037] It should be noted that, in addition to the preparation method of crystalline form C described in Table 2, crystalline form C can also be prepared by the following method. Compound X7 hydrochloride is dissolved in water, stirred, and filtered. The filtrate is slowly cooled, and the precipitated solid is collected and dried under vacuum at room temperature to obtain the crystalline form C. Preferably, the stirring is performed at 40-60°C for 2-4 hours. And / or preferably, the slow cooling is performed by cooling the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C / min; And / or preferably, the vacuum drying time is 0.5 to 1.5 days. Similarly, crystalline form F can be prepared by the following method. The hydrochloride of compound X7 is dissolved in a mixed solvent of ethanol and water in a volume ratio of (4-6):2, sonicated, filtered, and the filtrate is evaporated at room temperature to obtain crystalline form F; preferably, the sonication time is 20-40 seconds.

[0038] In a preferred embodiment of the present invention, as shown in Figure 1, the crystal forms can be transformed into each other, specifically, crystal form F is dissolved in water and stirred at room temperature, and then transformed into crystal form B; Alternatively, crystalline form C is heated to 155-165°C and cooled to room temperature to transform into crystalline form D; preferably, crystalline form C is heated to 160°C, cooled to room temperature, and then transformed into crystalline form D; Alternatively, crystalline form D or the crystalline form C is transformed into crystalline form A by stirring in at least one solvent selected from EtOH and CHCl3 for 2 to 4 days; preferably, the stirring temperature is room temperature or 45 to 55°C; more preferably, the stirring temperature is room temperature or 50°C; Alternatively, crystalline form B or crystalline form F is transformed into crystalline form A by stirring in acetone or a mixed solvent of acetone and water at room temperature, and preferably, the water activity of the mixed solvent of acetone and water is w ≦0.8.

[0039] Based on the same inventive concept, another aspect of the present invention provides a pharmaceutical composition comprising a crystal of compound X7 hydrochloride and a pharmaceutically acceptable carrier or excipient. In the present invention, the term "pharmaceutically acceptable carrier" refers to one or more solid or liquid fillers or gel substances suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Acceptability" here refers to the ability of the components of the composition to be mixed with and among the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Twain, etc.), wetting agents (e.g., sodium dodecyl sulfate, etc.), colorants, flavorings, stabilizers, antioxidants, preservatives, etc.

[0040] The dosage form of the pharmaceutical composition of the present invention includes tablets, capsules, granules, powders, pills, or films. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants such as glycerol; (d) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, and sodium carbonate; (e) lubricants such as talc, calcium stearate, magnesium stearate, or mixtures thereof.

[0041] Based on the same inventive concept, another aspect of the present invention provides the use of the crystals of compound X7 hydrochloride or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment and delay of hypertension, hypertension-induced target organ damage and hypertension-related diseases. In a preferred embodiment of the present invention, the target organ damage is a damage to the heart, brain, kidney or blood vessels caused by hypertension; the hypertension-related disease is atherosclerosis, hyperlipidemia, obesity, coronary artery disease, aortic aneurysm, hyperglycemia, impaired glucose tolerance, metabolic syndrome, diabetes, etc. In a preferred embodiment of the invention, the target organ damage is left ventricular hypertrophy, stroke, renal cortical atrophy or aortic hypertrophy, angina pectoris, myocardial infarction, heart failure, renal failure, retinal arteriosclerosis, or hypertensive ocular fundus hemorrhage.

[0042] All the test methods of the present invention are general methods, and the test methods are as follows:

[0043] 1. X-ray powder diffraction method (XRPD) XRPD patterns were collected on a PANalytical Empyrean and X'Pert 3-ray powder diffractometer, and the scan parameters are listed in Table 5. [Table 5]

[0044] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA and DSC plots were collected on a TA Q500 / 5000 thermogravimetric analyzer and a TA Q200 / 2000 differential scanning calorimeter, respectively, and the test parameters are shown in Table 6. [Table 6]

[0045] 3. Hydrogen Spectroscopy Liquid Nuclear Magnetic Resonance (1H Solution NMR) Hydrogen spectroscopy. Liquid nuclear magnetic resonance spectra were collected on a Bruker 400M nuclear magnetic resonance instrument, using DMSO-d6 as the solvent.

[0046] 4. Dynamic Water Sorption (DVS) Dynamic moisture sorption (DVS) curves are collected with a DVS Intrinsic from SMS (Surface Measurement System). The relative humidity at 25°C is corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. The DVS test parameters are shown in Table 7. [Table 7]

[0047] 5. Polarized Light Microscopy (PLM) Polarized light microscopy data are collected at room temperature using an Axio Lab. Al upright microscope.

[0048] Based on specific embodiments, the technical solutions provided by the present invention are further described below. [Example]

[0049] The following examples are only used to illustrate the present invention and do not limit the protection scope of the present invention.

[0050] Example 1 Preparation of Compound X7: Step 1: Preparation of 4-chlorobutyl-substituted benzotriazole (I) [ka]

[0051] 24.0 g of purified water was added to a 100 mL reaction flask, and 4.8 g of sodium hydroxide was added and dissolved. 3.0 g of benzotriazole, 3.9 g of 1-bromo-4-chlorobutane, and 0.18 g of tetrabutylammonium bromide were weighed, mixed, and stirred. The mixture was heated to 60°C and stirred for 6 hours. 24.0 g of purified water was added, stirred, and cooled to room temperature. 31.8 g of dichloromethane was added and stirred for 15 minutes. The mixture was allowed to stand for 15 minutes, the liquids were separated, and the aquifer was separated and discarded to obtain the organic phase (retained). 31.8 g of dichloromethane was added to the aqueous phase, stirred for 15 minutes, the liquids were allowed to stand for 15 minutes, the liquids were separated, and the aquifer was separated and discarded to obtain the organic phase (retained). The organic phases were combined, and the aquifer was treated separately. The organic phase was concentrated under reduced pressure to obtain an oily liquid (I).

[0052] Step 2: Preparation of 3-(4-(1H-benzotriazol-1-yl)butyl)piperazin-1-yl)benzisothiazole free base (II) [ka]

[0053] A 100 mL reaction vessel was charged with 15 g of acetonitrile, 1.9 g of 3-(1-piperazinyl)-1,2-benzisothiazole, 3.3 g of diisopropylethylamine, 1.4 g of potassium iodide, and 1.8 g of 1-(4-chlorobutyl)-1H-benzotriazole, and the mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated to give an oil. 30 mL of ethyl acetate was added to dissolve the oil, followed by extraction with purified water. The organic phase was concentrated under reduced pressure to give an oil (II).

[0054] Step 3: Preparation of 3-(4-(4-(1H-benzotriazol-1-yl)butyl)piperazin-1-yl)benzisothiazole hydrochloride (III) The oil (II) from step 2 was dissolved in 15 g of absolute ethanol and transferred to a 100 mL reaction flask. Concentrated hydrochloric acid (approximately 3 mL) was added dropwise to adjust the pH to 1-2, resulting in the precipitation of a pale yellow solid. The solid was filtered to obtain the solid, which was then added to 35 g of 95% ethanol, mixed uniformly, heated to dissolve completely, filtered, and crystallized. The precipitated crystals were filtered and dried to obtain 2.23 g of X7 hydrochloride. Mass spectrometry analysis of the white and near-white solids showed [M+H] + = 393.2.

[0055] Example 2 Preparation of Crystalline Form A and Crystalline Form F of Compound X7 Hydrochloride by Antisolvent Addition Method A total of 16 anti-solvent addition tests were conducted using different solvents. Approximately 15 mg of each initial sample (814802-05-A, prepared in Example 1) was weighed and placed in a 20 mL vial. The sample was dissolved in 0.8 to 4.0 mL of a good solvent (see Table 8). The anti-solvent in Table 8 was added to the clear solution, and the mixture was stirred dropwise until a solid precipitated. The stirring was stopped when no solid precipitated even after adding approximately 10 mL of anti-solvent. The solid was centrifuged and then subjected to XRPD analysis. As a result, as shown in Table 8, crystalline forms A, F, and a gel were obtained in the anti-solvent addition test.

[0056] [Table 8]

[0057] Example 3 Preparation of Crystalline Form A of Compound X7 Hydrochloride by Gas-Solid Permeation Method A total of 12 gas-solid diffusion tests were conducted using different solvents. Approximately 10 mg of the initial sample (814802-05-A, prepared in Example 1) was weighed into a 3 mL vial, and approximately 4 mL of solvent was added to a 20 mL vial. The 3 mL vial was then opened and placed inside the 20 mL vial, and the 20 mL vial was then sealed. After standing at room temperature for 8 days, the solid was collected and subjected to XRPD testing. As a result of the test, crystalline form A was obtained in the gas-solid permeation test, as shown in Table 9.

[0058] [Table 9]

[0059] Example 4 Preparation of Crystalline Forms A, B, and D of Compound X7 Hydrochloride by Room Temperature Volatilization Method A total of nine room-temperature volatilization tests were conducted using different solvents. Approximately 15 mg of sample (814802-05-A, prepared in Example 1) was weighed into a 3 mL vial, and 1.0 to 3.0 mL of each of the solvents listed in Table 10 was added. The vial was shaken and then filtered to obtain the supernatant. The vial was sealed with a sealing film, and several small holes were poked on the top. The solution was then allowed to slowly evaporate at room temperature. After the solvent had completely evaporated, the resulting solid was collected and subjected to XRPD analysis. As a result of the test, crystalline forms A, B, and D were obtained in the room-temperature volatilization test, as shown in Table 10.

[0060] [Table 10]

[0061] Example 5 Preparation of Crystalline Forms A, B, and E of Compound X7 Hydrochloride by Slow Cooling Method Approximately 15 mg of sample (814802-05-A, prepared in Example 1) was weighed into 5 mL vials, and 0.6 to 4.0 mL of the solvent shown in Table 11 was added. The mixture was stirred at 50°C for approximately 2 hours, and then filtered to obtain a filtrate. The filtrate was placed in a biochemical incubator and cooled from 50°C to 5°C at a rate of 0.1°C / min. The solid was collected and subjected to XRPD analysis. The test results are shown in Table 11. Crystalline forms A, B, and E, as well as a gel, were obtained by slow cooling.

[0062] [Table 11]

[0063] Example 6 Preparation of Crystalline Forms A and B of Compound X7 Hydrochloride by Room Temperature Suspension Stirring Method Approximately 15 mg of each initial sample (814802-05-A, prepared in Example 1) was weighed into an HPLC vial, and 0.3 mL of each of the solvents shown in Table 12 was added. The resulting suspension was left at room temperature with magnetic stirring (~1000 rpm) for approximately 4 days, after which the solid was centrifuged and subjected to XRPD analysis. The test results are shown in Table 12. Crystalline Forms A and B were obtained by room temperature suspension stirring test.

[0064] [Table 12]

[0065] Example 7 Preparation of Crystalline Form A of Compound X7 Hydrochloride by Suspension Stirring Method at Room Temperature (50°C) Approximately 20 mg of each initial sample (814802-05-A, prepared in Example 1) was weighed into an HPLC vial, and 0.3 mL of each solvent listed in Table 13 was added. The resulting suspension was placed at 50°C with magnetic stirring (~1000 rpm) for approximately 4 days, after which the solid was centrifuged and subjected to XRPD analysis. The results are shown in Table 13. Crystalline Form A was obtained by room temperature suspension stirring test.

[0066] [Table 13]

[0067] Example 8 Preparation of Crystalline Forms A and D of Compound X7 Hydrochloride by Gas-Solid Permeation Method Approximately 15 mg of each initial sample (814802-05-A, prepared in Example 1) was weighed and dissolved in 1.2 to 2.4 mL of a good solvent. The filtrate was transferred to a 3 mL vial through filtration. Approximately 4 mL of a poor solvent was added to another 20 mL vial. The 3 mL vial containing the filtrate was placed in an open state on the 20 mL vial, which was then sealed and allowed to stand at room temperature. If solid precipitation was observed, the solid was separated and collected for XRPD testing. As a result of the test, crystalline forms A and D were obtained in the gas-solid permeation test, as shown in Table 14.

[0068] [Table 14]

[0069] Example 9 Preparation of crystalline form A of compound X7 hydrochloride by polymer-induced method Approximately 15 mg of each initial sample (814802-05-A, prepared in Example 1) was weighed and dissolved in 1.0 to 3.0 mL of the solvent listed in Table 15. The solution was filtered, and the filtrate was transferred to a 3 mL vial containing approximately 2 mg of polymer. The vial containing the clear solution was sealed with a sealing film and several small holes were drilled on it. The solution was allowed to slowly evaporate at room temperature, and the resulting solid was collected and subjected to XRPD analysis. As shown in Table 15, all of the samples obtained in the polymer-induced precipitation test were crystalline form A.

[0070] [Table 15]

[0071] Mixed polymer material A: Polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose (equal mass mixture) Mixed polymer material B: Polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose (equal mass mixture)

[0072] Example 10 Preparation of Crystalline Form B of Compound X7 Hydrochloride by Gas-Solid Permeation Method In this example, the method for preparing crystalline form B of compound X7 hydrochloride includes the following steps: 1. Weigh 199.8 mg of the initial sample (814802-05-A, prepared in Example 1) into a 20 mL vial, add 18.0 mL of water, and stir magnetically (approximately 800 rpm) at 50° C. for approximately 1 day. 2. Filter (0.45 m PTFE filter head) and slowly cool the filtrate to 5°C at a rate of 0.1°C / min. 3. Isolate the solid and dry it under room temperature and humidity.

[0073] Example 11 Preparation of Crystalline Form C of Compound X7 Hydrochloride In this example, the method for preparing crystalline form C of compound X7 hydrochloride includes the following steps: 1. Weigh 202.1 mg of the initial sample (814802-05-A, prepared in Example 1) into a 20 mL vial, add 18 mL of water and stir magnetically (approximately 800 rpm) at 50° C. for approximately 3 hours. 2. Filter (through a 0.45 m PTFE filter head) and slowly cool the filtrate to 5°C at a rate of 0.1°C / min. 3. Isolate the solid and dry it under vacuum at room temperature for 1 day.

[0074] Example 12 Preparation of Crystalline Form D of Compound X7 Hydrochloride In this example, the crystalline form D of compound X7 hydrochloride is obtained by heating the crystalline form C, which includes the following steps: 1. Weigh 100.4 mg of crystalline form C (814802-32-A2, prepared in Example 11) sample into a 20 mL vial. 2. Heat in an oven at 160°C for about 5 minutes. 3. Cool at room temperature.

[0075] Example 13 Preparation of Crystalline Form F of Compound X7 Hydrochloride In this example, the method for preparing crystalline form F of compound X7 hydrochloride includes the following steps: 1. Weigh 102.4 mg of the initial sample (814802-05-A, prepared in Example 1) into a 20 mL vial and add 14.0 mL EtOH / H2O (5:2, v / v). 2. After sonication for approximately 30 seconds, filter (0.45 m PTFE tip) and transfer the filtrate to a new 20 mL vial. 3. Leave open and evaporate at room temperature.

[0076] The prepared crystalline forms A, B, C, D, E and F of compound X7 were analyzed by XRPD, TGA, DSC and 1 It was characterized by 1 H NMR.

[0077] (1) Characterization results of crystalline form A The XRPD characterization result of crystalline form A (814802-11-A17, prepared in Example 6) is shown in Figure 2a, and the XRPD characterization results of crystalline form A prepared in other examples were found to be consistent with Figure 2a. The XRPD diffraction peak data of crystalline form A are shown in Table 16.

[0078] [Table 16]

[0079] In the selection of characteristic peaks for crystalline form A, the main characteristic peaks were 15.12±0.2°, 11.57±0.2°, and 21.03±0.2°, and the sub-characteristic peaks were 26.01±0.2°, 17.92±0.2°, and 27.89±0.2°. The TGA / DSC characterization results for crystalline form A (814802-11-A17, prepared in Example 6) are shown in Figure 2b. The TGA / DSC characterization results for crystalline form A prepared in other examples were consistent with Figure 2b. A sample of crystalline form A had a weight loss of 0.8% when heated at 150°C and had a sharp endothermic peak at 211.7°C (onset temperature). The XRPD characterization results for crystalline form A (814802-11-A17, prepared in Example 6) are shown in Figure 2a. The XRPD characterization results for crystalline form A prepared in other examples were consistent with Figure 2a. Based on the small TGA weight loss and single endothermic peak, it is inferred that crystalline form A is an anhydrous crystalline form.

[0080] (2) Characterization results of crystalline form B The XRPD characterization result of crystalline form B (814802-09-A9, prepared in Example 4) is shown in Figure 3a, and the XRPD characterization results of crystalline form B prepared in other examples were found to be consistent with Figure 3a. The XRPD diffraction peak data of crystalline form B is shown in Table 17.

[0081] [Table 17]

[0082] In the selection of characteristic peaks for crystalline form B, the main characteristic peaks were 7.38±0.2°, 13.19±0.2°, and 16.99±0.2°, and the sub-characteristic peaks were 25.57±0.2°, 14.48±0.2°, and 25.05±0.2°. The TGA / DSC characterization results of crystalline form B (814802-09-A9, prepared in Example 4) are shown in Figure 3b, and the TGA / DSC characterization results of other crystalline form B prepared in Example A were found to be consistent with Figure 3b. The TGA results showed that the sample lost 8.3% weight when heated to 70°C, and the DSC results showed two endothermic peaks at 68.3°C (peak) and 201.3°C (onset), and a weak exothermic peak at 126.9°C (initial). 1 The H NMR characterization results (shown in Figure 3c) show that there is no residual solvent ACN in the crystalline form B sample, and that the crystalline form B prepared in other examples is 1 1 H NMR characterization results showed that the detection was consistent with Figure 3c. 1 Based on the results of H NMR, it is speculated that crystalline form B is a hydrate, which is transformed into an anhydrous crystalline form by thermal dehydration.

[0083] (3) Characterization results of crystalline form C The XRPD characterization result of crystalline form C (prepared in Example 11) is shown in Figure 4a, and the XRPD characterization results of crystalline form C prepared in other examples were found to be consistent with Figure 4a. The XRPD diffraction peak data of crystalline form C is shown in Table 18.

[0084] [Table 18]

[0085] In the selection of characteristic peaks for crystalline form C, the major characteristic peaks were 8.26±0.2°, 15.68±0.2°, and 14.03±0.2°, and the minor characteristic peaks were 21.25±0.2°, 25.30±0.2°, and 13.43±0.2°. The TGA / DSC characterization results for crystalline form C (prepared in Example 11) are shown in Figure 4b, and the TGA / DSC characterization results for crystalline form A prepared in other examples were found to be consistent with Figure 2b. When heated at 180°C, the sample of crystalline form A had a weight loss of 1.8%, an exothermic peak at 134.8°C (onset temperature), and a sharp endothermic peak at 204.6°C (onset temperature). Form C is presumed to be an anhydrous crystalline form due to its gradual weight loss and one sharp endothermic peak.

[0086] (4) Characterization results of crystalline form D The XRPD characterization result of crystalline form D (prepared in Example 12) is shown in Figure 5a, and the TGA / DSC characterization results of crystalline form D prepared in other examples were found to be consistent with Figure 5a. The XRPD diffraction peak data of crystalline form D is shown in Table 19.

[0087] [Table 19]

[0088] In the selection of characteristic peaks for crystalline form D, the major characteristic peaks were 15.69±0.2°, 24.98±0.2°, and 8.69±0.2°, and the minor characteristic peaks were 15.12±0.2°, 12.67±0.2°, and 22.11±0.2°. The TGA / DSC characterization results of crystalline form D (prepared in Example 12) are shown in Figure 5b, and the TGA / DSC characterization results of other crystalline form D prepared in Example A were found to be consistent with Figure 5b. When the crystalline form D sample was heated to 180°C, it lost 2.4% weight and had a sharp endothermic peak (initial) at 204.5°C. Based on the small TGA weight loss and single endothermic peak, crystalline form D is inferred to be an anhydrous crystalline form.

[0089] (5) Characterization of Crystal Form E The XRPD characterization result of crystalline form E (814802-10-A5, prepared in Example 5) is shown in Figure 6, and the TGA / DSC characterization results of crystalline form E prepared in other examples were found to be consistent with Figure 6. The XRPD diffraction peak data of crystalline form E is shown in Table 20.

[0090] [Table 20]

[0091] In the selection of characteristic peaks for crystalline form D, the main characteristic peaks were 23.08±0.2°, 19.05±0.2°, and 13.01±0.2°, and the sub-characteristic peaks were 26.12±0.2°, 21.56±0.2°, and 11.81±0.2°; the next sub-characteristic peaks were 15.36±0.2°, 23.83±0.2°, and 24.75±0.2°.

[0092] (6) Characterization results of crystalline form F The XRPD characterization result of crystalline form F (prepared in Example 13) is shown in Figure 7a, and the TGA / DSC characterization results of crystalline form E prepared in other examples were found to be consistent with Figure 7a. The XRPD diffraction peak data of crystalline form F is shown in Table 21.

[0093] [Table 21]

[0094] In the characteristic peak selection of crystalline form D, the main characteristic peaks were 11.74±0.2°, 5.77±0.2° and 15.66±0.2°. The TGA / DSC characterization results of crystalline form F (prepared in Example 13) are shown in Figure 7b, and the TGA / DSC characterization results of other crystalline form F prepared in Example A were found to be consistent with Figure 7b. When the crystalline form F sample was heated to 80°C, the weight loss was 8.3%, and there were three endothermic peaks at 71.2°C, 203.4°C, and 208.9°C (peaks). 1The H NMR results (shown in Figure 7c) indicate that the sample is free of residual solvent ACN and is consistent with the crystalline form F prepared in other examples. 1 H NMR characterization results also showed that the detection was consistent with Figure 7c. 1 The H NMR results, combined with the gradual weight loss in TGA, suggest that crystalline form F is a hydrate.

[0095] Test Example 1: Study of transition relationships between crystalline forms To further investigate the stability relationship between anhydrous crystalline forms A, C, and D and hydrated forms B and F, a suspension competition test was conducted for crystalline forms A, C, and D in EtOH or CHCl3 at room temperature and 50 °C, and in acetone / H2O (a w Suspension competition tests between crystalline forms were conducted, including suspension competition tests between crystalline forms A, B, and F in HCl (0-1).

[0096] 1.1 Suspension competition of anhydrous crystalline forms A / C / D To study the stability relationship of anhydrous crystalline forms A, C, and D at different temperatures and in different solvents, a suspension competition test was set up in EtOH and CHCl3 at room temperature and 50°C. The specific steps are as follows: 1) Prepare saturated solutions of the initial sample (814802-05-A, prepared in Example 1) in different solvents at specific temperatures. 2) Equal masses of crystalline forms A (814802-11-A17, prepared in Example 6), C (prepared in Example 11) and D sample (prepared in Example 12) (4 mg each) are added to 0.5 mL of the saturated solution to form a suspension. 3) The suspension is stirred (at a speed of ∼800 rpm / min) at room temperature and 50°C for approximately 2 days, respectively. 4) Separate the remaining solid (wet sample) and measure XRPD (transmission). In all tests, the initial mixed crystalline form eventually transformed into anhydrous crystalline form A, indicating that crystalline form A is more stable than crystalline forms C and D in the temperature range from room temperature to 50°C.

[0097] 1.2 Suspension competition between anhydrous crystalline form A and hydrate B / F To study the stability relationship between Form A and the hydrate forms B / F under different water activity conditions, a suspension competition test was conducted in acetone / H2O solvent systems with different water activities at room temperature. The specific steps were as follows: 1) Prepare 0.5 mL of saturated solutions of the initial sample (814802-05-A, prepared in Example 1) in different solvents at room temperature. 2) Equal masses of crystalline forms A (814802-11-A17, prepared in Example 6), B (814802-09-A9, prepared in Example 4), and F sample (prepared in Example 13) (~5 mg each) were added to the saturated solution to form a suspension, which was stirred magnetically (~800 rpm) at room temperature for 2 days. 2 . 3) Separate the remaining solid and measure XRPD (transmission).

[0098] As a result, the water activity a w When the α-tocopherol ratio is ≦0.8, all of the initial mixed crystalline forms eventually transform into anhydrous crystalline form A; after suspension and stirring in H2O (a w = 1), the initial mixed crystal form finally transforms into the hydrate crystal form B. The above results indicate that the anhydrous crystal form A is more stable at room temperature in the range of water activity aw = 0-0.8, and the hydrate crystal form B is more stable at room temperature in the range of water activity aw = 0-0.8. w It was shown that the case of ≈1 is more stable.

[0099] Test Example 2 Evaluation of crystalline form Combined with the test results of the mixed suspension competition in Test Example 1, the anhydrous crystalline form A has the highest thermodynamic stability among the three anhydrous crystalline forms, and the hydrate crystalline form B has the highest thermodynamic stability among the three anhydrous crystalline forms. w = 1, the crystalline forms A and B were shown to be more stable than the other crystalline forms. Therefore, crystalline forms A and B were selected and further evaluated for their equilibrium solubility in water, solid-state stability, water adsorption, and PLM morphology.

[0100] 2.1 Equilibrium solubility in water The equilibrium solubilities in water were measured at room temperature for a sample of crystalline form A (814802-11-A17, prepared in Example 6) and a sample of crystalline form B (814802-09-A9, prepared in Example 4). As controls, the equilibrium solubilities of a sample of crystalline form C (prepared in Example 11), a sample of crystalline form D (prepared in Example 12), and a sample of crystalline form F (prepared in Example 13) were also measured under the same conditions. In the test, a suspension (∼10 mg / mL) of each crystalline form was prepared and magnetically stirred (∼800 rpm) at room temperature for 24 hours, then centrifuged (10,000 rpm, 5 minutes), and the supernatant was filtered (through a 0.22 μm PTFE filter film). The solubility and pH were measured, and the solids were subjected to XRPD (transmittance) analysis. The test results are summarized in Table 22 below. Forms A and B remained unchanged before and after the test, and their aqueous solubilities were 3.8 and 3.4 mg / mL, respectively; forms C, D, and F all transformed into form B after equilibration in water for 24 hours.

[0101] [Table 22]

[0102] 2.2 Solid state stability To evaluate the solid-state stability of anhydrous crystalline form A (814802-11-A17, prepared in Example 6) and hydrate crystalline form B (814802-09-A9, prepared in Example 4), appropriate samples were weighed and stored in a closed container at 80°C for 1 day, and in an open container at 25°C / 60% RH and 40°C / 75% RH for 1 week. The solid samples isolated under different conditions were evaluated for chemical stability by HPLC purity, and for physical stability by XRPD. The evaluation results are summarized in Table 23. Crystalline form A showed good physical and chemical stability, with no polymorphic transformation or decrease in HPLC purity under any of the three test conditions. Crystalline form B showed no change in crystalline form or HPLC purity even after 1 week at 25°C / 60% RH.

[0103] 2.3 Water adsorption The moisture sorption of the crystalline form A sample (814802-11-A17, prepared in Example 6) and the crystalline form B sample (814802-09-A9, prepared in Example 4) was evaluated in a dynamic moisture sorption test at 25°C, and the results are shown in Figures 8a and 8b. The sample of crystalline form A absorbed 0.08% water at 25°C / 80% RH, indicating that crystalline form A had no water adsorption property and no polymorphic transition occurred after the DVS test. During the desorption process, the crystalline form B sample absorbed 12.3% water at a relative humidity of 50% RH, and the amount of water absorption rapidly decreased when the relative humidity was reduced to 30% RH, absorbing 0.4% at 30% RH, suggesting that a transition from the hydrate to the anhydrous crystalline form occurred during this process. During the adsorption process, the water absorption rate rapidly increased when the relative humidity was increased to 80% RH, and the water absorption rate was estimated to be 12.5% ​​at 95% RH, suggesting that a transition from the anhydrous crystalline form to the hydrate occurred during this process.

[0104] 2.4 PLM The morphology of the crystals was evaluated by PLM testing on a sample of crystalline form A (814802-11-A17-11-A17, prepared in Example 6) and a sample of crystalline form B (814802-09-A9, prepared in Example 4). The results are shown in Figures 9a and 9b. Form A was a needle-like crystal, while form B was a granular crystal with a particle size of <20 μm.

[0105] Test Example 3: Crystalline Form A as a vasodilator activity test (1) Preparation of isolated rabbit vascular smooth muscle specimens After stunning the rabbit, the chest was rapidly incised, the descending aorta was excised, and the connective tissue and surrounding adipose tissue (endothelial cells must be removed with a smooth stainless steel rod for serotonin receptor antagonism experiments) were removed. Then, a 3-5 mm vascular ring was cut. A steel wire hook was then passed through the vascular ring, one end of which was fixed to the ventilation hook, and the other end was connected to a tension transducer. The tension change was recorded on a recorder in a bath tube containing 20 mL of nutrient solution. The temperature in the bath tube was maintained at 37 ± 0.5 °C, and a mixed gas (95% O2 + 5% CO2) was passed through at a rate of 1-2 bubbles per second. The specimen was initially loaded with 1.5 g. The nutrient solution was replaced every 20 minutes, and the specimen was allowed to equilibrate for 2 hours. Experiments were initiated after the baseline had stabilized.

[0106] (2) Relaxant effect of crystalline form A (814802-11-A17, prepared in Example 6) on spasmogen AD-induced contraction of rabbit vascular smooth muscle After the tension of the specimen was stabilized, the waveform was recorded and the convulsive agent adrenaline hydrochloride (AD) (10 -5 Contraction was induced by adding 1 × 10 mol / L of KH solution to the bath tube. Once maximum contraction was reached, the specimen was thoroughly washed. The KH solution was replaced every 20 minutes, equilibrated for 60 minutes, and after the baseline had stabilized, contraction was again induced using the same concentration of spasmodic agent. If the latter maximum contractile response was essentially the same as the former, the prepared X7 solution (1 × 10 -9 ~1×10 -6 The maximum diastolic response of X7 was taken as 100%, and the diastolic response rate for each concentration was calculated. The dose-effect curve was plotted with the ordinate and the logarithm of each concentration as the abscissa. X7 exhibited a dilating effect on the AD contraction of the preparations induced by spasmodic drugs, and showed a certain dose-dependence on the dilating effect of epinephrine. The -logEC 50 The value was 8.07±0.09.

[0107] (3) Antagonistic effect of crystalline form A (814802-11-A17, prepared in Example 6) on pentahydroxytryptamine (5-HT) receptors in rabbit vascular smooth muscle After the tension of the specimen stabilized, the waveform was recorded and 5-HT (10 -7 ~3×10 -4 The specimen was then repeatedly washed with KH solution and equilibrated for 1.5 hours, after which the (10 -7 mol / L) was added, and 20 minutes later, 5-HT was added in the same manner. The maximum response was set to 100%, and the contraction rate of 5-HT was plotted as the ordinate, with the negative logarithm of each concentration of 5-HT as the abscissa of the quantitative effect curve. -7 When 5-HT (0.01 mol / L) was added, the 5-HT dose-effect curve shifted significantly to the right, with almost no change in the maximum response. Therefore, a statistical test was performed on the response rate at each concentration, and a P value of <0.01 indicated a significant difference. Pharmacological antagonism of 5-HT contracted the rabbit aorta, with a PA2 value of 8.86 ± 0.14.

[0108] (4) Effect of the positive control drug sagrelate on the dose-response curve of cumulative 5-HT contraction After the tension of the specimen stabilized, the waveform was recorded and 5-HT (10 -7 ~3×10 -4 The specimen was then repeatedly washed with KH solution and equilibrated for 1.5 hours, after which sagrelate (10 -6 mol / L) was added, and 20 minutes later, 5-HT was added in the same manner. The maximum response was set to 100%, and the contraction rate of 5-HT was plotted as the ordinate, with the negative logarithm of each concentration of 5-HT as the abscissa. -6 Addition of 5-HT (500mg / L) significantly shifted the 5-HT dose-effect curve to the right, with almost no change in the maximum response. A statistical test was therefore performed on the response rates at each concentration, with P values ​​of <0.01 indicating significant differences. Pharmacological antagonism of 5-HT contracted the rabbit aorta, with a PA2 value of 7.21 ± 0.08.

[0109] (5) Antagonistic effect of crystalline form A (814802-11-A17, prepared in Example 6) on rabbit vascular smooth muscle α-receptors After the tension of the specimen stabilized, the waveform was recorded and norepinephrine (10 -8 ~6×10 -5 mol / L) was added to the bath tube in a cumulative manner, and the waveform was recorded. Next, the specimen was repeatedly washed with KH solution and equilibrated for 1 hour. -8 mol / L) was added, and 20 minutes later, phenylephrine was added in the same manner. The maximum response was set to 100%, and the contraction rate of 5-HT was plotted as the ordinate, with the negative logarithm of each concentration of phenylephrine as the abscissa of the quantitative effect curve. -8 When phenylephrine was added (mol / L), the dose-effect curve for phenylephrine shifted significantly to the right, with almost no change in the maximum response. Therefore, a statistical t-test was performed on the response rates at each concentration, and a P value of <0.01 indicated a significant difference. The PA2 value for the drug antagonizing norepinephrine contraction in rabbit aorta was 7.98 ± 0.04.

[0110] (6) Effect of the positive control drug doxazosin on the cumulative contractile efficacy curve of norepinephrine After the tension of the specimen stabilized, the waveform was recorded and norepinephrine (10 -8 ~3×10 -3 The specimen was then repeatedly washed with KH solution, and equilibrated for 60 minutes with a new KH solution every 20 minutes. After the baseline had stabilized, doxazosin (10 -7 mol / L) was added, and after 15 minutes, norepinephrine (10 -6 ~10 -2 The maximum response was set at 100%, and the contraction rate of norepinephrine was plotted as the ordinate, with the negative logarithm of each concentration of phenylephrine as the abscissa of the quantitative effect curve. -7When phenylephrine (2000 mol / L) was added, the dose-effect curve for phenylephrine shifted significantly to the right, with almost no change in the maximum response. A statistical test was therefore performed on the response rates at each concentration, with P values ​​of <0.01 indicating significant differences. The antagonistic NA of the positive drug doxazosin was a PA2 value of 7.83±0.05, which contracted the rabbit aorta.

[0111] Test Example 4 Dissolution test data of crystalline form A of solid dosage form X7 is stable under various pH conditions and at high temperatures, making it suitable for development into gastric-soluble formulations. The crystalline form A of this test example (814802-11-A17, prepared in Example 6) was prepared as a tablet by a conventional formulation method, and the dissolution test data are as follows. (1) Dissolution conditions: Dissolving solution: 1000 mL of water, pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer are used as dissolving solutions. Method: The second method of dissolution and release test in the 4th chapter 0931 of the Chinese Pharmacopoeia 2015 Rotation speed: 50 r / min Temperature: 37℃ Sampling points: Collect the eluate at 5, 10, 15, 20, 30, 45, and 60 minutes, filter it through a 0.45 μm organic filter membrane, and then use the filtrate directly for high-performance liquid-phase detection. Measurement method: Chinese Pharmacopoeia 2015, Part 4, General Provisions 0512, high performance liquid chromatography method

[0112] (2) Test results: [Table 23] [Table 24] [Table 25] [Table 26]

[0113] From the dissolution curves of the four media, it was found that the dissolution behavior of tablets of formulation X7 developed with crystalline form A in this test example was basically consistent with that of three batches of self-prepared samples, with good batch-to-batch reproducibility and uniform quality of the self-prepared samples.

Claims

1. The crystal of compound X7 hydrochloride is in crystalline form A, the powder X-ray diffraction pattern of which is shown in FIG. 2a, and the structural formula of compound X7 hydrochloride is shown in formula (I). [Formula 1]

2. The thermogravimetric analysis graph of the crystalline form A has a weight loss of 0.8±0.5% in the range of 30.0 to 155.0°C; and / or the differential scanning calorimetry graph of said crystalline form A has an endothermic peak in the range of 210.0 to 220.0°C; And / or the crystalline form A is an anhydrous crystalline form, the crystalline form of compound X7 hydrochloride according to claim 1.

3. A method for preparing the crystals of compound X7 hydrochloride according to claim 1 or 2, comprising: (a) A process for preparing crystalline form A comprises the steps of: Compound X7 hydrochloride is dissolved in a first good solvent, and a first poor solvent is added dropwise to the solution, and the precipitated solid is collected to obtain said crystalline form A; The first good solvent is selected from the group consisting of methanol, trichloromethane, dimethylsulfoxide, and N-methylpyrrolidone; The first anti-solvent is selected from the group consisting of acetone, isopropyl acetate, 2-methyltetrahydrofuran, methyl isobutyl ketone, toluene, isopropanol, methyl tert-butyl ether, acetonitrile, and ethyl acetate; Or, (b) a process for preparing crystalline form A comprising the steps of: Putting the open container containing compound X7 hydrochloride into a closed container containing the first solvent and allowing to stand to collect the solid, thereby obtaining said crystalline form A; The first solvent is selected from the group consisting of water, methylene chloride, ethanol, methanol, acetonitrile, tetrahydrofuran, trichloromethane, acetone, dimethylsulfoxide, ethyl acetate, 1,4 dioxane, and isopropanol; The standing is at room temperature for 6 to 10 days; Or, (c) a process for preparing crystalline form A comprising the steps of: Put compound X7 hydrochloride into a container, add a second solvent to dissolve compound X7 hydrochloride in the second solvent to prepare a clear solution, and then evaporate it, and collect the solid to obtain said crystalline form A; The second solvent is selected from the group consisting of methanol, ethanol, methylene chloride, trichloromethane, a mixed solvent of methanol and acetone in a volume ratio of (0.5-1.5):1, a mixed solvent of ethanol and acetonitrile in a volume ratio of (3.5-4.5):1, or a mixed solvent of methylene chloride and tetrahydrofuran in a volume ratio of (3.5-4.5):1; Or, (d) a process for preparing crystalline form A comprising the steps of: Dissolving compound X7 hydrochloride in a third solvent, heating to clarify the solution, filtering, and slowly cooling the filtrate to collect the precipitated solid to obtain the crystalline form A; The third solvent is selected from the group consisting of methanol, trichloromethane, acetonitrile, a mixed solvent of methanol and isopropyl acetate in a volume ratio of (0.5-1.5):1, a mixed solvent of ethanol and methyl tert-butyl ether in a volume ratio of (3.5-4.5):1, and a mixed solvent of trichloromethane and acetonitrile in a volume ratio of (0.5-1.5):1; The heating is performed at 40 to 60° C. for 1.5 to 2.5 hours; The slow cooling is performed by cooling the filtrate from 40-60°C to 3-8°C at a cooling rate of 0.05-0.1°C / min; Or, (e) a process for preparing crystalline form A comprising the steps of: Adding a fourth solvent to compound X7 hydrochloride to obtain a turbid solution, stirring the turbid solution at room temperature, and centrifuging to collect the solid to obtain said crystalline form A; The fourth solvent is ethanol, methyl isobutyl ketone, ethyl acetate, methyl tert-butyl ether, acetonitrile, toluene, a mixed solvent of ethanol and 1,4-dioxane in a volume ratio of 0.5 to 1.5: 1, a mixed solvent of methyl isobutyl ketone and n-heptane in a volume ratio of 0.5 to 1.5: 1, a mixed solvent of isopropyl acetate and dichloromethane in a volume ratio of 3.5 to 4.5: 1, a mixed solvent of tetrahydrofuran and acetonitrile in a volume ratio of 0.5 to 1.5: 1, a mixed solvent of acetone and N-methylpyrrolidone in a volume ratio of 3.5 to 4.5: 1, a mixed solvent of isopropanol, methanol and ethyl acetate in a volume ratio of 0.5 to 1.5: 1, a mixed solvent of methanol and methyl tert-butyl ether in a volume ratio of 0.5 to 1.5: 1, a mixed solvent of 2-methyltetrahydrofuran and trichloromethane in a volume ratio of 3.5 to 4.5:

1. a mixed solvent of methyl isobutyl ketone and dimethyl sulfoxide in a volume ratio of (3.5-4.5):1, or a mixed solvent of ethanol and water in a volume ratio of (70-97):(3-30); Stir the suspension at room temperature for 3-5 days; Or, (f) a process for preparing crystalline form A comprising the steps of: Adding the fifth solvent to compound X7 hydrochloride to obtain a turbid solution, stirring the turbid solution at 45-55°C, and collecting the solid by centrifugation to obtain said crystalline form A; The fifth solvent is selected from the group consisting of ethanol, isopropanol, acetone, isopropyl acetate, 1,4-dioxane, acetonitrile, n-heptane, a mixed solvent of isopropanol and 2-methyltetrahydrofuran in a volume ratio of 0.5 to 1.5:1, a mixed solvent of methyl isobutyl ketone and ethyl acetate in a volume ratio of 0.5 to 1.5:1, a mixed solvent of chloroform and n-heptane in a volume ratio of 3.5 to 4.5:1, a mixed solvent of ethanol and acetone in a volume ratio of 0.5 to 1.5:1, a mixed solvent of acetonitrile and water in a volume ratio of 0.5 to 1.5:1, a mixed solvent of isopropyl acetate and N,N-dimethylacetamide in a volume ratio of 8.5 to 9.5:1, a mixed solvent of methyl tert-butyl ether and N-methylpyrrolidone in a volume ratio of 8.5 to 9.5:1, a mixed solvent of acetone and acetonitrile in a volume ratio of 0.5 to 1.5:

1. or a mixed solvent of 2-methyltetrahydrofuran and toluene in a volume ratio of (0.5-1.5):1; Stir the suspension at 45-55° C. for 3-5 days; Or, (g) a process for preparing crystalline form A comprising the steps of: Dissolving compound X7 hydrochloride in a second good solvent to prepare a clear solution, opening the container containing the clear solution and placing it in a closed container containing a second poor solvent, and recovering the precipitated solid to obtain the crystalline form A; The second good solvent is selected from the group consisting of methanol, methylene chloride, and chloroform; The second anti-solvent is selected from the group consisting of ethyl acetate, 1,4-dioxane, isopropyl acetate, toluene, methyl isobutyl ketone, acetonitrile, 2-methyltetrahydrofuran, n-heptane, isopropanol, ethyl acetate, and methyl tert-butyl ether; Or, (h) a process for preparing crystalline form A comprising the steps of: Dissolving compound X7 hydrochloride in a sixth solvent, adding a polymeric material, volatilizing, and collecting the solid to obtain said crystalline form A; The sixth solvent is selected from the following mixtures: methanol, methylene chloride, acetonitrile and trichloromethane in a volume ratio of (0.5-1.5):1, trichloromethane, acetone and methylene chloride in a volume ratio of 1:(1-3), or ethanol and water in a volume ratio of (0.5-1.5):1; The polymer material includes a mixed polymer material A and a mixed polymer material B, the mixed polymer material including an equal mass mixture of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose, and the mixed polymer material B including an equal mass mixture of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, or hydroxyethyl cellulose.

4. A pharmaceutical composition comprising the crystals of compound X7 hydrochloride according to claim 1 or 2 and a pharma- ceutically acceptable carrier or excipient.

5. A method for producing a medicine for preventing, treating and delaying hypertension, hypertension-induced target organ damage and hypertension-related diseases, using the crystals of compound X7 hydrochloride according to claim 1 or 2 or the pharmaceutical composition according to claim 4.

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