A fluorofavudine hydrobromide and a method for preparing the same

Abstract

The application discloses fluorofavudine hydrobromide and a preparation method thereof. The fluorofavudine hydrobromide has good dissolution characteristics. Meanwhile, the application further comprises a crystal form of fluorofavudine hydrobromide, especially crystal form III, which has the advantages of crystal stability and difficulty in generating genotoxicity, and has very good drug property and safety.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a fluvatinib hydrobromide or its crystal form and its preparation method. Background Technology

[0002] Liver cancer is a common malignant tumor in my country. Data published by the National Cancer Center in 2017 showed that in 2013, there were 362,000 new cases of liver cancer in my country, ranking third in incidence nationwide; the number of deaths from liver cancer reached 316,000, ranking second. Hepatocellular carcinoma (HCC) has an insidious onset, with few or no early symptoms. Most patients are diagnosed too late for surgery. Treatment outcomes for liver cancer, whether through surgery, interventional therapy, or chemotherapy, remain unsatisfactory, and the current 5-year survival rate is still very low.

[0003] With the development of science and technology, targeted drug therapy for HCC has emerged. Currently, targeted drugs for liver cancer mainly include epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VEGFR) antagonists, multi-kinase inhibitors, PI3K / Akt / mTOR signaling pathway inhibitors, hepatocyte growth factor receptor (Met) inhibitors, and TGFβ receptor inhibitors. Currently approved targeted TKI drugs include sorafenib, lenvatinib, and regorafenib. Therefore, the number of treatment options is very limited.

[0004] CN109134365A discloses a drug compound with multi-target activity against VEGFR types 1-3, fibroblast growth factor receptor types 1-3, RET, Kit, and PDGFR. This drug compound is named fluvatinib, and its chemical structural formula is shown in Formula I below:

[0005]

[0006] I

[0007] The chemical name of fluvatinib is 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide. Fluvatinib, as a promising anti-tumor drug, offers a potential new treatment option for patients with liver and kidney tumors. However, our research has found that the free base of fluvatinib has a very low dissolution rate, which is detrimental to formulation development since the drug's efficacy requires a certain concentration. Salting the free base can often effectively increase the drug's solubility and dissolution rate. However, studies have shown that the dissolution effects of hydrochloride and sulfate are still unsatisfactory. Therefore, it is necessary to develop an inorganic salt form of the fluvatinib free base with better dissolution. Summary of the Invention

[0008] The purpose of this invention is to provide a 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide (fluvatinib as shown in Formula I) hydrobromide. This invention also provides a crystalline form of fluvatinib hydrobromide.

[0009] The "fluvatinib hydrobromide" mentioned in this article can also be called "fluvatinib hydrobromide," both referring to the same compound.

[0010] To achieve the objectives of this invention, the following implementation scheme is provided.

[0011] In one embodiment, fluvatinib hydrobromide is provided.

[0012] In another embodiment, the present invention provides a crystalline form of fluvatinib hydrobromide.

[0013] In one specific embodiment, the crystalline form of fluvatinib hydrobromide of the present invention is selected from the following crystalline form IV:

[0014] Crystal form I has the characteristic peaks shown in Figure 1 in its X-ray powder diffraction pattern.

[0015] Crystal form II, its X-ray powder diffraction pattern has the characteristic peaks shown in Figure 2.

[0016] Crystal form III exhibits characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 7.36±0.2°, 14.61±0.2°, and 20.71±0.2°.

[0017] Crystal form IV, its X-ray powder diffraction pattern has the characteristic peaks shown in Figure 4, and

[0018] Crystal form V has characteristic peaks in its X-ray powder diffraction as shown in Figure 5.

[0019] Preferably, the crystalline form of fluvatinib hydrobromide of the present invention, crystalline form III, further has characteristic peaks in its X-ray powder diffraction pattern at 2θ values ​​of 7.36±0.2°, 14.61±0.2°, 18.21±0.2°, 20.71±0.2°, 23.12±0.2°, 25.83±0.2°, 28.11±0.2°, and 33.71±0.2°. More preferably, the X-ray powder diffraction pattern of crystalline form III has the characteristic peaks shown in Figure 3.

[0020] In one embodiment, the present invention provides a method for preparing fluvatinib hydrobromide crystal form III, comprising: mixing fluvatinib with an organic solvent (mass-volume ratio) to form a suspension, adding hydrobromic acid, stirring at 29-64°C for a period of time, and filtering and drying to obtain fluvatinib hydrobromide crystal form III.

[0021] Preferably, in the method described above, the mass-to-volume ratio of fluvatinib to the organic solvent is not greater than 50 mg / mL, more preferably 10-50 mg / mL, the organic solvent is selected from methanol, ethanol, propanol, isopropanol and mixtures thereof, and the stirring time is 30 min-72 h.

[0022] In some specific embodiments, a method for preparing fluvatinib hydrobromide crystal form III according to the present invention involves mixing fluvatinib and methanol at a mass-volume ratio of 10-50 (mg / mL) to form a suspension, adding hydrobromic acid, stirring at 29-64°C for 30 min-24 h, filtering and drying to obtain fluvatinib hydrobromide crystal form III.

[0023] In some specific embodiments, a method for preparing fluvatinib hydrobromide crystal form III according to the present invention involves mixing fluvatinib and ethanol at a mass-to-volume ratio of 10-50 (mg / mL) to form a suspension, adding hydrobromic acid, stirring at 29-64°C for 24-72 hours, filtering and drying to obtain fluvatinib hydrobromide crystal form III.

[0024] In one embodiment, the present invention also provides a method for preparing fluvatinib hydrobromide crystal form I, comprising: mixing fluvatinib and methanol in a mass-volume ratio to form a suspension, adding hydrobromic acid, stirring at 5~25°C for 30 min~24 h, filtering and drying to obtain fluvatinib hydrobromide crystal form I, wherein the mass-volume ratio of fluvatinib to methanol is 10~20 mg / mL.

[0025] In one embodiment, the present invention also provides a method for preparing fluvatinib hydrobromide crystal form II, comprising: mixing fluvatinib and ethanol in a certain mass-volume ratio to form a suspension, adding hydrobromic acid, stirring at 5~25°C for 30 min~24 h, filtering and drying to obtain fluvatinib hydrobromide crystal form II, wherein the mass-volume ratio is 10~20 mg / mL.

[0026] In one embodiment, the present invention also provides a method for preparing fluvatinib hydrobromide crystal form V, comprising: mixing fluvatinib and methanol in a certain mass-volume ratio to form a suspension, adding hydrobromic acid, stirring at 5-25°C for 6-24 hours, filtering and drying to obtain fluvatinib hydrobromide crystal form V, wherein the mass-volume ratio is greater than 50 and not greater than 100 mg / mL.

[0027] In one embodiment, the present invention also provides a method for preparing fluvatinib hydrobromide crystal form IV, comprising: mixing fluvatinib and ethanol in a certain mass-volume ratio to form a suspension, adding hydrobromic acid, stirring at a certain temperature for a period of time until crystal form is generated, filtering and drying to obtain fluvatinib hydrobromide crystal form IV. Further, crystal form IV is converted into crystal form III.

[0028] A pharmaceutical composition of the present invention comprises fluvatinib hydrobromide or its crystal form and pharmaceutically acceptable excipients.

[0029] In the pharmaceutical composition of the present invention described above, the crystalline form of fluvatinib hydrobromide is selected from crystalline form I, crystalline form II, crystalline form III, crystalline form IV and crystalline form V of the present invention, preferably crystalline form III.

[0030] The present invention also provides the use of fluvatinib hydrobromide or its crystal form in the manufacture of a tumor-treating drug.

[0031] In one embodiment, a fluvatinib hydrobromide crystal form III of the present invention is characterized by having characteristic diffraction peaks in its X-ray powder diffraction pattern at 2θ values ​​of 7.36±0.2°, 14.61±0.2°, and 20.71±0.2°.

[0032] The fluvatinib hydrobromide crystal form III further exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern at 2θ values ​​of 7.36±0.2°, 14.61±0.2°, 18.21±0.2°, 20.71±0.2°, 23.12±0.2°, 25.83±0.2°, 28.11±0.2°, and 33.71±0.2°.

[0033] Preferably, the fluvatinib hydrobromide crystal form III has an X-ray powder diffraction pattern showing that... Figure 3 The characteristic diffraction peaks shown are...

[0034] The above-mentioned use of fluvatinib hydrobromide and fluvatinib hydrobromide crystal forms I, II, III, IV, and V in the preparation of antitumor drugs, wherein the tumors include, but are not limited to, liver cancer, kidney cancer, gastric cancer, colorectal cancer, pancreatic cancer, and lung cancer.

[0035] The present invention also provides a pharmaceutical composition comprising an effective amount of fluvatinib hydrobromide or its crystal form thereof and a pharmaceutical excipient, wherein the crystal form is selected from fluvatinib hydrobromide crystal forms I, II, III, IV and V, preferably fluvatinib hydrobromide crystal form III.

[0036] Preferably, the crystal form is fluvatinib hydrobromide crystal form III.

[0037] The excipients in the above-described compositions of the present invention include, but are not limited to, fillers, disintegrants, binders, lubricants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption promoters, etc., and the above excipients can be appropriately combined according to the needs of different formulations of the composition.

[0038] Specifically, the filler is selected from one or more of lactose, white sugar, glucose, corn starch, mannitol, sorbitol, starch, α-starch, dextrin, crystalline cellulose, light silicic anhydride, aluminum silicate, calcium silicate, magnesium aluminosilicate, and calcium hydrogen phosphate. The disintegrant is selected from one or more of crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl starch, and sodium carboxymethyl starch. The binder is selected from one or more of polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, astragalus gum, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol. The lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium octadecyl fumarate, talc, polyethylene glycol, and colloidal silica. The colorants mentioned above are selected from pharmaceutical colorants such as ferric oxide, yellow ferric oxide, carmine, caramel, β-carotene, titanium dioxide, talc, sodium riboflavin phosphate, and yellow aluminum lake. The flavoring agents mentioned above are selected from cocoa powder, menthol, aromatic powders, peppermint oil, borneol, and cinnamon powder. The surfactants mentioned above are selected from octadecyl triethanolamine, sodium lauryl sulfate, dodecyl aminopropionic acid, lecithin, glyceryl monostearate, sucrose fatty acid esters, and glyceryl fatty acid esters. The solubilizers mentioned above are selected from polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and Tween 80.

[0039] The antioxidants mentioned above can be sulfites, ascorbic acid, α-tocopherol, etc.

[0040] The above-described compositions of the present invention may be in the form of oral preparations such as tablets, powders, granules, capsules, syrups, tablet-containing preparations, inhalers, or injections.

[0041] The oral preparations mentioned above may also be coated as needed.

[0042] The above-mentioned injectable preparations may contain appropriate additives, such as emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption promoters, etc.

[0043] When the crystals of this invention are used as medicine, the dosage varies depending on the symptoms, age, and method of administration. Generally, the adult dosage is 100 μg to 10 g per day, divided into one or several doses.

[0044] The crystal form of the present invention is very useful as an angiogenesis inhibitor, and is useful as a preventive or therapeutic agent for diseases that can be effectively treated through angiogenesis inhibition, such as angiogenesis inhibitors, antitumor agents, hemangioma treatment agents, and cancer metastasis inhibitors.

[0045] Furthermore, when the composition of the present invention described above is used as an antitumor agent, the tumor includes liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, colorectal cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, leukemia, or ovarian cancer, and is particularly preferred to be liver cancer, thyroid cancer, gastric cancer, colorectal cancer, prostate cancer, lung cancer, or kidney cancer.

[0046] The inherent dissolution rate of a drug represents the dissolution characteristics of each fixed compound in a solvent under solid conditions, and this characteristic is affected by the crystal form of the drug. Fluvatinib hydrobromide crystal form III of the present invention exhibits excellent dissolution characteristics, with a dissolution amount of 40.2 μg / mL in an aqueous hydrochloric acid solution at pH 1.2 after 600 min, which is superior to fluvatinib sulfate and fluvatinib hydrochloride.

[0047] The fluvatinib hydrobromide of this invention exhibits excellent dissolution rate or amount in the inorganic salts of fluvatinib. However, fluvatinib hydrobromide exhibits a typical polymorphic morphology. This invention has developed and screened five crystalline forms, among which fluvatinib hydrobromide crystalline form III exhibits relatively better specific physicochemical properties, good stability, and is not prone to crystal transformation. In methanol or ethanol solvents, it maintains crystalline stability after suspension and stirring at 50°C for 48 hours, without undergoing crystalline transformation. Another advantage of fluvatinib hydrobromide crystalline form III is its low risk of genotoxic impurities.

[0048] The main advantages of this invention are:

[0049] (1) The present invention provides the hydrobromide of fluvatinib and its five polymorphs, especially fluvatinib hydrobromide polymorph III, which is a non-solvent compound with crystal stability, including no crystal transformation under suspension, pressure and high temperature and humidity, maintaining stability, and has good formulation processability and pharmaceutical feasibility. Most importantly, it has a faster inherent dissolution rate than inorganic salts such as fluvatinib sulfate and fluvatinib hydrochloride.

[0050] (2) A method for preparing fluvatinib hydrobromide crystal form III is provided. This method is simple to operate and suitable for industrial scale-up production. Attached Figure Description

[0051] Figure 1PXRD pattern of fluvatinib hydrobromide crystal form I.

[0052] Figure 2 PXRD pattern of fluvatinib hydrobromide crystal form II.

[0053] Figure 3 PXRD pattern of fluvatinib hydrobromide crystal form III.

[0054] Figure 4 TGA / DSC image of fluvatinib hydrobromide crystal form III

[0055] Figure 5 Infrared spectrum of fluvatinib hydrobromide crystal form III.

[0056] Figure 6 PXRD pattern of fluvatinib hydrobromide crystal form IV.

[0057] Figure 7 PXRD pattern of fluvatinib hydrobromide crystal form V.

[0058] Figure 8 PXRD patterns of fluvatinib hydrobromide crystal form III before and after stability testing.

[0059] Figure 9 PXRD patterns of fluvatinib hydrobromide crystal form V before and after stability testing.

[0060] Figure 10 PXRD patterns of fluvatinib hydrobromide crystal form III before and after pressure crystallization test.

[0061] Figure 11 PXRD patterns of fluvatinib hydrobromide crystal form I before and after pressure crystallization test. Detailed Implementation

[0062] The following examples are merely representative and are used to further illustrate or understand the spirit of the present invention, but do not limit the scope of the present invention in any way. Any simple modifications made within the scope of the spirit of the present invention also fall within the scope of the present invention.

[0063] In this paper, the determination of crystal form parameters, such as X-ray powder diffraction (PXRD), DSC, and TGA, are all standard methods in this field. The specific detection instruments used are as follows: Due to the inherent errors of the instruments and the detection process, the error range of the detection results, such as PXRD, is ±0.2. For the determination of the intrinsic dissolution rate, an optical fiber intrinsic dissolution analyzer was used.

[0064] (1) X-ray powder diffractometer (PXRD)

[0065] Test conditions: Approximately 10 mg of sample is evenly spread on a single-crystal silicon / glass slide sample tray for PXRD detection.

[0066] X-ray source: Cu target

[0067] Phototube voltage: 40 kV

[0068] Phototube current: 30 mA

[0069] Scanning angle range: 3-40 degrees

[0070] Step width angle: 0.026 deg

[0071] (2) Differential Scanning Calorimeter (DSC)

[0072] Test conditions 1: Starting temperature 35℃, ending temperature 250℃, heating rate 10℃ / min

[0073] Test Condition 2: Starting temperature 35℃, ending temperature 300℃, heating rate 10℃ / min

[0074] Method: Weigh approximately 3 mg of sample into an aluminum crucible for testing.

[0075] (3) Thermogravimetric analyzer (TGA)

[0076] Test conditions 1: Starting temperature 35℃, ending temperature 250℃, heating rate 10℃ / min

[0077] Test Condition 2: Starting temperature 35℃, ending temperature 300℃, heating rate 10℃ / min

[0078] Method: Weigh an appropriate amount of sample into a crucible for testing.

[0079] (4) Particle size test (Malvin MS3000)

[0080] Attachment: Aero S (Dry Process)

[0081] Atmospheric pressure: 2.5 bar

[0082] Hopper gap: 1.00mm

[0083] Non-spherical particle mode: Yes

[0084] Result category: Volume

[0085] (5) Inherent dissolution test

[0086] Instrument Model: FODT-101 / FODT-101Y Fiber Optic Intrinsic Dissolution Tester, Shanghai FODT

[0087] Test method: After pressing the sample powder in the mold for 2 minutes, the dissolution test was performed without demolding. Specific conditions are shown in Table 1 below.

[0088] surface Inherent dissolution test conditions

[0089]

[0090] Example 1: Preparation of Fluvatinib Hydrobromide Crystal Form I

[0091] Fluvatinib free base (300 mg) was added to methanol (30 mL), stirred until a suspension was formed, and incubated at 20°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension. The mixture was stirred at 20°C for 6 h, filtered, and the filter cake was dried under vacuum at 20°C. The product was analyzed by PXRD, and the results are shown below. Figure 1 The PXRD data are shown in Table 2. It is named fluvatinib hydrobromide crystal form I, which is a non-solvent compound with a decomposition temperature of 233.5℃.

[0092] Table 2. PXRD data for fluvatinib hydrobromide crystal form I

[0093]

[0094] Example 2 Preparation of Fluvatinib Hydrobromide Crystal Form II

[0095] Fluvatinib free base (300 mg) was added to ethanol (30 mL), stirred until a suspension was formed, and incubated at 20°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension, stirred at 20°C for 6 h, filtered, and the filter cake was dried under vacuum at 20°C. The product was analyzed by PXRD, and the results are shown below. Figure 2 The PXRD data are shown in Table 3. It is named fluvatinib hydrobromide crystal form II. It is a solvate, and the decomposition temperature after solvent removal is about 219.4℃.

[0096] Table 3. PXRD data for fluvatinib hydrobromide crystal form II

[0097]

[0098] Example 3 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0099] Fluvatinib free base (1500 mg) was added to methanol (30 mL), stirred until a suspension was formed, and incubated at 29°C for 10 min. Hydrobromic acid (40 wt%, 685 mg) was added to the suspension. The mixture was stirred at 29°C for 24 h, filtered, and a filter cake was obtained. The filter cake was vacuum dried at 25°C for 24 h, and the PXRD data were analyzed. The PXRD data are shown in Table 4. Figure 3 It was named fluvatinib hydrobromide crystal form III. Its DSC and TGA results are shown in [link to DSC and TGA results]. Figure 4 Its decomposition temperature is 230.2℃, and its infrared spectrum is shown below. Figure 5 .

[0100] Table 4. PXRD data of fluvatinib hydrobromide crystal form III in Example 3

[0101]

[0102] Example 4 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0103] Fluvatinib free base (300 mg) was added to methanol (30 mL), stirred until a suspension was formed, and kept at 50°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension. The mixture was stirred at 50°C for 18 h, filtered, and the filter cake was vacuum dried at 25°C for 24 h. The product was analyzed by PXRD, and its 2θ value was basically consistent with that of fluvatinib hydrobromide crystal form III. Its DSC and TGA data were within the allowable error range. Figure 4 The decomposition temperature was the same, at 230.1℃. The obtained particle size distribution is shown in Table 5.

[0104] Table 5. Particle size of fluvatinib hydrobromide crystal form III

[0105]

[0106] Example 5 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0107] The free base of fluvatinib (300 mg) was added to ethanol (30 mL), stirred until a suspension was formed, and kept at 55°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension. The mixture was stirred at 55°C for 48 h, filtered, and the filter cake was dried under vacuum at 25°C for 24 h. The product was analyzed by PXRD, and its PXRD data are shown in Table 6, indicating that it is fluvatinib hydrobromide crystal form III.

[0108] Table 6. PXRD data of fluvatinib hydrobromide crystal form III in Example 5

[0109]

[0110] Example 6 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0111] Fluvatinib free base (300 mg) was added to ethanol (30 mL), stirred until a suspension was formed, and incubated at 29°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension. The mixture was stirred at 29°C for 72 h, filtered, and a filter cake was obtained. The filter cake was vacuum dried at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III.

[0112] Example 7 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0113] Fluvatinib free base (1500 mg) was added to ethanol (30 mL), stirred until a suspension was formed, and incubated at 64°C for 10 min. Hydrobromic acid (40 wt%, 685 mg) was added to the suspension. The mixture was stirred at 64°C for 24 h, filtered, and a filter cake was obtained. The filter cake was vacuum dried at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, indicating that it was fluvatinib hydrobromide crystal form III.

[0114] Example 8 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0115] Fluvatinib free base (1500 mg) was added to methanol (30 mL), stirred until a suspension was formed, and incubated at 64°C for 10 min. Hydrobromic acid (40 wt%, 685 mg) was added to the suspension. The mixture was stirred at 64°C for 16 h, filtered, and the resulting filter cake was dried under vacuum at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, confirming it as fluvatinib hydrobromide crystal form III.

[0116] Example 9 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0117] Fluvatinib free base (1200 mg) was added to methanol (30 mL), stirred until a suspension was formed, and kept at 50°C for 10 min. Hydrobromic acid (40 wt%, 548 mg) was added to the suspension. The mixture was stirred at 50°C for 30 min, filtered, and a filter cake was obtained. The filter cake was vacuum dried at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, indicating that it is fluvatinib hydrobromide crystal form III.

[0118] Example 10 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0119] Fluvatinib free base (1500 mg) was added to methanol (30 mL), stirred until a suspension was formed, and incubated at 64°C for 10 min. Hydrobromic acid (40 wt%, 685 mg) was added to the suspension. The mixture was stirred at 64°C for 24 h, filtered, and the resulting filter cake was dried under vacuum at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, confirming it as fluvatinib hydrobromide crystal form III.

[0120] Example 11 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0121] Fluvatinib free base (900 mg) was added to methanol (30 mL), stirred until a suspension was formed, and kept at 50°C for 10 min. Hydrobromic acid (40 wt%, 411 mg) was added to the suspension. The mixture was stirred at 50°C for 2 h, filtered, and the resulting filter cake was dried under vacuum at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, confirming it as fluvatinib hydrobromide crystal form III.

[0122] Example 12 Preparation of Fluvatinib Hydrobromide Crystal Form III

[0123] Fluvatinib free base (36000 mg) was added to methanol (850 mL), stirred until a suspension was formed, and kept at 50°C for 10 min. Hydrobromic acid (40 wt%, 16440 mg) was added to the suspension. The mixture was stirred at 50°C for 24 h, filtered, and a filter cake was obtained. The filter cake was vacuum dried at 25°C for 24 h. PXRD analysis showed that the 2θ value of the product was essentially consistent with that of fluvatinib hydrobromide crystal form III, indicating that it was fluvatinib hydrobromide crystal form III.

[0124] Example 13 Preparation of Fluvatinib Hydrobromide Crystal Form IV

[0125] Fluvatinib free base (1500 mg) was added to ethanol (30 mL), stirred until a suspension was formed, and incubated at 27°C for 10 min. Hydrobromic acid (40 wt%, 685 mg) was added to the suspension. The mixture was stirred at 27°C for 24 h, filtered, and the resulting filter cake was vacuum dried at 50°C. The PXRD results are shown in the figure below. Figure 6 The PXRD data are shown in Table 7. It is named fluvatinib hydrobromide crystal form IV. It is a non-solvent compound with a decomposition temperature of approximately 202.2°C.

[0126] Table 7. PXRD data for fluvatinib hydrobromide crystal form IV

[0127]

[0128] Example 14 Preparation of Fluvatinib Hydrobromide Crystal Form V

[0129] Fluvatinib free base (300 mg) was added to methanol (4 mL), stirred until a suspension was formed, and incubated at 20°C for 10 min. Hydrobromic acid (40 wt%, 137 mg) was added to the suspension. The mixture was stirred at 20°C for 24 h, filtered, and the resulting filter cake was vacuum dried at 20°C. The PXRD results are shown in the figure below. Figure 7 The PXRD data are shown in Table 8. It is named fluvatinib hydrobromide crystal form V, and its decomposition temperature is approximately 216.9℃.

[0130] Hygroscopicity test: Fluvatinib hydrobromide crystal form III and crystal form V were placed at RH=43.16% and 20℃ for 6 hours, and then the moisture content was measured. The hygroscopicity of crystal form III was 0.514%, and that of crystal form V was 0.979%.

[0131] Table 8. PXRD data for fluvatinib hydrobromide crystal form V

[0132]

[0133] Comparative Example 1

[0134] 0.674 mol of free fluvatinib base was added to 30 mL of ethanol and stirred to form a suspension. The suspension was kept at 50 °C for 10 min. 0.674 mol of hydrochloric acid was added dropwise to the suspension. The mixture was stirred at 50 °C for 24 h, filtered, and the filter cake was dried under vacuum at 20 °C to obtain fluvatinib hydrochloride crystals.

[0135] Comparative Example 2

[0136] 0.674 mol of free fluvatinib base was added to 30 mL of ethanol and stirred to form a suspension. The suspension was then incubated at 50 °C for 10 min. 0.674 mol of sulfuric acid was added to the suspension. The mixture was stirred at 50 °C for 24 h, filtered, and the filter cake was dried under vacuum at 20 °C to obtain fluvatinib sulfate crystals.

[0137] Example 1: Study on Crystal Form Stability

[0138] (1) Stability of samples under temperature and humidity conditions

[0139] Samples of fluvatinib hydrobromide in crystal forms I, II, III, IV, and V were stored under the conditions shown in Table 9 to investigate their stability. After a period of time, they were removed and tested for PXRD. Fluvatinib hydrobromide crystal forms I, II, and IV all underwent crystal transformation, while only crystal forms III and V did not. Fluvatinib hydrobromide crystal form III, stored at 50°C and 75% RH, remained crystal form III after 6 months; its PXRD results are shown below. Figure 8 The crystal form remained unchanged after sample retention. Fluvatinib hydrobromide crystal form V, when stored at 50°C and 75% RH for 6 months, still remained crystal form V. PXRD results are shown below. Figure 9 The crystal form remained unchanged after the sample was retained, indicating that crystal forms III and V have good stability.

[0140] Table 9. Changes in crystal form of hydrobromide before and after sample retention.

[0141]

[0142] (2) Pressure stability

[0143] Fluvatinib hydrobromide crystal form III was held at 119 MPa for 20 min, and then PXRD was measured. The results are shown in [Figure 1]. Figure 10 (Before and after tableting) it remains fluvatinib hydrobromide crystal form III, and pressure did not cause crystal transformation. Crystal form III showed good stability at 119 MPa pressure.

[0144] Fluvatinib hydrobromide crystal form I was held at 119 MPa for 20 min, and then PXRD was measured. The results are shown in [Figure 1]. Figure 11 (Before and after tableting) Fluvatinib hydrobromide crystal form III, pressure causes crystal form I to transform into crystal form.

[0145] Example 2: Inherent Dissolution Measurement

[0146] Inherent dissolution determination of fluvatinib sulfate, hydrochloride and hydrobromide (crystal form III).

[0147] Fluvatinib sulfate, fluvatinib hydrochloride, and fluvatinib hydrobromide (crystal form III) were prepared into tablets, and their inherent dissolution in hydrochloric acid solution at pH 1.2 was determined. The amount of dissolution at 600 minutes was investigated.

[0148] The results are shown in Table 10 below:

[0149] Table 10 Results of Inherent Dissolution Tests for Various Inorganic Salts

[0150]

[0151] During the screening of inorganic salts of fluvatinib, three types of inorganic salts were found to be capable of salt formation: hydrochloride, sulfate, and hydrobromide. Studies of the physicochemical properties of these three salts revealed a surprising finding: fluvatinib hydrobromide crystal form III exhibits remarkably high dissolution characteristics, as shown in Table 10. Among the inorganic salt forms of fluvatinib, fluvatinib hydrobromide demonstrates an unexpectedly high dissolution rate.

Claims

1. A fluvatinib hydrobromide crystal form III, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values ​​of 7.36±0.2°, 14.61±0.2°, 18.21±0.2°, 20.71±0.2°, 23.12±0.2°, 25.83±0.2°, 28.11±0.2°, and 33.71±0.2°.

2. The fluvatinib hydrobromide crystal form III as described in claim 1 has the characteristic peaks shown in Figure 3 in its X-ray powder diffraction pattern.

3. A method for preparing fluvatinib hydrobromide crystal form III according to claim 1, comprising: Fluvatinib was mixed with an organic solvent to form a suspension, hydrobromic acid was added, and the mixture was stirred, filtered, and dried at 29-64°C to obtain fluvatinib hydrobromide crystal form III. The organic solvent was methanol or ethanol.

4. The method of claim 3, wherein the mass-to-volume ratio of fluvatinib to organic solvent is not greater than 50 mg / mL.

5. The method of claim 4, wherein the mass-to-volume ratio of fluvatinib to the organic solvent is 10-50 mg / mL.

6. The method as described in claim 3, wherein the stirring time is 30 min to 72 h.

7. A pharmaceutical composition comprising the fluvatinib hydrobromide crystal form III of claim 1 and pharmaceutically acceptable excipients.

8. Use of the fluvatinib hydrobromide crystal form III of claim 1 in the manufacture of a tumor-treating drug.

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