A crystalline form of fluvatinib or mesylate and a preparation method thereof

Abstract

The present invention discloses a crystalline form of fluvatinib or its mesylate and a preparation method thereof. The crystalline form I of fluvatinib has the characteristic diffraction peak shown in Figure 1. The crystalline form of fluvatinib mesylate is polymorphic and has seven crystalline forms, namely, forms I-VII. Among them, form III has the characteristic diffraction peak shown in Figure 9. These crystalline forms are suitable for the manufacturing process of fluvatinib mesylate preparations.

Description

[0001] This application is a divisional application of the application with application date of January 18, 2021, application number 202110060334.8, and invention name “A crystalline form of fluvatinib or mesylate and its preparation method”. Technical Field

[0002] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a crystalline form of fluvatinib or its mesylate and a preparation method thereof. Background Art

[0003] Hepatocellular carcinoma (HCC) has an insidious onset and mild early symptoms. By the time most patients seek medical treatment, the opportunity for surgery has been missed. Whether it is surgery, interventional therapy or chemotherapy, the treatment effect on liver cancer is still not very satisfactory. The current 5-year survival rate of liver cancer is still very low.

[0004] With the advancement of science and technology, targeted drugs for the treatment of HCC have emerged. Currently, targeted drugs for liver cancer mainly include epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VEGFR) antagonists, multikinase inhibitors, PI3K / Akt / mTOR signaling pathway inhibitors, hepatocyte growth factor receptor (Met) inhibitors, and TGFβ receptor inhibitors. Currently approved targeted TKI drugs mainly include sorafenib, lenvatinib, and regorafenib. Therefore, the treatment options are very limited.

[0005] CN109134365 discloses an active compound or pharmaceutically acceptable salt having multiple target effects on VEGFR types 1 to 3, fibroblast growth factor receptor types 1 to 3, RET, Kit, and PDGFR, and its chemical structure is as follows:

[0006]

[0007] The chemical name is 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, and the drug name is fluvatinib. This compound is highly active and offers a potential new treatment option for patients with liver and kidney tumors.

[0008] However, the present inventors have discovered that both the free base of fluvatinib and its pharmaceutically acceptable salts, particularly the mesylate salt, exhibit polymorphic forms. These polymorphic forms exhibit varying properties, such as stability, solubility, and drugability, which significantly impact drug quality control. Therefore, it is crucial to develop a stable and druggable crystalline form. Summary of the Invention

[0009] The object of the present invention is to provide a crystalline form of 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (fluvatinib as shown in Formula I) or its mesylate.

[0010]

[0011] The fluvatinib mesylate (also referred to as "fluvatinib mesylate", both referring to the same compound) is a compound represented by the following formula II:

[0012] .

[0013] The present invention provides a crystalline form of fluvatinib, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ values ​​of 11.60±0.2°, 16.72±0.2°, and 20.25±0.2°; further, the X-ray powder diffraction pattern also includes characteristic diffraction peaks at 2θ values ​​of 8.28±0.2°, 11.60±0.2°, 15.42±0.2°, 16.72±0.2°, 20.25±0.2°, 21.81±0.2°, 22.36±0.2°, and 24.08±0.2°.

[0014] The present invention provides a crystalline form of fluvatinib mesylate, wherein the X-ray powder diffraction pattern of the crystalline form has characteristic diffraction peaks at 2θ values ​​of 9.60±0.2°, 22.49±0.2° and 23.07±0.2°; further, the X-ray powder diffraction pattern of the crystalline form of fluvatinib mesylate has characteristic peaks at 2θ values ​​of 10.74±0.2°, 16.79±0.2°, 17.51±0.2°, 18.50±0.2°, 20.64±0.2°, 20.85±0.2°, 21.51±0.2°, 23.73±0.2°, 24.84±0.2°, 26.51±0.2°, 27.05±0.2°, 27.88±0.2°, 28.60±0.2° and 29.74±0.2°.

[0015] The present invention provides a crystalline form of fluvatinib mesylate, the X-ray powder diffraction pattern of which has the following characteristics: Figure 7 Characteristic diffraction peaks are shown.

[0016] The present invention provides a crystalline form of fluvatinib mesylate, wherein the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at 2θ values ​​of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°. Furthermore, the X-ray powder diffraction pattern thereof also has characteristic diffraction peaks at 2θ values ​​of 10.25±0.2°, 14.44±0.2°, 15.28±0.2°, 18.91±0.2°, 19.98±0.2°, 20.86±0.2°, 21.77±0.2°, 22.78±0.2°, and 24.98±0.2°.

[0017] The present invention provides a crystalline form of fluvatinib mesylate, the X-ray powder diffraction of which has the following characteristics: Figure 11 Characteristic peaks shown.

[0018] The present invention provides a crystalline form of fluvatinib mesylate, the X-ray powder diffraction of which has the following characteristics: Figure 12 Characteristic peaks shown.

[0019] The present invention provides a crystalline form of fluvatinib mesylate, the X-ray powder diffraction of which has the following characteristics: Figure 13 Characteristic peaks shown.

[0020] The present invention provides a crystalline form of fluvatinib mesylate, the X-ray powder diffraction of which has the following characteristics: Figure 14 Characteristic peaks shown.

[0021] On the other hand, the present invention provides a method for preparing a crystalline form of fluvatinib mesylate, comprising mixing fluvatinib mesylate with an organic solvent, stirring the mixture at a temperature greater than 20° C., filtering, and drying the obtained solid.

[0022] Preferred:

[0023] In the above method of the present invention, the temperature is greater than 20°C and less than 70°C.

[0024] In the above method of the present invention, the stirring time is at least 1 hour.

[0025] In the above method of the present invention, the stirring time is 2 to 48 hours.

[0026] In the above method of the present invention, the temperature is 20-30°C.

[0027] In the above method of the present invention, the organic solvent is selected from methanol, ethanol, acetone, THF, isopropanol, ethyl acetate, acetonitrile, cyclohexane, n-hexane, n-heptane, 1,4-dioxane, dichloromethane and any combination thereof.

[0028] More preferred:

[0029] In the above method of the present invention, the organic solvent is ethanol.

[0030] In the above method of the present invention, the temperature is 20-30° C., and the stirring time is at least 2 hours, or at least 12 hours, or at least 16 hours, or at least 24 hours, or 48 hours.

[0031] In the above method of the present invention, the temperature is greater than 30° C. and less than 70° C., and the stirring time is 1-3 hours.

[0032] In the above method of the present invention, the temperature is 20-30° C. and the stirring time is 1-2 hours.

[0033] In any of the methods described above of the present invention, the organic solvent is ethanol.

[0034] Optionally, in the above method of the present invention, the organic solvent may be a mixed solvent containing water, preferably, a mixed solvent of ethanol and water or THF and water.

[0035] The above method of the present invention can obtain different crystalline forms of fluvatinib mesylate by controlling the process.

[0036] In some specific embodiments, the following embodiments are also provided:

[0037] In one embodiment, a fluvatinib crystalline form I of the present invention is characterized in that: its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ values ​​of 11.60±0.2°, 16.72±0.2°, and 20.25±0.2°.

[0038] Furthermore, the fluvatinib crystalline form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ values ​​of 8.28±0.2°, 11.60±0.2°, 15.42±0.2°, 16.72±0.2°, 20.25±0.2°, 21.81±0.2°, 22.36±0.2° and 24.08±0.2°.

[0039] Preferably, the fluvatinib crystal form I has an X-ray powder diffraction pattern of Figure 1 Characteristic diffraction peaks are shown.

[0040] In some embodiments, the present invention provides a method for preparing fluvatinib Form I, comprising: dissolving fluvatinib in an organic solvent to form a suspension, stirring, and filtering to obtain Form I. Preferably, the organic solvent is selected from methanol, ethanol, acetone, THF, isopropanol, ethyl acetate, and any mixture thereof.

[0041] In one embodiment, the present invention provides a crystalline form I of fluvatinib mesylate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ values ​​of 9.60±0.2°, 22.49±0.2° and 23.07±0.2°.

[0042] Furthermore, the above-mentioned crystalline form I of fluvatinib mesylate also includes characteristic diffraction peaks at 2θ (±0.2°) values ​​of 10.74, 16.79, 17.51, 18.50, 20.64, 20.85, 21.51, 23.73, 24.84, 26.51, 27.05, 27.88, 28.60 and 29.74 in its X-ray powder diffraction.

[0043] Preferably, the fluvatinib mesylate crystal form I has an X-ray powder diffraction pattern of Figure 4 Characteristic diffraction peaks are shown.

[0044] In some embodiments, the present invention also provides a method for preparing fluvatinib mesylate crystal form I, comprising: dissolving fluvatinib in an organic solvent, adding methanesulfonic acid to react, and after the reaction is complete, heating at 20 to 30 O C, stirred for 1 to 2 hours, filtered and dried. Preferably, the organic solvent is selected from: methanol, ethanol, acetone, THF, isopropanol, ethyl acetate and any mixed solvents thereof. The drying is carried out under reduced pressure at a drying temperature of 40 to 50 O C.

[0045] In one embodiment, the present invention provides a crystalline form II of fluvatinib mesylate, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ (± 0.2°) values ​​of 4.88±0.2°, 6.93±0.2°, 9.77±0.2°, and 10.93±0.2°, and further includes an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ (± 0.2°) values ​​of 12.07, 14.81, 15.56, 17.72, 18.56, 19.74, 21.11, 21.73, 22.73, 24.68, 25.70, 6.19, and 27.49±0.2°.

[0046] Preferably, the crystalline form II of fluvatinib mesylate has an X-ray powder diffraction pattern as follows: Figure 7 Characteristic peaks shown.

[0047] In some embodiments, the present invention also provides a method for preparing fluvatinib mesylate crystal form II, comprising: reacting fluvatinib with mesylate in an organic solvent, and then O C and stirred for 2 hours, solid precipitated, filtered and dried.

[0048] In the above method of the present invention, the organic solvent includes but is not limited to methanol, ethanol, acetone, THF or isopropanol.

[0049] In another embodiment, the present invention provides a crystalline form III of fluvatinib mesylate, which has an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ values ​​of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°.

[0050] Furthermore, the above-mentioned crystalline form III of fluvatinib mesylate further includes an X-ray powder diffraction pattern having characteristic diffraction peaks at 2θ values ​​of 10.25±0.2°, 14.44±0.2°, 15.28±0.2°, 18.91±0.2°, 19.98±0.2°, 20.86±0.2°, 21.77±0.2°, 22.78±0.2°, and 24.98±0.2°.

[0051] Preferably, the crystalline form III of fluvatinib mesylate of the present invention has an X-ray powder diffraction pattern as follows: Figure 9 Characteristic diffraction peaks are shown.

[0052] In some embodiments, the present invention further provides a method for preparing fluvatinib mesylate crystalline form III, comprising: stirring fluvatinib mesylate in an organic solvent for at least 2 hours to obtain fluvatinib mesylate.

[0053] In some specific embodiments, the method for preparing fluvatinib mesylate Form III comprises dissolving fluvatinib mesylate in an organic solvent, stirring at 20-30° C. for at least 12 hours, preferably at least 16 hours, 24 hours or 48 hours, filtering, and drying the filter cake.

[0054] In some specific embodiments, the method for preparing fluvatinib mesylate Form III comprises dissolving fluvatinib mesylate in an organic solvent, stirring at 30-65° C. for 2-3 hours, filtering, and drying the filter cake to obtain fluvatinib mesylate.

[0055] In the above method of the present invention, the drying is performed under reduced pressure at a temperature of 40 to 50° C. The organic solvent is selected from ethanol, methanol, isopropanol, acetone, THF, cyclohexane, n-hexane, n-heptane, 1,4-dioxane, dichloromethane and ethyl acetate, preferably ethanol, acetone and ethyl acetate.

[0056] The present invention also provides a crystalline form IV of fluvatinib mesylate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ (±0.2°) values ​​of 6.22±0.2°, 10.59±0.2°, 11.58±0.2°, 14.41±0.2°, 17.93±0.2°, 20.32±0.2°, 23.58±0.2°, 24.09±0.2°, 24.59±0.2°, and 25.79±0.2°. Preferably, its X-ray powder diffraction pattern has the following characteristics: Figure 11 Characteristic diffraction peaks are shown.

[0057] The present invention provides a method for preparing crystalline form IV of fluvatinib mesylate, comprising dissolving fluvatinib mesylate in an ethanol / water mixed solvent system, stirring at 20-30° C. for 20-48 hours, filtering, and drying the filter cake under reduced pressure in a rotary evaporation chamber at 40-50° C. to obtain crystalline form IV of fluvatinib mesylate.

[0058] The present invention also provides a crystalline form V of fluvatinib mesylate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ values ​​of 4.81±0.2°, 10.64±0.2°, 10.99±0.2°, 16.00±0.2°, 20.50±0.2°, 21.10±0.2°, 24.59±0.2°, 25.57±0.2° and 26.46±0.2°. Preferably, its X-ray powder diffraction pattern has the following characteristics: Figure 12 Characteristic diffraction peaks are shown.

[0059] The present invention provides a method for preparing the crystalline form V of fluvatinib mesylate, comprising dissolving fluvatinib mesylate in a tetrahydrofuran / water mixed solvent system, stirring at 20-30° C. for 20-48 hours, filtering, and drying the filter cake under reduced pressure at 40-50° C. to obtain the crystalline form V of fluvatinib mesylate.

[0060] The present invention also provides a crystalline form VI of fluvatinib mesylate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ (±0.2°) values ​​of 5.61±0.2°, 9.98±0.2°, 10.61±0.2°, 16.84±0.2°, 20.14±0.2°, and 20.89±0.2°. Preferably, its X-ray powder diffraction pattern has the following characteristics: Figure 13 Characteristic diffraction peaks are shown.

[0061] The present invention provides a method for preparing Form VI of fluvatinib mesylate, comprising adding fluvatinib free base to a methanol solvent, and then adding methanesulfonic acid under stirring to react. The reaction solution is stirred at 20-30°C for 2-10 hours, preferably 4 hours, filtered, and the filter cake is dried under reduced pressure at 40-50°C to obtain Form VI of fluvatinib mesylate.

[0062] The present invention also provides a crystal VII of fluvatinib mesylate, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ values ​​of 5.57±0.2°, 6.17±0.2°, 9.93±0.2°, 10.56±0.2°, 14.34±0.2°, 16.81±0.2°, 17.76±0.2°, 20.10±0.2°, 20.81±0.2°, 24.85±0.2°, and 25.60±0.2°. Preferably, its X-ray powder diffraction pattern has the following characteristics: Figure 14 Characteristic peaks shown.

[0063] The present invention provides a method for preparing the crystalline form VII of fluvatinib mesylate, comprising dissolving the crystalline form VI of fluvatinib mesylate in an ethanol solvent, stirring at 20-30°C for 2-10 hours, filtering, and drying the filter cake under reduced pressure in a rotary oven at 40-50°C to obtain the crystalline form VII of fluvatinib mesylate.

[0064] The use of the above-mentioned fluvatinib crystalline form I and fluvatinib mesylate crystalline forms I, II, III, IV, V, VI, and VII of the present invention in the preparation of drugs for treating tumors, including but not limited to liver cancer, kidney cancer, gastric cancer, colorectal cancer, pancreatic cancer, lung cancer, etc.

[0065] The present invention also provides a pharmaceutical composition comprising an effective amount of the crystalline form of fluvatinib or its mesylate salt according to the present invention and a pharmaceutical excipient, wherein the crystalline form is selected from the group consisting of Form I of fluvatinib and Forms I, II, III, IV, V, VI, and VII of fluvatinib mesylate. Preferably, the crystalline form is Form I or Form III of fluvatinib mesylate.

[0066] The excipients in the composition 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 enhancers, etc. The excipients can be appropriately combined for use according to the requirements of different formulation forms of the composition.

[0067] 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, carboxymethyl cellulose calcium, 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, tragacanth gum, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and polyethylene glycol. The lubricant is selected from one or more of magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and colloidal silicon dioxide. The colorant is selected from pharmaceutical colorants such as ferric oxide, yellow ferric oxide, carmine, caramel, β-carotene, titanium oxide, talc, sodium riboflavin phosphate, and yellow aluminum lake. The flavoring agent is selected from cocoa powder, menthol, aromatic powder, peppermint oil, borneol, and cinnamon powder. The surfactant is selected from octadecyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, glycerol monostearate, sucrose fatty acid esters, and glycerol fatty acid esters. The solubilizer is selected from polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and Tween 80.

[0068] The above-mentioned antioxidants may be sulfites, ascorbic acid, α-tocopherol, and the like.

[0069] The composition of the present invention can be in the form of tablets, powders, granules, capsules, syrups, lozenges, inhalants and other oral preparations, or injections.

[0070] The oral preparation may be coated on its surface as needed.

[0071] The above-mentioned injections may be added with appropriate additives, such as emulsifiers, surfactants, solubilizers, suspending agents, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption enhancers, etc.

[0072] When the crystal of the present invention is used as a medicine, the dosage varies depending on the symptoms, age, and administration method. Generally, adults are given 100 μg to 10 g per day, which can be administered once or several times.

[0073] The crystalline 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 by angiogenesis inhibition, such as angiogenesis inhibitors, antitumor agents, hemangioma therapeutic agents, and cancer metastasis inhibitors.

[0074] In addition, when the above-mentioned composition of the present invention 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, blood cancer or ovarian cancer, and is particularly preferably liver cancer, thyroid cancer, gastric cancer, colorectal cancer, prostate cancer, lung cancer or kidney cancer.

[0075] The crystal form of the present invention has not been reported previously. Fluvatinib was tested for stability under high temperature and humidity conditions for two weeks and three months, revealing no crystal transformation and no significant change in the impurity content. Furthermore, no crystal transformation occurred after stirring for at least two days in organic solvents such as methanol, ethanol, acetone, THF, isopropanol, ethyl acetate, and mixtures thereof with water, demonstrating its stability in solvents including water, making it suitable for formulation processing.

[0076] The fluvatinib mesylate crystalline form of the present invention exhibits a typical polymorphic morphology. Seven crystalline forms have been discovered, of which Forms I and III exhibit relatively good specific properties. Stability tests conducted under harsh experimental conditions of high temperature and humidity for at least half a month and three months revealed that Forms I and III of fluvatinib mesylate did not undergo crystal transformation, and the contents of related substances remained unchanged compared to before the tests, demonstrating physical and chemical stability. Form III, in particular, exhibited favorable formulation characteristics, such as good flowability and hygroscopicity.

[0077] When fluvatinib mesylate Forms II, III, VI, and VII were stirred in ethanol for 2-4 days, Forms II, VI, and VII of fluvatinib mesylate all transformed into Form III, while Form III did not undergo transformation under these conditions. This indicates that Form III has greater stability than Forms II, VI, and VII, making it more suitable for formulation processing. It also has superior solubility to lenvatinib. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 XRPD pattern of Form I of Fluvatinib,

[0079] Figure 2 DSC diagram of Form I of Fluvatinib,

[0080] Figure 3 TGA diagram of Form I of Fluvatinib,

[0081] Figure 4 XRPD pattern of Form I of fluvatinib mesylate,

[0082] Figure 5 DSC and TGA diagrams of Form I of fluvatinib mesylate,

[0083] Figure 6 Hygroscopicity DVS diagram of Form I of fluvatinib mesylate,

[0084] Figure 7 XRPD pattern of Form II of fluvatinib mesylate,

[0085] Figure 8 DSC and TGA diagrams of Form II of fluvatinib mesylate,

[0086] Figure 9 XRPD pattern of Form III of fluvatinib mesylate,

[0087] Figure 10 DSC and TGA diagrams of Form III of fluvatinib mesylate,

[0088] Figure 11 XRPD pattern of Form IV of fluvatinib mesylate,

[0089] Figure 12 XRPD pattern of Form V of fluvatinib mesylate,

[0090] Figure 13 XRPD pattern of Form VI of fluvatinib mesylate,

[0091] Figure 14 XRPD pattern of Form VII of fluvatinib mesylate,

[0092] Figure 15 The XPRD pattern of the sample after the crystal transformation experiment of Form I of Fluvatinib in Example 9,

[0093] Figure 16 XPRD patterns of the sample of Form I of fluvatinib mesylate of Example 10 before and after DVS test,

[0094] Figure 17 The XRPD pattern of fluvatinib mesylate form III obtained by the crystal transformation experiment in Example 11 is as follows:

[0095] Figure 18 The XRPD pattern of the high temperature suspension crystal experiment of Example 11 is as follows:

[0096] Figure 19 DVS spectrum of fluvatinib mesylate form III,

[0097] Figure 20 XRPD patterns of fluvatinib mesylate form I before and after tableting and after 6 months of storage.

[0098] Figure 21XRPD patterns of fluvatinib mesylate Form III before and after tableting and after 6 months of storage. DETAILED DESCRIPTION

[0099] The following examples are merely representative and are used to further illustrate or understand the spirit of the present invention, but are not intended to limit the scope of the present invention in any way. Any simple modifications within the spirit of the present invention also fall within the scope of the present invention.

[0100] In this paper, the determination of crystal parameters, such as X-ray powder diffraction (XRPD), DSC and TGA, are conventional methods in the field. The specific detection instruments used are as follows: Based on the errors caused by the instruments and the detection, the error range of the detection results such as XRPD is + 0.2.

[0101] X-ray powder diffractometer (XRPD) method

[0102] Instrument model: Bruker D8 advance X-ray diffractometer

[0103] Test method: Approximately 10 to 20 mg of sample was used for XRPD detection.

[0104] Detailed XRPD parameters are as follows:

[0105] Fluorescent tube: Cu, kα, (λ=1.54056Ǻ).

[0106] Light tube voltage: 40 kV, light tube current: 40 mA

[0107] Divergence slit: 0.60 mm

[0108] Detector slit: 10.50 mm

[0109] Anti-scatter slit: 7.10 mm

[0110] Scan range: 4-40 degrees

[0111] Step diameter: 0.02 deg

[0112] Step size: 0.12 seconds.

[0113] Differential Scanning Calorimetry (DSC)

[0114] Test conditions: About 0.5 to 1 mg of sample is used for DSC detection

[0115] Method: The samples were heated from room temperature to 300°C or 350°C at a heating rate of 10°C / min under 50 mL / min N2.

[0116] Thermogravimetric Analyzer (TGA)

[0117] Test conditions: About 2 to 5 mg of sample is used for TGA testing

[0118] Method: The sample was heated at a rate of 10°C / min from room temperature to 20% weight loss or 300°C under 25 mL / min N2.

[0119] Dynamic moisture sorption (DVS)

[0120]

[0121] The sample is placed on a glass slide and observed after the coverslip is spread. Objective lens: 20 / 50 times.

[0122] Example 1 Preparation of Fluvatinib Crystal Form I

[0123] Fluvatinib free base of formula I (50 mg, 112.40 umol) was added to EtOH (2 mL), stirred at 15-20°C for 12 h, filtered to obtain a filter cake, which was added to 200 mL of acetone, stirred at 15-20°C for 12 h, filtered, and the filter cake was dried under reduced pressure at 40°C to obtain fluvatinib solid. XRPD analysis showed that the results were as follows: Figure 1 , named as Fluvatinib Form I, and its DSC and TGA test results are shown in Figure 2 and Figure 3 .

[0124] Example 2 Preparation of Fluvatinib Mesylate (also referred to herein as "Fluvatinib Mesylate") Crystalline Form I

[0125] 4-[3-chloro-4-(cyclopropylaminocarbonylamino)-2-fluoro-phenoxy]-7-methoxy-quinoline-6-carboxamide, i.e., fluvatinib (0.5 g, 1.12 mmol) was added to EtOH (10 mL) solvent and heated to 55-60°C. Methanesulfonic acid (108.02 mg, 1.12 mmol, 80.02 μL, 1 eq) was added to the reaction flask while stirring at the same temperature. The reaction solution became clear. The reaction solution was cooled to 20-30°C and stirred at the same temperature for 1 hour. A brown solid precipitated and was filtered under reduced pressure. The filter cake was rinsed with ethanol (2 mL*2) and dried under reduced pressure at 40-50°C to obtain a solid product, named Form I of fluvatinib mesylate. The product was detected by XRPD, DSC, and TGA. The XRPD test results are shown in Table 1 and Figure 4, DSC and TGA test results are shown in Figure 5 Melting point is about 232-237 o C.

[0126] Table 1 XRPD diffraction data of fluvatinib mesylate form I

[0127] .

[0128] Example 3 Preparation of Fluvatinib Methanesulfonate Form II

[0129] Fluvatinib free base (55 g) was added to EtOH (1.1 L) and heated to 55-60°C. Methanesulfonic acid (11.88 g) was added to the reaction flask while stirring (300 rpm). After the reaction, the temperature was lowered to 10-20°C and stirred at this temperature for 2 hours. A brown solid precipitated and was filtered under reduced pressure. The filter cake was rinsed with ethanol (50 mL*2) and dried under reduced pressure at 40-50°C to obtain the product, a brown solid crystalline form (52.5 g). The product was then tested by XRPD, TGA, and DSC. The results are shown in Table 2. Figure 7 and Figure 8 , named Form II of fluvatinib mesylate.

[0130] Table 2 XRPD diffraction data of fluvatinib mesylate form II

[0131] .

[0132] Example 4 Preparation of Fluvatinib Methanesulfonate Form III

[0133] Method 1: Add 100 g of fluvatinib (free) to MeOH (2.2 L) solvent, add methanesulfonic acid (16.64 mL) to the reaction flask under stirring, and then stir at 20-30°C for 4 h. A brown solid precipitates, which is filtered under reduced pressure. The filter cake is rinsed with ethanol (50 mL*2) to obtain a filter cake that is dried under reduced pressure at 40-50°C to obtain a solid product (106.2 g). The solid product (105 g) is added to a reaction flask containing 1 L of ethanol, stirred at 20-30°C for 48 h, and filtered under reduced pressure to obtain a filter cake. The filter cake is dried under reduced pressure at 40-50°C to obtain a solid crystalline product. The product is subjected to XRPD, TGA, and DSC detection. The results are shown in Table 3. Figure 9 and Figure 10 XRPD data showed that the product was Form III of fluvatinib mesylate. The melting point was about 220-226 o C.

[0134] Method 2: Fluvatinib mesylate crystal form II (52 g) obtained in Example 3 was added to 420 mL of ethanol, stirred at 20-30°C with mechanical stirring (300 rpm) for 16 h, filtered under reduced pressure, and the filter cake was dried under reduced pressure at 40-50°C to obtain the product, which was then subjected to XRPD analysis. The results showed that the 2θ value of the XRPD was consistent with that of the product. Figure 9 The results are basically consistent, indicating that the obtained crystal form is Form III.

[0135] Method 3: Take 0.5g of fluvatinib free base, add it to 10mL of ethanol, add 0.1mL of methanesulfonic acid, suspend it at 40℃ for 3-4 hours, centrifuge and filter, and dry it in an oven at 40℃. After testing, the prepared product is mesylate crystal form III. Its XRPD 2θ value is the same as Figure 9 Basically the same.

[0136] Method 4: 0.9 g of fluvatinib mesylate was added to a reaction flask containing 7.2 mL of ethanol under stirring. After the addition was complete, the temperature was raised to 55-65°C and stirred at this temperature for about 2-3 hours. The filter cake was filtered under reduced pressure and rinsed with ethanol (0.5 mL*2). The filter cake was dried under vacuum at 45 degrees to obtain the product. The XRPD 2θ value of the product was the same as Figure 9 Basically the same.

[0137] Table 3 XRPD data of fluvatinib mesylate form III

[0138] .

[0139] Example 5 Preparation of Fluvatinib Methanesulfonate Form IV

[0140] Approximately 1.0 g of fluvatinib mesylate was weighed and added to a 4 mL ethanol / 4 mL water (1:1) mixed solvent system to form a suspension. The suspension sample was placed on a magnetic stirrer (20-30°C) and stirred. After 48 hours, a brown suspension was obtained. The suspension was filtered under reduced pressure, and the filter cake was dried under reduced pressure at 40-50°C to obtain 625 mg of a dry solid crystalline product with a yield of 62.5%. The product was sent for XRPD analysis, and the results are shown in Tables 4 and 5 below. Figure 11 , which is the crystalline form IV of fluvatinib mesylate.

[0141] Table 4 XRPD data of Form IV of Fluvatinib mesylate

[0142] .

[0143] Example 6 Preparation of Fluvatinib Methanesulfonate Form V

[0144] Approximately 1.0 g of fluvatinib mesylate was weighed and added to a 4 mL tetrahydrofuran / 4 mL water (1:1) mixed solvent system to form a suspension. The suspension sample was stirred on a magnetic stirrer at 20-30°C. After 48 hours, a brown suspension was obtained. The filter cake was filtered and dried under reduced pressure at 40-50°C to obtain 430 mg of dry sample with a yield of 43.00%. The sample was sent for XRPD analysis, and the results are shown in Tables 5 and 6 below. Figure 12 , the sample is Form V of fluvatinib mesylate.

[0145] Table 5 XRPD data of Form V of Fluvatinib mesylate

[0146] .

[0147] Example 7 Preparation of Fluvatinib Methanesulfonate Form VI

[0148] Approximately 2.0 g of fluvatinib free base was weighed and added to a reaction flask containing methanol to form a suspension. The suspension was stirred at 20-30°C. 0.32 mL of methanesulfonic acid was added and the reaction mixture was stirred at 20-30°C for 4 h. The suspension was filtered and the filter cake was dried under reduced pressure at 40-50°C. The dried sample was then sent for XRPD analysis. The results are shown in Tables 6 and Figure 13 The sample is Form VI of fluvatinib mesylate.

[0149] Table 6 XRPD data of Form VI of Fluvatinib mesylate

[0150] .

[0151] Example 8 Preparation of Fluvatinib Methanesulfonate Form VII

[0152] About 0.2 g of fluvatinib mesylate form VI of Example 7 was weighed and added to an ethanol solvent to form a suspension. The suspension was magnetically stirred at 20-30 ° C. After 4 h, it was filtered, and the filter cake was dried under reduced pressure at 40-50 ° C. The obtained dry sample was sent for XRPD detection. The results are shown in Table 7 and Figure 14 The sample is Form VII of fluvatinib mesylate.

[0153] Table 7 XRPD data of Form VII of Fluvatinib mesylate

[0154] .

[0155] Example 9 Stability Study of Fluvatinib Form I

[0156] The crystalline form I of fluvatinib was placed in an organic solvent and an aqueous organic solvent and stirred at 40° C. for 2 days to investigate whether there was crystal transformation.

[0157] Several portions of approximately 30 mg of fluvatinib Form I were weighed and placed in separate glass bottles. Appropriate amounts of a single organic solvent or aqueous solvent mixture (see Table 8) were added to form suspensions. The suspension samples were placed on a magnetic stirrer (40°C) for a stirring test. After stirring the suspension samples at 40°C for 2 days, they were filtered. The filter cake samples were then dried in a vacuum oven (40°C) overnight. The dried samples were then subjected to XRPD analysis (see Table 8 and ). Figure 15 The results showed that Form I of fluvatinib was stable in various solvents (especially in solvents containing water) without crystal transformation, and was suitable for industrial production of its preparations.

[0158] Table 8 Solvents and crystal forms after stirring for 2 days

[0159] .

[0160] Example 10 Stability Study of Form I of Fluvatinib Mesylate

[0161] The crystalline form I of fluvatinib mesylate was stored in acetone, ethanol and ethyl acetate to investigate whether there was crystal transformation.

[0162] Three portions of approximately 50 mg of fluvatinib mesylate Form I were weighed and added to a reaction flask containing appropriate amounts of acetone, ethanol, and ethyl acetate. The suspension sample was placed on a magnetic stirrer and stirred at room temperature for 10 h. The filter cake was then dried under reduced pressure at 40-50°C. The resulting dried sample was subjected to XRPD analysis. The XRPD 2θ values ​​were consistent with the results. Figure 4 The results were basically consistent (within the error range). Conclusion: Fluvatinib mesylate Form I was maintained under the conditions of single solvents ethanol, acetone, and ethyl acetate. This indicates that Form I of fluvatinib mesylate is stable.

[0163] At the same time, the dynamic moisture absorption test of the crystalline form I of fluvatinib mesylate was carried out, and the water content was detected by DVS. The mesylate absorbed moisture and gained 1.3% under the conditions of 25°C / 80%RH (see Figure 6 ), the sample is slightly hygroscopic. After completing the DVS test, the sample crystal form did not change. Figure 16 This indicates again that Form I of fluvatinib mesylate has good stability.

[0164] Example 11 Stability Study of Form III of Fluvatinib Mesylate

[0165] 1. Investigate the stability of Form III of fluvatinib mesylate in air (oxygen)

[0166] The stability of Form III of fluvatinib mesylate was investigated by exposing Form III to air and oxygen. The results are shown in Table 9. The results indicate that the mesylate was stable when exposed to air at both 20-30°C and 60°C. The mesylate exhibited stable antioxidant properties, with no significant generation of new impurities.

[0167] Table 9 Stability data of Form III of fluvatinib mesylate in oxygen

[0168] .

[0169] 2. Is there a crystal transformation phenomenon in organic solvents?

[0170] The stability of the crystal form of fluvatinib mesylate in ethanol was investigated to determine whether crystal transformation occurred.

[0171] Approximately 0.15 g each of Form II, Form III, Form VI, and Form VII of fluvatinib mesylate were weighed and added to a reaction flask containing ethanol. The mixture was magnetically stirred at room temperature for 2 days. The mixture was filtered, and the filter cake was dried under reduced pressure at 40-50°C. XRPD analysis of the resulting dried sample revealed that all the results were Form III, indicating that Form III did not undergo crystal transformation, while Form II, Form VI, and Form VII did undergo crystal transformation, and the transformation to Form III was as follows: Figure 17 The results show that the crystalline form III of fluvatinib mesylate has good stability, is particularly suitable for and adapts to the processing of preparations, and is particularly suitable for preparing fluvatinib mesylate tablets or granules using a granulation and tableting process containing ethanol as a binder or wetting agent.

[0172] 3. Stability Study of Fluvatinib Mesylate Form III in Various Organic Solvents

[0173] Fluvatinib mesylate salt form III was subjected to a high temperature suspension experiment (50°C). The experiment was conducted to investigate whether fluvatinib mesylate salt form III has a crystal transformation phenomenon in different types of commonly used organic solvents and whether it is stable. Specifically, 12 organic solvents and water in Table 10 below were used to suspend fluvatinib mesylate salt form III in 12 organic solvents and water. The suspension temperature was 50 degrees, the suspension amount was about 25 mg, the solvent was 1 mL, and the suspension time was 24 hours. The experimental conditions and results are shown in Table 10 below. The solids after suspension in the organic solvent showed the 2θ characteristics of form III by XRPD detection, as shown in Table 10. Figure 18 .

[0174] Table 10 High temperature suspension test and results

[0175] .

[0176] Example 12 Investigation of the Hygrothermal Stability of Fluvatinib Mesylate Crystalline Form

[0177] Fluvatinib mesylate crystalline forms I, III, IV, V, VI, and VII of the present invention were subjected to harsh environments to investigate their stability. The conditions included: high temperature and high humidity conditions: 25°C, 92.5% RH, for 7 days; 40°C, 75% RH, for 14 days; and 60°C, for 14 days. XRPD analysis was then performed on the investigated samples, and the results are shown in Table 11.

[0178] Table 11 Results of the wet heat stability test of fluvatinib mesylate crystal

[0179] .

[0180] The results in Table 11 show that fluvatinib mesylate Forms I and III did not undergo crystal transformation under high temperature and high humidity conditions, demonstrating good stability. However, mevatinib mesylate Forms V, VI, and VII underwent crystal transformation under high temperature and high humidity conditions, demonstrating instability to high temperature and high humidity.

[0181] Example 13 Hygroscopicity Investigation

[0182] The dynamic moisture tester (DVS) was used to test the fluvatinib mesylate form III at 25 o C, hygroscopicity under humidity conditions of 0-90% RH. Figure 19 .

[0183] Figure 19 The results showed that the moisture absorption weight of fluvatinib mesylate form III was 0.44%, showing low hygroscopicity and stability to moisture.

[0184] Example 14 Preparation

[0185]

[0186] The prescribed amount of fluvatinib mesylate crystal form, anhydrous lactose, and direct-compressed starch were mixed, and magnesium stearate was added and mixed, and then tablets were prepared by direct tableting method, each tablet weighing 200 mg.

[0187] The prepared tablets were sampled before and after tableting and o C. After being placed in a 75% RH environment for 6 months, samples were taken for XRPD testing. The results are shown in the figure. Figure 20 and 21In the figure, A, B, and C represent the XRPD patterns of the crystalline form before tableting, after tableting, and after the tablets were stored for 6 months, respectively. Comparison of the test patterns with the XRPD patterns of the corresponding API crystalline forms revealed that neither fluvatinib mesylate Form I nor fluvatinib mesylate Form III underwent crystal transformation during tablet preparation or after the tablets were stored for 6 months.

[0188] The above test results show that fluvatinib mesylate crystal forms I and III remain stable during the formulation process, especially in high temperature and high humidity environments, demonstrating the excellent stability characteristics of crystal forms I and III.

Claims

1. A crystalline form III of fluvatinib mesylate, having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2θ values ​​of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°.

2. The crystalline form III according to claim 1, further comprising an X-ray powder diffraction pattern having characteristic diffraction peaks at 2θ values ​​of 10.25 ± 0.2°, 14.44 ± 0.2°, 15.28 ± 0.2°, 18.91 ± 0.2°, 19.98 ± 0.2°, 20.86 ± 0.2°, 21.77 ± 0.2°, 22.78 ± 0.2°, and 24.98 ± 0.2°.

3. A method for preparing the fluvatinib mesylate crystalline form III according to claim 1 or 2, comprising mixing fluvatinib mesylate with an ethanol solvent, stirring the mixture at a temperature of 20°C to 30°C for 16 to 48 hours, or suspending the mixture at a temperature of 40°C for 3 to 4 hours, or stirring the mixture at 55 to 65°C for 2 to 3 hours, filtering, and drying the obtained solid.

4. A pharmaceutical composition comprising the crystalline form III of fluvatinib mesylate according to claim 1 and a pharmaceutically acceptable excipient.

5. Use of the composition of claim 4 in the manufacture of drugs for treating tumors.

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