Novel sarpogrelate hydrochloride crystal form and preparation method and application thereof

Abstract

The invention provides a novel sarpogrelate hydrochloride crystal form and a preparation method and application thereof, an X-ray powder diffraction pattern of a crystal with the novel crystal form has characteristic peaks at 2theta values of 10.88 + / -0.1 degrees, 16.64 + / -0.1 degrees and 18.83 + / -0.1 degrees, and a differential scanning calorimetry analysis pattern of the crystal has an endothermic peak at 153-156 DEG C. The crystal has excellent stability, solubility and hygroscopicity as well as relatively high bioavailability and purity, and meanwhile, the preparation method is simple, the crystallization condition is mild, the cost is low, and the crystal is suitable for industrial production and can be used for preparing related pharmaceutical preparations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal form technology, specifically relating to a new crystal form of sargrelate hydrochloride, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Sarpogrelate hydrochloride is a known compound that can be manufactured according to literature, and its structural formula is:

[0003]

[0004] Sagrelate hydrochloride is a 5-HT2A receptor antagonist with antiplatelet aggregation effects. It was launched in 1993 to improve ischemic symptoms such as ulcers, pain, and coldness caused by chronic arterial occlusive disease.

[0005] Reported literature indicates that sarpogrelate hydrochloride exhibits polymorphisms. JP2006160764A discloses type I and type II crystals of sarpogrelate hydrochloride, which possess good chemical and physical stability. JP2008255065A discloses mixed crystal forms of sarpogrelate hydrochloride with varying proportions of type I and type II. Besides the aforementioned type I, type II, and mixed crystal forms, no other crystal forms have been reported to date.

[0006] Crystal form is one of the important physicochemical properties of drugs. Crystals with different crystal forms have different crystal habits and crystal habits, and may have significant differences in some physicochemical properties such as melting point, solubility, and stability. These differences can significantly affect the stability and bioavailability of the corresponding drug formulations, thereby affecting the safety and efficacy of the drugs.

[0007] Therefore, it is necessary to develop new crystal forms of sargrelate hydrochloride with superior bioavailability, stability, and solubility to provide more options for industrial research and production. Summary of the Invention

[0008] The problem the invention aims to solve

[0009] The present invention aims to provide a novel crystal form of sargrelate hydrochloride, which exhibits excellent stability, solubility, and hygroscopicity, as well as high bioavailability and purity. The present invention also aims to provide a preparation method and pharmaceutical applications for sargrelate hydrochloride. The preparation method is simple, has mild crystallization conditions, is low in cost, and is suitable for industrial production.

[0010] Solution for solving the problem

[0011] In a first aspect, the present invention provides a crystal of sarpogrelate hydrochloride, which satisfies at least one of the following conditions:

[0012] (1) Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.88±0.1°, 16.64±0.1° and 18.83±0.1°;

[0013] (2) Its differential scanning calorimetry chart has an endothermic peak at 153-156℃.

[0014] Preferably, the X-ray powder diffraction pattern of the crystal has characteristic peaks at 2θ values ​​of 10.88±0.1°, 16.64±0.1° and 18.83±0.1°, and the differential scanning calorimetry pattern of the crystal has an endothermic peak at 153 to 156°C.

[0015] Preferably, the X-ray powder diffraction pattern of the crystal also has a characteristic peak at at least one of the following 2θ values: 18.32±0.1°, 20.44±0.1°, 21.01±0.1°, and 25.51±0.1°.

[0016] More preferably, the X-ray powder diffraction pattern of the crystal also has a characteristic peak at at least one of the following 2θ values: 15.28±0.1°, 23.68±0.1°, 24.53±0.1°, 29.02±0.1°, and 32.67±0.1°.

[0017] Most preferably, the X-ray powder diffraction pattern of the crystal is as follows: Figure 1 As shown.

[0018] Preferably, the differential scanning calorimetry (DSC) curve of the crystal has an endothermic peak at 154–155 °C.

[0019] More preferably, the differential scanning calorimetry (DSC) curve of the crystal is as follows: Figure 2 As shown.

[0020] Secondly, the present invention provides a method for preparing the above-mentioned sarpogrelate hydrochloride crystals, which includes the following steps:

[0021] Mix sugrel hydrochloride and ketone solvent 1, then add an alcohol solvent, stir, heat, filter while hot, optionally add ketone solvent 2 to the filtrate, cool to crystallize, filter, and obtain the final product.

[0022] Preferably, the ketone solvent 1 or ketone solvent 2 is acetone or butanone.

[0023] Preferably, the alcohol solvent is methanol, isopropanol, or ethanol.

[0024] More preferably, the alcohol solvent is methanol.

[0025] Preferably, the heating temperature is 40–80°C.

[0026] More preferably, the heating temperature is 50–60°C.

[0027] Preferably, the cooling and crystallization step is: cooling to room temperature or -10 to 15°C for crystallization.

[0028] More preferably, the cooling crystallization step is: cooling to room temperature for crystallization.

[0029] Alternatively, preferably, the cooling and crystallization step is as follows: first cool to room temperature, then cool to -10 to 15°C for crystallization.

[0030] More preferably, the cooling and crystallization step is as follows: first, cool to room temperature and stir, then cool to -10 to 5°C and let it stand to grow crystals.

[0031] Preferably, the volume ratio of the ketone solvent 1 to the mass ratio of the sugrel hydrochloride is 6–15 mL / g.

[0032] More preferably, the volume ratio of the ketone solvent 1 to the mass ratio of the sugrel hydrochloride is 7 to 13 mL / g.

[0033] More preferably, the volume ratio of the ketone solvent 1 to the mass ratio of the saprogallol hydrochloride is 8-12 mL / g.

[0034] Preferably, the volume ratio of the ketone solvent 2 to the mass ratio of the sagorel hydrochloride is 3 to 8 mL / g.

[0035] More preferably, the volume ratio of the ketone solvent 2 to the mass ratio of the saprogallol hydrochloride is 4 to 7 mL / g.

[0036] More preferably, the volume ratio of the ketone solvent 2 to the mass ratio of the saprogallol hydrochloride is 4-6 mL / g.

[0037] Preferably, the volume ratio of the alcohol solvent to the mass ratio of the sagorel hydrochloride is 1 to 6 mL / g.

[0038] More preferably, the volume ratio of the alcohol solvent to the mass of the saprogallol hydrochloride is 1 to 5 mL / g.

[0039] More preferably, the volume ratio of the alcohol solvent to the mass ratio of the sagorel hydrochloride is 2–4 mL / g.

[0040] Preferably, the preparation method further includes the steps of cooling and crystallization, filtration, and drying.

[0041] Furthermore, the drying process is vacuum drying.

[0042] Thirdly, the present invention provides a pharmaceutical composition comprising crystals of sarpogrelate hydrochloride as described in the first aspect.

[0043] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0044] Fourthly, the present invention provides the use of sargrelate hydrochloride crystals according to the first aspect or the pharmaceutical composition according to the third aspect in the preparation of a medicament used as a 5-HT2 receptor antagonist.

[0045] Preferably, the drug used as a 5-HT2 receptor antagonist is a drug used as a 5-HT2A receptor antagonist.

[0046] Fifthly, the present invention provides the use of sarpogrelate hydrochloride crystals according to the first aspect or pharmaceutical compositions according to the third aspect in the preparation of medicaments for the prevention, improvement and / or treatment of cardiovascular and cerebrovascular diseases, intermittent claudication or herpes zoster neuralgia.

[0047] Preferably, the cardiovascular and cerebrovascular diseases include ischemic cerebrovascular disorders, chronic arterial occlusive disease, hypertension, hyperlipidemia, blood viscosity, and atherosclerosis.

[0048] Furthermore, the ischemic cerebrovascular disorder is a transient ischemic attack and / or cerebral infarction.

[0049] Preferably, the drug is used to improve ischemic symptoms caused by chronic arterial occlusive disease.

[0050] Furthermore, the ischemic symptoms include ulcers, pain, and coldness.

[0051] The effects of the invention

[0052] This invention provides a crystal of sarpogrelate hydrochloride, which has crystal form A, unlike any previously disclosed crystal forms. The sarpogrelate hydrochloride crystal provided by this invention exhibits excellent stability, solubility, and hygroscopicity, as well as high bioavailability and purity. Furthermore, its preparation method is simple, the crystallization conditions are mild, and the cost is low, making it suitable for industrial production and applicable to the preparation of related pharmaceutical formulations. Attached Figure Description

[0053] Figure 1 The image shows the XRPD pattern of saxagrel ester hydrochloride crystal form A prepared in Example 1.

[0054] Figure 2 The image shows the DSC diagram of crystal form A of sargrelate hydrochloride prepared in Example 1.

[0055] Figure 3 XRPD image of sargrelate hydrochloride crystal form I prepared in Comparative Example 1.

[0056] Figure 4The DSC diagram shows the crystal form I of sargrelate hydrochloride prepared in Comparative Example 1.

[0057] Figure 5 XRPD image of sago palmitate crystal form II prepared in Comparative Example 2.

[0058] Figure 6 The DSC diagram of sargrelate hydrochloride crystal form II prepared in Comparative Example 2. Detailed Implementation

[0059] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0060] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0061] Unless otherwise stated, all units used in this specification are international standard units, and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0062] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0063] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., refer to specific elements (e.g., features, structures, properties, and / or characteristics) related to that embodiment, which are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Furthermore, it should be understood that these elements may be combined in any suitable manner in various embodiments.

[0064] In this specification, the range of values ​​referred to as “value A to value B” or “value A to value B” refers to the range including the endpoint values ​​A and B.

[0065] In this instruction manual, when "room temperature" or "room temperature" is used, the temperature can be 15-30°C, or more specifically 15-25°C, such as 20°C.

[0066] In this manual, the term "optionally" has both the meaning of performing a certain operation and the meaning of not performing a certain operation.

[0067] This invention provides a crystal of sargrelate hydrochloride, wherein the crystal has crystal form A, which can be characterized by methods such as X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The above methods can use parameter settings conventional in the art, and can be adjusted or varied according to the specific physicochemical properties of the substance to be tested.

[0068] In this invention, the method parameters for X-ray powder diffraction are as follows:

[0069] Test instrument: X-ray powder diffractometer; Instrument model: XD6; Start angle: 3°; End angle: 60°; Scanning speed: 8° / min; Sampling step width: 0.01; High voltage setting: 36kV; Current: 20mA; Power: 1.5kW.

[0070] In this invention, the method parameters for differential scanning calorimetry are as follows:

[0071] Test instrument: thermogravimetric analyzer; temperature range: 30~250℃; heating rate: 10℃ / min.

[0072] In this invention, impurities and purity are detected by high performance liquid chromatography (HPLC), and the chromatographic conditions are as follows: octadecyl silica-bonded silica gel is used as the packing material (LC2103), water-acetonitrile-trifluoroacetic acid (1300:700:1) is used as the mobile phase, the column temperature is 40℃, the detection wavelength is 272nm, the injection volume is 10μL, the flow rate is 1.5mL / min, and the injector temperature is 5℃.

[0073] Sapogrelate hydrochloride crystals with crystal form A

[0074] The present invention provides a crystal of saxoprene hydrochloride having crystal form A, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values ​​of 10.88±0.1°, 16.64±0.1° and 18.83±0.1°.

[0075] In some embodiments, the differential scanning calorimetry (DSC) curve of saprogallol hydrochloride crystals provided by the present invention has an endothermic peak at 153–156 °C, preferably one endothermic peak, and more preferably a peak value at 154.3 ± 1.0 °C.

[0076] In some embodiments, the sugrel ester hydrochloride crystals provided by the present invention have characteristic peaks in their X-ray powder diffraction patterns at 2θ values ​​of 10.88±0.1°, 18.83±0.1°, and 16.64±0.1°, and their differential scanning calorimetry (DSC) patterns have endothermic peaks at 153–156 °C, preferably one endothermic peak, and more preferably a peak value at 154.3±1.0 °C.

[0077] In some specific embodiments, the X-ray powder diffraction pattern also has a characteristic peak at at least one of the 2θ values ​​of 18.32±0.1°, 20.44±0.1°, 21.01±0.1°, and 25.51±0.1°.

[0078] In some specific embodiments, the X-ray powder diffraction pattern also has a characteristic peak at at least one of the 2θ values ​​of 15.28±0.1°, 23.68±0.1°, 24.53±0.1°, 29.02±0.1°, and 32.67±0.1°.

[0079] In some specific embodiments, the X-ray powder diffraction pattern also has a characteristic peak at at least one of the following 2θ values: 13.20±0.1°, 14.66±0.1°, 23.37±0.1°, 24.26±0.1°, and 31.82±0.1°.

[0080] In some preferred embodiments, the X-ray powder diffraction pattern is as follows: Figure 1 As shown.

[0081] In some preferred embodiments, the differential scanning calorimetry (DSC) curve has an endothermic peak at 154–155 °C, preferably one endothermic peak, and more preferably reaches its peak value at 154.3 ± 0.3 °C.

[0082] In some preferred embodiments, the differential scanning calorimetry graph is as follows: Figure 2 As shown.

[0083] Preparation method

[0084] The present invention also provides a method for preparing the above-mentioned saprogallol hydrochloride crystals, the method comprising the following steps: mixing saprogallol hydrochloride and ketone solvent 1, then adding an alcohol solvent, stirring, heating, filtering while hot, optionally adding ketone solvent 2 to the filtrate, cooling to precipitate crystals, filtering, and obtaining the crystals.

[0085] In some embodiments, the ketone solvent 1 may be acetone or butanone.

[0086] In some embodiments, the ketone solvent 2 may be acetone or butanone.

[0087] In some embodiments, the ketone solvent 1 and ketone solvent 2 can be the same solvent.

[0088] In some embodiments, the addition of ketone solvent 2 can improve the yield of sagofloxacin hydrochloride crystals of the present invention.

[0089] In some embodiments, the alcohol solvent may be methanol, isopropanol, or ethanol, with methanol being preferred.

[0090] In some embodiments, the heating temperature can be 40–80°C; in some preferred embodiments, the heating temperature can be 50–60°C.

[0091] In some embodiments, the cooling crystallization step can be: cooling to room temperature or -10 to 15°C for crystallization, preferably cooling to room temperature for crystallization. In some embodiments, after hot filtration, adding ketone solvent 2 to the filtrate allows crystallization to proceed at room temperature without further cooling, thereby reducing process costs.

[0092] In some implementations, the cooling and crystallization step can be: first cooling to room temperature, then cooling to -10 to 15°C for crystallization, preferably first cooling to room temperature for stirring, then cooling to -10 to 5°C for static crystal growth.

[0093] In some embodiments, the volume ratio of the ketone solvent 1 to the mass ratio of the saprogallol hydrochloride can be 6 to 15 mL / g, preferably 7 to 13 mL / g, and more preferably 8 to 12 mL / g.

[0094] In some embodiments, the volume ratio of the ketone solvent 2 to the mass ratio of the saprogallol hydrochloride can be 3 to 8 mL / g, preferably 4 to 7 mL / g, and more preferably 4 to 6 mL / g.

[0095] In some embodiments, the volume ratio of the alcohol solvent to the mass of the saprogallol hydrochloride can be 1 to 6 mL / g, preferably 1 to 5 mL / g, and more preferably 2 to 4 mL / g.

[0096] In some embodiments, the preparation method further includes the steps of cooling and crystallization, filtering, and drying; in some preferred embodiments, the drying can be vacuum drying.

[0097] Pharmaceutical Composition

[0098] The present invention also provides a pharmaceutical composition comprising the crystals of the above-mentioned sarpogrelate hydrochloride.

[0099] In some embodiments, the pharmaceutical composition may also contain at least one pharmaceutically acceptable carrier.

[0100] The term "pharmaceuticalally acceptable carrier" refers to pharmaceutical excipients that are compatible with the active ingredient of a drug and are harmless to the subjects, including (but not limited to) diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, etc.

[0101] Medical Use

[0102] The present invention also provides pharmaceutical uses for the above-mentioned sarpogrelate hydrochloride crystals or the above-mentioned pharmaceutical composition, specifically:

[0103] First, the present invention provides the use of the above-described sarpogrelate hydrochloride crystals or the above-described pharmaceutical composition in the preparation of a medicament used as a 5-HT2 receptor antagonist. In some embodiments, the medicament used as a 5-HT2 receptor antagonist may be a medicament used as a 5-HT2A receptor antagonist.

[0104] Secondly, the present invention provides the use of the crystals of the above-mentioned sargrelate hydrochloride or the above-mentioned pharmaceutical composition in the preparation of medicaments for the prevention, improvement and / or treatment of cardiovascular and cerebrovascular diseases, intermittent claudication or herpes zoster neuralgia.

[0105] Furthermore, the sargrelate hydrochloride crystals or pharmaceutical compositions containing thereof provided by the present invention can be used as 5-HT2 receptor antagonists. In some embodiments, the 5-HT2 receptor antagonist may be a 5-HT2A receptor antagonist.

[0106] Finally, the present invention also provides a method for preventing, improving and / or treating cardiovascular and cerebrovascular diseases, intermittent claudication or herpes zoster neuralgia, the method comprising the steps of: administering an effective amount of the above-mentioned sarpogrelate hydrochloride crystals or the above-mentioned pharmaceutical composition for prevention, improvement and / or treatment to a patient in need.

[0107] In this invention, the cardiovascular and cerebrovascular diseases may include ischemic cerebrovascular disorders, chronic arterial occlusive disease, hypertension, hyperlipidemia, blood viscosity, arteriosclerosis, and other diseases; in some embodiments, the ischemic cerebrovascular disorders are transient ischemic attacks and / or cerebral infarctions.

[0108] In this invention, the drugs for preventing, improving and / or treating cardiovascular and cerebrovascular diseases can be used to improve ischemic symptoms caused by chronic arterial occlusive disease; in some embodiments, the ischemic symptoms may include symptoms such as ulcers, pain, and coldness.

[0109] Example

[0110] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0111] Example 1: Preparation of Crystal Form A

[0112] 620 g (1.70 mol) of 3-dimethylamine-1-[2-(3-methoxyphenethyl)phenoxy]-2-propanol hydrochloride was dispersed in 600 mL of purified water and added to a glass reactor. A 10% sodium carbonate solution (3.73 mol) was added dropwise with stirring. After the addition was complete, the mixture was stirred for 15–20 min, resulting in a white turbid liquid. 4-methyl-2-pentanone was added, and the mixture was stirred for 30–40 min. The mixture was allowed to stand and then separated. The aqueous phase was extracted twice with 4-methyl-2-pentanone, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was transferred to a 30 L glass reactor. After cooling to 5–10 °C, 254 g (2.54 mol) of succinic anhydride was added. The reaction was allowed to proceed for 2–3 h, and TLC showed complete reaction. Hydrochloric acid / acetone solution was added dropwise to the reaction system, and a solid precipitated with stirring. Crystallization was allowed to occur for 1–2 h. Filter, wash the filter cake with acetone, and vacuum dry to obtain crude saprogallol hydrochloride.

[0113] Take 190g of the above crude product, disperse it in 1.5L of acetone in a four-necked flask, add 400mL of methanol, stir and heat to 50-60℃, the system is a clear solution. Hot filter, solid gradually precipitates out of the filtrate under stirring at room temperature, cool to -10 to -5℃ for crystal growth for 2-3 hours, filter, vacuum dry to obtain 162.5g of pure sarpogrelate hydrochloride, purity 99.80%.

[0114] XRPD analysis confirmed that the obtained pure sargrelate hydrochloride was crystal form A, and its XRPD spectrum is shown below. Figure 1 As shown, the 2θ value, d value, and relative peak intensity of its diffraction peaks are shown in Table 1.

[0115] Table 1. XRPD data for crystal form A

[0116] Serial Number 2θ(°) d-value (A) Peak intensity (%) Serial Number 2θ(°) d-value (A) Peak intensity (%) 1 9.470 9.3312 5.0 15 23.680 3.7542 14.3 2 10.331 8.5558 2.9 16 24.260 3.6657 8.5 3 10.880 8.1248 100.0 17 24.529 3.6261 15.0 4 13.200 6.7016 7.3 18 25.510 3.4889 16.8 5 14.660 6.0375 7.8 19 27.010 3.2984 3.9 6 15.280 5.7937 11.8 20 28.470 3.1325 6.2 7 15.840 5.5904 5.6 21 29.020 3.0744 12.9 8 16.640 5.3232 10.2 22 30.730 2.9071 1.8 9 18.320 4.8387 18.7 23 30.970 2.8851 5.5 10 18.830 4.7087 26.3 24 31.820 2.8099 7.1 11 20.440 4.3413 19.1 25 32.670 2.7387 11.9 12 21.010 4.2249 25.9 26 37.090 2.4219 4.0 13 22.250 3.9921 4.1 27 39.661 2.2706 1.8 14 23.370 3.8033 7.0

[0117] The obtained pure sargrelate hydrochloride was subjected to DSC analysis, and its DSC chromatogram is shown below. Figure 2 As shown, one endothermic peak was observed in the sample within the test temperature range, with a peak temperature of 154.3℃.

[0118] Example 2 Preparation of crystal form A

[0119] 10 g of crude sarpogrelate hydrochloride was dispersed in 80 mL of butanone in a four-necked flask, and 40 mL of methanol was added. The mixture was stirred and heated to 50–70 °C, resulting in a clear solution. After hot filtration, another 40 mL of butanone was added to the filtrate, and the solution was gradually cooled to room temperature with stirring. A solid precipitated out. Crystallization was continued at room temperature for 2–3 hours. The solution was then filtered and dried under vacuum to obtain 8.56 g of pure sarpogrelate hydrochloride with a purity greater than 99.80%. XRPD analysis confirmed that the obtained pure sarpogrelate hydrochloride was crystal form A.

[0120] Example 3 Preparation of crystal form A

[0121] 10 g of crude sarpogrelate hydrochloride was dispersed in 80 mL of acetone in a four-necked flask, and 35 mL of methanol was added. The mixture was stirred and heated to 50–70 °C, resulting in a clear solution. After hot filtration, another 40 mL of acetone was added to the filtrate, and the mixture was gradually cooled to room temperature with stirring. A solid precipitated out. Crystallization was continued at room temperature for 2–3 hours. The solution was then filtered and dried under vacuum to obtain 8.52 g of pure sarpogrelate hydrochloride with a purity greater than 99.80%. XRPD analysis confirmed that the obtained pure sarpogrelate hydrochloride was in crystal form A.

[0122] Preparation of crystal form I in Comparative Example 1

[0123] According to the method in the reference, saxagrel ester hydrochloride crystal form I was prepared:

[0124] Mix 60g of sarpogrelate hydrochloride with 20mL of water, stir and heat to about 60°C, stir for about 1 hour, filter while hot, cool the filtrate to 45°C, stir to precipitate crystals, filter the crystals, wash with acetone, dry and obtain crystals with a purity of greater than or equal to 98%.

[0125] The XRPD of the obtained sargrelate hydrochloride crystals (crystal form I) was determined, and the XRPD spectrum is shown below. Figure 3 As shown, the 2θ value, d value, and relative peak intensity of its diffraction peaks are shown in Table 2.

[0126] Table 2. XRPD data for crystal form I

[0127] Serial Number 2θ(°) d-value (A) Peak intensity (%) Serial Number 2θ(°) d-value (A) Peak intensity (%) 1 9.310 9.4914 14.2 14 22.020 4.0333 22.8 2 10.710 8.2536 36.5 15 22.530 3.9432 6.6 3 12.970 6.8201 15.9 16 23.200 3.8308 20.7 4 13.990 6.3250 13.5 17 24.180 3.6777 57.1 5 14.500 6.1037 28.3 18 25.330 3.5132 65.9 6 15.120 5.8548 60.7 19 26.870 3.3153 25.5 7 15.720 5.6326 32.7 20 28.320 3.1488 39.5 8 16.500 5.3681 63.5 21 28.880 3.0890 25.2 9 17.320 5.1157 19.3 22 29.210 3.0548 15.0 10 18.160 4.8809 100.0 23 30.140 2.9626 12.4 11 18.640 4.7563 62.9 24 32.540 2.7494 13.7 12 20.280 4.3752 41.2 25 35.520 2.5253 3.5 13 20.870 4.2529 51.5 26 36.980 2.4288 13.0

[0128] The obtained sarpogrelate hydrochloride crystals were subjected to DSC analysis, and the DSC spectrum is shown below. Figure 4 As shown, one endothermic peak was observed in the sample within the test temperature range, with a peak temperature of 152.9℃.

[0129] Preparation of crystal form II in Comparative Example 2

[0130] Following the method described in the reference, saprogallol hydrochloride crystal form II was prepared as follows: 10 g of saprogallol hydrochloride was mixed with 200 mL of xylene, heated to 130–140 °C and stirred for 3 h, cooled to room temperature, filtered, the filter cake was washed with acetone, and dried under reduced pressure to obtain white crystals with a purity greater than or equal to 98%.

[0131] The XRPD of the obtained sargrelate hydrochloride crystals (crystal form II) was determined, and its XRPD spectrum is shown below. Figure 5 As shown, the 2θ value, d value, and relative peak intensity of its diffraction peaks are shown in Table 3.

[0132] Table 3. XRPD data for crystal form II

[0133] Serial Number 2θ(°) d-value (A) Peak intensity (%) Serial Number 2θ(°) d-value (A) Peak intensity (%) 1 9.550 9.2533 4.5 16 23.490 3.7841 88.7 2 10.320 8.5646 100.0 17 24.430 3.6406 11.7 3 10.649 8.3004 4.3 18 24.900 3.5730 7.2 4 11.100 7.9646 34.6 19 25.230 3.5269 9.2 5 13.920 6.3567 56.9 20 27.540 3.2361 6.8 6 14.260 6.2058 12.1 21 28.390 3.1411 2.0 7 15.700 5.6398 4.0 22 28.850 3.0921 2.9 8 17.470 5.0722 19.0 23 29.630 3.0125 11.9 9 19.170 4.6260 8.5 24 30.440 2.9341 5.8 10 19.710 4.5005 3.3 25 30.710 2.9089 11.6 11 20.240 4.3838 68.6 26 31.520 2.8360 5.9 12 21.300 4.1680 12.0 27 31.870 2.8056 57.9 13 21.670 4.0976 29.0 28 32.351 2.7650 2.9 14 22.820 3.8937 4.2 29 32.780 2.7298 10.3 15 13.170 3.8356 5.5 30 33.089 2.7050 7.2

[0134] The obtained sarpogrelate hydrochloride crystals were subjected to DSC analysis, and the DSC spectrum is shown below. Figure 6 As shown, one endothermic peak was observed in the sample within the test temperature range, with a peak temperature of 157.9℃.

[0135] Experiment Example 1: Solubility Experiment

[0136] The solubility of crystal form A, crystal form I, and crystal form II prepared in Example 1 and Comparative Examples 1 and 2 in hydrochloric acid aqueous solution at pH=1, acetate buffer at pH=4.5, phosphate buffer at pH=6.8, and phosphate buffer at pH=7.4 were determined, and the results are shown in Table 4.

[0137] Table 4. Solubility Test Results

[0138]

[0139] As can be seen from Table 4, the solubility of crystal form A, crystal form I, and crystal form II in hydrochloric acid aqueous solution at pH 1, acetate buffer at pH 4.5, phosphate buffer at pH 6.8, and phosphate buffer at pH 7.4 are basically the same.

[0140] Experiment Example 2 Hygroscopicity Experiment

[0141] In accordance with the guidelines for hygroscopicity testing of drugs in Part IV, 9103 of the 2020 edition of the Chinese Pharmacopoeia, the hygroscopicity of crystal form A, crystal form I, and crystal form II prepared in Example 1 and Comparative Examples 1 and 2 was determined, and the results are shown in Table 5.

[0142] Table 5. Results of hygroscopicity test

[0143] sample flat volumetric flask g bottle + sample g Total weight after moisture absorption (g) Weight gain in conclusion Crystal form A 20.5267 20.7802 20.7806 0.16％ Non-hygroscopic Crystal form I 19.7272 20.2411 20.2413 0.04％ Non-hygroscopic Crystal form II 20.3793 21.1843 21.1850 0.09％ Non-hygroscopic

[0144] The results showed that the hygroscopic weight gain of crystal form A, crystal form I, and crystal form II did not exceed 0.2%, and crystal form A, crystal form I, and crystal form II were not hygroscopic.

[0145] Experiment Example 3: Stability Experiment

[0146] Crystal form A, crystal form I, and crystal form II prepared in Example 1 and Comparative Examples 1 and 2 were placed at 60°C and samples were taken at 0 days, 3 days, 5 days / 6 days, and 10 days. Impurities and purity were detected by high performance liquid chromatography. The results are shown in Tables 6 to 8.

[0147] Table 6. Stability results of crystal form I under high temperature conditions

[0148]

[0149] Table 7. Stability results of crystal form II under high temperature conditions

[0150]

[0151] Table 8. Stability results of crystal form A under high temperature conditions

[0152]

[0153] Note: "Time" in Tables 6 to 8 refers to "Retention Time".

[0154] The results show that crystal form A of the present invention, as well as the previously reported crystal forms I and II, all have good chemical stability, and their purity remains basically unchanged under high temperature conditions, with virtually no degradation.

[0155] Experiment Example 4: Pharmacokinetic Experiment

[0156] 1. Grouping and feeding of laboratory animals

[0157] Twelve SPF-grade male SD rats aged 56-62 days and weighing 250-300 g were housed in an SPF environment. After completing the acclimatization feeding in a free-water and food-giving environment, the rats were weighed and randomly divided into four groups (A, B, C, and D), with three rats in each group.

[0158] 2. Administration

[0159] After the adaptation feeding was completed, the patients were fasted for 12 hours before administration, but had free access to water. They were fed uniformly 4 hours after administration. The dry powder was administered via gavage in a single dose of 9 mg / kg. Group A received 1 dose, Group B received 2 doses, Group C received a mixture of drug 1 and drug 2 (1:1), and Group D received 3 doses.

[0160] Drug Name Crystal form 1 Crystal form I 2 Crystal form II 3 Crystal form A

[0161] 3. Sample collection and storage

[0162] Plasma samples: Plasma was collected before administration and at 5 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration. Blood was collected from the jugular vein of rats using EDTA anticoagulant blood collection tubes. After mixing, the samples were centrifuged for 10 min (4℃, 3000 rpm), and the supernatant, i.e., plasma, was collected and stored at -80℃ for testing.

[0163] 4. Sample and Standard Preparation

[0164] (1) Sample: Take 10 μL of plasma sample, add 5 μL of blank solution (ACN / H2O = 1:1) and 200 μL of protein precipitant, vortex to mix, and centrifuge for 15 min. After centrifugation, take the supernatant, dilute it 3 times with water, and inject it into LC-MS / MS for detection.

[0165] (2) Standards: Prepare sarpogrel standard working solutions with concentrations of 1, 2, 4, 10, 20, 100, 200, 1000, 2000, and 4000 ng / mL using 50% acetonitrile. Add 5 μL of the working solution to 10 μL of blank plasma to obtain standard working solutions with plasma concentrations of 0.5, 1, 2, 5, 10, 50, 100, 500, 1000, and 2000 ng / mL, respectively, for testing and to prepare standard curves.

[0166] Six QC samples were prepared separately using the same method, with concentrations of 1, 2, 5, 50, 800, and 1600 ng / mL.

[0167] 5. LC-MS / MS detection

[0168] Take 15 μL of standard / QC sample / sample, add acetonitrile containing internal standard to remove protein, vortex for 30 s, then centrifuge for 15 min (4℃, 3900 rpm), take the supernatant and dilute it 3 times with water, and then perform quantitative analysis in an LC / MS / MS system.

[0169] The assay was performed using AB API 5500+ LC / MS / MS with a Shim-pack Velox Biphenyl 1.8 μm (50*2.1 mm) column. The mobile phases were: Phase A was 5% acetonitrile aqueous solution (0.1% formic acid), and Phase B was 95% acetonitrile (0.1% formic acid).

[0170] (Acid). The elution program was set as follows: using 5% B phase as the starting buffer solution, running at this concentration for 0.3 min, setting the B phase to rise to 95% at 1.9 min, maintaining this concentration until 2.2 min, running at 2.21 min, setting the B phase to drop to 5%, maintaining this concentration until 2.5 min. The injection volume was set to 10 μL, and the flow rate to 0.5 mL / min.

[0171] The compound has a molecular weight of 429.51, an ion pair of 429.96 / 312.10, and a detection limit of 0.5 ng / mL.

[0172] 6. Statistical analysis of the data

[0173] Statistical analyses were performed using GraphPadPrism 9.5. Data are expressed as mean ± SD. One-way ANOVA was used to compare data from two or more groups. *P < 0.05 was considered statistically significant, and **P < 0.01 was considered highly statistically significant.

[0174] The PK parameters were calculated using the WinNonlin 8.3 non-compartmental model.

[0175] 7. Pharmacokinetic parameters of sargrelate hydrochloride in different crystal forms

[0176] The calculated pharmacokinetic parameters are expressed as x±s, and the results are shown in Table 9. AUC for group D only. Inf The pharmacokinetic parameters were higher than those in group C (P<0.05), representing an increase of approximately 65%. There were no statistically significant differences in the remaining pharmacokinetic parameters among the groups.

[0177] Table 9. Pharmacokinetic parameters of sarpogrelate hydrochloride

[0178] PK parameters Group A Group B Group C Group D <![CDATA[T 1 / 2 / h]]> 4.057 3.880±3.367 9.066±10.539 4.143±2.391 <![CDATA[T max / h]]> 3.916±5.310 1.274±1.148 3.34±2.312 2.741±2.394 <![CDATA[C max / (ng / mL)]]> 508±254.682 773.333±320.857 446±178.502 324.4±236.124 <![CDATA[AUC 0-24 / (ng·h / mL)]]> 2746.722±953.245 2700.684±750.316 2179.93±1006.688 3355.398±2685.527 <![CDATA[AUC Inf / (ng·h / mL)]]> 2953.504 2796.779±870.842 2622.533±999.111 4322.381±2517.404* <![CDATA[MRT Inf / h]]> 6.060 5.740±1.487 13.018±5.163 9.280±1.692

[0179] Note: Compared with Group C, Group D's AUC Inf P < 0.05. In group A, T 1 / 2 AUC Inf MRT Inf The SD is not displayed because the number of samples tested is 3. One of the samples could not be selected, so the above parameters could not be calculated for that sample. Therefore, the above parameters actually only have two values, and the SD cannot be calculated.

[0180] The results showed that group D mice had higher drug exposure in their blood, and the sarpogrelate hydrochloride crystals of crystal form A of the present invention had significantly higher bioavailability.

[0181] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0182] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A crystal of sarpogrelate hydrochloride, which satisfies at least one of the following conditions: (1) Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.88±0.1°, 16.64±0.1° and 18.83±0.1°; (2) Its differential scanning calorimetry chart has an endothermic peak at 153-156℃.

2. The saprogallol hydrochloride crystals according to claim 1, characterized in that, Its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 10.88±0.1°, 16.64±0.1° and 18.83±0.1°, and its differential scanning calorimetry pattern has endothermic peaks at 153 to 156 °C.

3. The crystal of sarpogrelate hydrochloride according to claim 1 or 2, characterized in that, Its X-ray powder diffraction pattern has a characteristic peak at least at one of the 2θ values ​​of 18.32±0.1°, 20.44±0.1°, 21.01±0.1° and 25.51±0.1°, preferably it also has a characteristic peak at least at one of the 2θ values ​​of 15.28±0.1°, 23.68±0.1°, 24.53±0.1°, 29.02±0.1° and 32.67±0.1°, more preferably its X-ray powder diffraction pattern is shown in Figure 1.

4. The crystals of sarpogrelate hydrochloride according to any one of claims 1-3, characterized in that, Its differential scanning calorimetry (DSC) curve has an endothermic peak at 154–155 °C, and its preferred DSC curve is shown in Figure 2.

5. A method for preparing sargrelate hydrochloride crystals according to any one of claims 1-4, comprising the following steps: Mix saprogallol hydrochloride and ketone solvent 1, then add an alcohol solvent, stir, heat, filter while hot, optionally add ketone solvent 2 to the filtrate, cool to crystallize, filter, and obtain the product; Preferably, the ketone solvent 1 or ketone solvent 2 is acetone or butanone; Preferably, the alcohol solvent is methanol, isopropanol, or ethanol, with methanol being the most preferred.

6. The preparation method according to claim 5, characterized in that, The heating temperature is 40–80°C, preferably 50–60°C; Further, the cooling crystallization step is as follows: cooling to room temperature or -10 to 15°C for crystallization, preferably cooling to room temperature for crystallization; or, the cooling crystallization step is as follows: first cooling to room temperature, then cooling to -10 to 15°C for crystallization, preferably first cooling to room temperature for stirring, then cooling to -10 to 5°C for static crystal growth.

7. The preparation method according to claim 5 or 6, characterized in that, The preparation method also satisfies at least one of the following conditions: The volume ratio of the ketone solvent 1 to the mass of the saprogallol hydrochloride is 6-15 mL / g, preferably 7-13 mL / g, and more preferably 8-12 mL / g. The volume ratio of the ketone solvent 2 to the mass of the saprogallol hydrochloride is 3-8 mL / g, preferably 4-7 mL / g, and more preferably 4-6 mL / g. The volume ratio of the alcohol solvent to the mass of the saprogallol hydrochloride is 1 to 6 mL / g, preferably 1 to 5 mL / g, and more preferably 2 to 4 mL / g. The preparation method further includes the steps of cooling and crystallization, filtering, and drying, preferably vacuum drying.

8. A pharmaceutical composition comprising crystals of sargrelate hydrochloride according to any one of claims 1-4; further, the pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.

9. Use of crystals of sargrelate hydrochloride according to any one of claims 1-4 or the pharmaceutical composition according to claim 8 in the preparation of a medicament used as a 5-HT2 receptor antagonist, wherein the medicament used as a 5-HT2 receptor antagonist is preferably a medicament used as a 5-HT2A receptor antagonist.

10. Use of sargrelate hydrochloride crystals according to any one of claims 1-4 or the pharmaceutical composition according to claim 8 in the preparation of medicaments for the prevention, improvement and / or treatment of cardiovascular and cerebrovascular diseases, intermittent claudication or herpes zoster neuralgia; Preferably, the cardiovascular and cerebrovascular diseases include ischemic cerebrovascular disorders, chronic arterial occlusive disease, hypertension, hyperlipidemia, blood viscosity, and atherosclerosis; wherein, The ischemic cerebrovascular disorder is preferably a transient ischemic attack and / or cerebral infarction; Preferably, the drug is used to improve ischemic symptoms caused by chronic arterial occlusive disease; further, the ischemic symptoms include ulcers, pain, and coldness.

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