A crystal form of a tyrosine kinase inhibitor and a preparation method thereof

Abstract

The present invention discloses a crystalline form LX-I of a tyrosine kinase inhibitor, pesidatinib hydrochloride, and a preparation method thereof. The pesidatinib hydrochloride crystalline form LX-I of the present invention has an X-ray powder diffraction pattern represented by 2θ angles at 6.6±0.2°, 12.2±0.2°, 16.0±0.2°, 18.4±0.2°, 19.8±0.2° and 20.8±0.2°, and a differential scanning calorimetry pattern has an endothermic peak at 234.6±5°C. The crystalline form has good stability, solubility and fluidity, and its preparation process is simple and controllable, and has good prospects for drug development.

Description

Technical Field

[0001] The present invention relates to a medicine and a preparation method thereof, and in particular to a crystal form of tyrosine kinase inhibitor pesidatinib hydrochloride and a preparation method thereof. Background Art

[0002] Pexidartinib is a small molecule tyrosine kinase inhibitor that inhibits colony stimulating factor receptor (CSF1R). Overexpression of CSF1R ligands promotes cell proliferation and accumulation in the synovium. In vitro, Pexidartinib inhibits the proliferation of cell lines that depend on CSF1R and ligand-induced CSF1R autophosphorylation. Pexidartinib can also inhibit the proliferation of CSF1R-dependent cell lines in vivo. In addition, Pexidartinib can also inhibit proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 (FLT3) with internal tandem duplication (ITD) mutations. At present, the disease is generally treated clinically by surgical resection, and surgical treatment of this disease may lead to worsening of functional impairment and serious complications. And because TGCT has many types and generally occurs in bone tissue and joints, new interventional therapies are urgently needed in the clinic. Its chemical structure is as follows.

[0003]

[0004] Polymorphism or polymorphism is a unique property of certain molecules and molecular combinations. The same molecule may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility, stability, thermal properties, mechanical properties, purification ability, X-ray diffraction spectra, infrared absorption spectra, Raman spectroscopy and solid-state nuclear magnetic resonance, etc. One or more analytical detection methods can be used to distinguish different crystal forms of the same molecule or molecular combination.

[0005] The discovery of new crystalline forms of active pharmaceutical ingredients (including anhydrates, hydrates, and solvates) may produce more processing advantages or provide substances with better physical and chemical properties, such as better bioavailability, storage stability, easy processing, easy purification, or serve as intermediate crystalline forms that promote conversion to other crystalline forms. New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of drugs. It expands the raw material forms available in pharmacy, such as improving solubility, improving shelf life, and being easier to process.

[0006] Different crystal forms of solid chemical drugs can cause different solubility and stability, thus affecting the absorption and bioavailability of the drug, and leading to differences in clinical efficacy. The clinical form of pegidatinib is monohydrochloride. The crystal forms of PLX3397 monohydrochloride were first reported in patent WO2016179415A1, which are crystal forms A, B, C, and D. Among them, crystal form A transforms into crystal form C at 80°C in 7 days, crystal form B is an impure crystal form mixed with crystal form C, and crystal form D is a methanol solvate, which is not suitable for direct use in product development. Crystal form C is the only crystal form suitable for drug development.

[0007] Therefore, it is necessary to conduct a comprehensive and systematic polymorph screening of pecidinib hydrochloride and select a crystalline form with more beneficial properties for the development of pecidinib hydrochloride products.

[0008] The inventors of the present invention surprisingly discovered a hydrochloride crystal form LX-I of pemidatinib hydrochloride during the research process. Crystal form LX-I has better solubility and larger particle size than the crystal form C of pemidatinib hydrochloride provided by the present invention, which is conducive to the separation of products in the subsequent production process, and has good stability, especially better fluidity than the crystal form of the prior art, providing a better choice for the preparation of pharmaceutical preparations containing pemidatinib hydrochloride, and has very important value for drug development. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the defects of the crystal form of peicidinib hydrochloride in the prior art, and to provide a crystal form of peicidinib hydrochloride and a preparation method thereof. The crystal form of peicidinib hydrochloride of the present invention has good stability, high solubility, good fluidity, simple preparation, is suitable for industrial production and preparation production, and has good drug development prospects.

[0010] The present invention solves the above technical problems through the following technical solutions:

[0011] A pesidatinib hydrochloride crystal form LX-I, whose chemical formula is shown in formula (I):

[0012]

[0013] The crystal form is an anhydrous crystal form, and its X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.6±0.2°, 12.2±0.2°, 16.0±0.2°, 18.4±0.2°, 19.8±0.2° and 20.8±0.2°, and its differential scanning calorimetry pattern has an endothermic peak at 234.6±5°C.

[0014] The relative intensities of the interplanar spacing and peak heights of the X-ray powder diffraction pattern expressed in 2θ angles are shown below:

[0015]

[0016] Pesidatinib hydrochloride crystal form LX-I has the instructions attached Figure 1 The X-ray powder diffraction pattern shown, and / or, with the specification attached Figure 2 The differential scanning calorimetry curve shown, and / or, with the instructions attached Figure 3 Thermogravimetric analysis curve shown.

[0017] Pecidinib hydrochloride crystal form LX-I is prepared by the following method: dissolving pcidinib hydrochloride in ethanol: water (V: V) = 5: 1 at 40-60° C., controlling the concentration to be 100 mg / ml-150 mg / ml, slowly dropping an anti-solvent, controlling the dropping time to be 30-60 min, and controlling the volume ratio of ethanol: water (V: V) = 5: 1 (good solvent) to the anti-solvent to be 1: 5, to obtain pcidinib hydrochloride anhydrous crystal form LX-I;

[0018] The anti-solvent is selected from one or more of isopropyl ether, n-heptane, water or methyl tert-butyl ether.

[0019] As a preferred embodiment, the anti-solvent is water. By selecting water as the anti-solvent, the activity of ethanol: water (V:V) = 5:1 is reduced, so that the supersaturation is slowly released to obtain large-particle crystal habits. Using water as a poor solvent can save solvent costs, and has the advantages of simple storage and simple waste liquid treatment.

[0020] The X-ray powder diffraction pattern of the crystalline form LX-II of pesidatinib hydrochloride expressed in 2θ angles has diffraction peaks at 6.9±0.2°, 12.8±0.2°, 13.6±0.2°, 16.2±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 24.1±0.2°, 25.3±0.2°, 26.9±0.2° and 28.7±0.2°.

[0021] The relative intensities of the interplanar spacing and peak heights of the X-ray powder diffraction pattern expressed in 2θ angles are shown below:

[0022]

[0023]

[0024] Pesidatinib hydrochloride crystal form LX-II has the instructions attached Figure 4 The X-ray powder diffraction pattern shown and / or the specification sheet Figure 5 The differential scanning calorimetry curve shown, and / or, with the instructions attached Figure 6 Thermogravimetric analysis curve shown.

[0025] Preparation method of pecidinib hydrochloride crystal form LX-II: dissolve pecidinib hydrochloride in a mixed solvent with a volume ratio of THF and water of 10:1 at 40-60°C, and quickly cool to 0 to -10°C to obtain a solid powder which is pecidinib hydrochloride crystal form LX-II.

[0026] The X-ray powder diffraction pattern of peicidinib hydrochloride form LX-III, expressed in 2θ angles, has diffraction peaks at 6.4±0.2°, 15.7±0.2°, 18.4±0.2°, 19.2±0.2°, 22.0±0.2°, 22.6±0.2°, 23.2±0.2°, 23.6±0.2°, 25.2±0.2°, 25.8±0.2° and 26.7±0.2°.

[0027] The relative intensities of the interplanar spacing and peak heights of the X-ray powder diffraction pattern expressed in 2θ angles are shown below:

[0028] serial number 2θ angle Interplanar spacing Relative Strength 1 6.4 13.9 32.7％ 2 15.7 5.6 19.0％ 3 18.4 4.8 100.0％ 4 19.2 4.6 24.8％ 5 22.0 4.0 42.6％ 6 22.6 3.9 16.5％ 7 23.2 3.8 22.9％ 8 23.6 3.8 15.7％ 9 25.2 3.5 22.0％ 10 25.8 3.5 18.3％ 11 26.7 3.3 29.2％

[0029] Pesidatinib hydrochloride crystal form LX-III has the instructions attached Figure 7 The X-ray powder diffraction pattern shown and / or the specification sheet Figure 8 The differential scanning calorimetry curve shown, and / or, with the instructions attached Fig. 9 Thermogravimetric analysis curve shown.

[0030] Preparation method of pecidinib hydrochloride crystal form LX-III: dissolve pecidinib hydrochloride C in a mixed solvent of acetic acid and water in a volume ratio of 1:2 at 40°C, and quickly cool to 0 to -10°C to obtain a solid powder which is pecidinib hydrochloride crystal form LX-III.

[0031] The X-ray powder diffraction pattern of the crystalline form LX-IV of pesidatinib hydrochloride expressed in 2θ angles has diffraction peaks at 6.0±0.2°, 11.5±0.2°, 13.5±0.2°, 15.8±0.2°, 17.5±0.2°, 18.1±0.2°, 18.9±0.2°, 20.5±0.2°, 23.8±0.2°, 24.5±0.2° and 24.5±0.2°.

[0032] The relative intensities of the interplanar spacing and peak heights of the X-ray powder diffraction pattern expressed in 2θ angles are shown below:

[0033] serial number 2θ angle Interplanar spacing Relative Strength 1 6.0 14.7 24.1％ 2 11.5 7.7 26.4％ 3 13.5 6.6 28.5％ 4 15.8 5.6 62.5％ 5 17.5 5.1 75.8％ 6 18.1 4.9 27.1％ 7 18.9 4.7 100.0％ 8 20.5 4.3 34.0％ 9 22.8 3.9 33.7％ 10 23.8 3.7 26.8％ 11 24.5 3.6 21.0％

[0034] Pesidatinib hydrochloride crystal form LX-IV has the instructions attached Fig.10 The X-ray powder diffraction pattern shown and / or the specification sheet Fig.11The differential scanning calorimetry curve is shown.

[0035] The preparation method of the pecidinib hydrochloride crystal form LX-IV is as follows: the pecidinib hydrochloride is dissolved in a mixed solvent of 1.4-dioxane and water in a volume ratio of 5:1 at 40° C., and its concentration is controlled to be 100 mg / ml. The solid powder obtained by rapid volatilization at room temperature is the pecidinib hydrochloride crystal form LX-IV.

[0036] Compared with the prior art, the crystal form prepared by the present invention has the following advantages:

[0037] 1. Good stability and easy storage, which can avoid the risk of crystal transformation during drug development or production, avoid changes in bioavailability and efficacy, and have good prospects for drug development;

[0038] 2. Low hygroscopicity, which is conducive to storage and transportation;

[0039] 3. High solubility, which can improve bioavailability in the body and has good drug development prospects;

[0040] 4. The preparation process is simple, the preparation steps of crystal form LX-I are short, the yield is high, the solvent composition is simple and the cost is low, and the waste liquid treatment is simple, which greatly improves the production efficiency and the quality is controllable, and can be mass-produced;

[0041] 5. The crystallization process is prepared by the dissolution method, which has the advantages of short process cycle and low energy consumption compared with other crystallization processes.

[0042] 6. Good fluidity, which is conducive to the development of formulation process. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The X-ray powder diffraction pattern of the crystalline form LX-I of the pesidatinib hydrochloride prepared in Example 1;

[0044] Figure 2 is a differential scanning calorimetry curve of the pesidatinib hydrochloride crystal form LX-I prepared in Example 1;

[0045] Figure 3 This is a thermogravimetric analysis curve of the pesidatinib hydrochloride crystal form LX-I prepared in Example 1;

[0046] Figure 4 The X-ray powder diffraction pattern of the crystalline form LX-II of the pesidatinib hydrochloride prepared in Example 6;

[0047] Figure 5 is a differential scanning calorimetry curve of the pesidatinib hydrochloride crystal form LX-II prepared in Example 6;

[0048] Figure 6This is a thermogravimetric analysis curve of the pesidatinib hydrochloride crystal form LX-II prepared in Example 6;

[0049] Figure 7 The X-ray powder diffraction pattern of the crystalline form LX-III of the pesidatinib hydrochloride prepared in Example 7;

[0050] Figure 8 is a differential scanning calorimetry curve of the pesidatinib hydrochloride form LX-III prepared in Example 7;

[0051] Fig. 9 This is a thermogravimetric analysis curve of the pesidatinib hydrochloride form LX-III prepared in Example 7;

[0052] Fig.10 The X-ray powder diffraction pattern of the crystalline form LX-IV of the pesidatinib hydrochloride prepared in Example 8;

[0053] Fig.11 is a differential scanning calorimetry curve of the pesidatinib hydrochloride crystal form LX-IV prepared in Example 8; DETAILED DESCRIPTION

[0054] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0055] The reagents and methods used in the examples of the invention are all conventional reagents and methods in the art. It should be clear to those skilled in the art that, hereinafter, unless otherwise specified, temperatures are expressed in degrees Celsius (° C.), and the operating temperature is carried out under room temperature, and the room temperature shown refers to 10° C. to 30° C., preferably 20° C. to 25° C.

[0056] Experimental methods:

[0057] 1. X-ray powder diffraction (XRPD)

[0058] The XRPD data of the crystal form was measured by Bruker (d8 advance), and the diffraction parameters are as follows:

[0059] X-ray: Cu, kα, 1.54060

[0060] X-ray tube setting: 40kV, 25mA

[0061] Divergence slit: Automatic

[0062] Monochromator: No

[0063] Scan mode: Continuous

[0064] Scanning range (°2Theta): 4°-40°

[0065] Scanning speed (seconds / step): 0.5

[0066] 2. Differential scanning calorimeter (DSC)

[0067] The DSC data of the crystal form was measured by a TA (DSC 25) differential scanning calorimeter, and the thermal analysis parameters were as follows:

[0068] Temperature range (℃): 30-250

[0069] Heating rate (℃ / min): 10

[0070] Protective gas: Nitrogen

[0071] 3. Thermogravimetric analysis (TGA)

[0072] The TGA data of the crystal form was measured by TA (TGA 550) instrument, and the thermal analysis parameters were as follows:

[0073] Temperature range (℃): 30-350℃

[0074] Heating rate (℃ / min): 10

[0075] Protective gas: Nitrogen

[0076] 4.HPLC

[0077] The high performance liquid chromatography (HPLC) data in the present invention is collected from Agilent 1260, and the detector used is Agilent UV detector (VWD). The relevant substance detection conditions and methods involved in the present invention are as follows: chromatographic conditions and system suitability use octadecylsilane bonded silica gel as filler; mobile phase is 0.1% formic acid aqueous solution and methanol, isocratic elution (0.1% formic acid solution; methanol = 63:37; running time: 30min; flow rate: 1ml / min); detection wavelength is 254nm.

[0078] Example 1

[0079] Preparation of Pecidinib Hydrochloride Form LX-I

[0080] 500.0 g of pesidatinib hydrochloride was dissolved in ethanol: water (V: V) = 5: 1 at 40 ° C to a concentration of 200 mg / mL. In this embodiment, the concentration of pesidatinib hydrochloride was controlled to be 200 mg / ml. The temperature was cooled to room temperature and anti-solvent water was slowly added dropwise. The volume was 5 times that of the ethanol-water mixed solvent. The solid powder obtained by filtration was pesidatinib hydrochloride crystal form LX-I, and the molar yield was 92.3%. Its XRPD spectrum is attached. Figure 1 、DSC spectrum is attached Figure 2 , TGA spectrum is attached Figure 3 .

[0081] from Figure 1 It can be seen that the X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.6±0.2°, 12.2±0.2°, 16.0±0.2°, 18.4±0.2°, 19.8±0.2° and 20.8±0.2°. More specifically, the relative intensity of the interplanar spacing and peak height is shown below:

[0082]

[0083]

[0084] from Figure 2 It can be seen that the anhydrous form of pesidatinib hydrochloride LX-I has an endothermic peak at 234.6±5°C. Figure 3 It can be seen from the TGA that there is almost no weight loss from room temperature to 100°C, and it is anhydrous. 1 The H NMR characterization results are shown in Figure 4 As shown, the peak results are consistent with the structure of the compound (C20H15CIF3N5.HCl).

[0085] Example 2

[0086] Preparation of Pecidinib Hydrochloride Form LX-I

[0087] 500.0 g of pesidatinib hydrochloride was dissolved in ethanol: water (V: V) = 5: 1 at 60 ° C to a concentration of 250 mg / mL. In this embodiment, the concentration of pesidatinib hydrochloride was controlled to be 200 mg / ml. The anti-solvent methyl tert-butyl ether was slowly added dropwise to room temperature, and its volume was 5 times that of the ethanol-water mixed solvent. The solid powder obtained by filtration was pesidatinib hydrochloride crystal form LX-I, and the molar yield was 90.9%. Its XRPD spectrum, DSC spectrum, and TGA spectrum were consistent with those in Example 1.

[0088] Example 3

[0089] Preparation of Pecidinib Hydrochloride Form LX-I

[0090] 500.0 g of pesidatinib hydrochloride was dissolved in ethanol: water (V: V) = 5: 1 at 50°C to a concentration of 200 mg / ml-250 mg / ml. In this embodiment, the concentration of pesidatinib hydrochloride was controlled to be 200 mg / ml. The temperature was lowered to room temperature and the anti-solvent n-heptane was slowly added dropwise, and its volume was 5 times that of the ethanol-water mixed solvent. The solid powder obtained by filtration was pesidatinib hydrochloride crystal form LX-I, and the molar yield was 91.8%. Its XRPD spectrum, DSC spectrum, and TGA spectrum were consistent with those in Example 1.

[0091] Example 4

[0092] Preparation of Pecidinib Hydrochloride Form LX-II

[0093] 20 mg of pemidatinib hydrochloride was dissolved in a mixed solvent of THF and water in a volume ratio of 10:1 at 40-60°C, and the solid powder obtained after rapid cooling to 0-10°C was pemidatinib hydrochloride crystal form LX-II. Its XRD spectrum is shown in Figure 4 , the X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.9±0.2°, 12.8±0.2°, 13.6±0.2°, 16.2±0.2°, 19.5±0.2°, 20.7±0.2°, 23.0±0.2°, 24.1±0.2°, 25.3±0.2°, 26.9±0.2° and 28.7±0.2°. The interplanar spacing and peak height relative intensity of the X-ray powder diffraction pattern expressed in 2θ angles are shown as follows:

[0094]

[0095] Example 5

[0096] Preparation of Pecidinib Hydrochloride Form LX-III

[0097] 20 mg of pemidatinib hydrochloride was dissolved in a mixed solvent of acetic acid and water in a volume ratio of 1:2 at 40°C, and the solid powder obtained after rapid cooling to 0 to -10°C was pemidatinib hydrochloride crystal form LX-IV. The XRD spectrum of the solid powder is shown in the attached Figure 7 The X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.0±0.2°, 11.5±0.2°, 13.5±0.2°, 15.8±0.2°, 17.5±0.2°, 18.1±0.2°, 18.9±0.2°, 20.5±0.2°, 23.8±0.2°, 24.5±0.2° and 24.5±0.2°.

[0098] The relative intensities of the interplanar spacing and peak heights of the X-ray powder diffraction pattern expressed in 2θ angles are shown below:

[0099] serial number 2θ angle Interplanar spacing Relative Strength 1 6.0 14.7 24.1％ 2 11.5 7.7 26.4％ 3 13.5 6.6 28.5％ 4 15.8 5.6 62.5％ 5 17.5 5.1 75.8％ 6 18.1 4.9 27.1％ 7 18.9 4.7 100.0％ 8 20.5 4.3 34.0％ 9 22.8 3.9 33.7％ 10 23.8 3.7 26.8％ 11 24.5 3.6 21.0％

[0100] Example 6

[0101] Preparation of Pecidinib Hydrochloride Form LX-IV

[0102] 20 mg of pesidatinib hydrochloride was dissolved in a mixed solvent of 1.4-dioxane and water at a volume ratio of 5:1 at 40°C, and its concentration was controlled to be 100 mg / ml. The solid powder obtained by rapid evaporation at room temperature was pesidatinib hydrochloride crystal form LX-IV. Its XRD spectrum is shown in the attached Fig.10 The X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.4±0.2°, 15.7±0.2°, 18.4±0.2°, 19.2±0.2°, 22.0±0.2°, 22.6±0.2°, 23.2±0.2°, 23.6±0.2°, 25.2±0.2°, 25.8±0.2° and 26.7±0.2°. The interplanar spacing and peak height relative intensity of the X-ray powder diffraction pattern expressed in 2θ angles are shown as follows:

[0103] serial number 2θ angle Interplanar spacing Relative Strength 1 6.4 13.9 32.7％ 2 15.7 5.6 19.0％ 3 18.4 4.8 100.0％ 4 19.2 4.6 24.8％ 5 22.0 4.0 42.6％ 6 22.6 3.9 16.5％ 7 23.2 3.8 22.9％ 8 23.6 3.8 15.7％ 9 25.2 3.5 22.0％ 10 25.8 3.5 18.3％ 11 26.7 3.3 29.2％

[0104] The pesidatinib hydrochloride used in the above examples is prepared according to patent CN107548394B. It should be understood that the above examples are only used to further illustrate the present invention, rather than to limit the scope of protection of the present invention, and some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention.

[0105] Experimental Example 1

[0106] Stability experiment of pecidinib hydrochloride anhydrous crystalline form LX-I

[0107] According to the original crystal form patent (CN107548394B specification (0088-0093)), the experiment was repeated to obtain the hydrochloride crystal form Form C, and the stability was tested. The data are as follows:

[0108]

[0109] The results of the crystal stability experiment show that the original crystal Form C and crystal Form LX-I have good crystal stability and chemical stability when placed at 40°C, 75% RH and 60°C, 92.5% RH for 10 days.

[0110] Experimental Example 2

[0111] Comparison of hygroscopicity:

[0112] According to the test method of the Pharmacopoeia: Take a dry stoppered glass weighing bottle and place it in an appropriate environment of 25℃±1℃ and relative humidity of 80%±2% the day before, and weigh it accurately (m1). Take an appropriate amount of the test sample and spread it in the weighing bottle. The thickness of the test sample is about 1mm, and weigh it accurately (m2). Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours, cover the weighing bottle cap, and weigh it accurately (m3).

[0113]

[0114] According to the data in the above table, it can be seen that the moisture weight gain of crystal form Form C and crystal form Form 7 is greater than 0.2% and less than 2%, and is slightly hygroscopic, while the moisture weight gain of crystal form LX-I is less than 0.2%, and is non-hygroscopic, which is more conducive to the storage and transportation of drugs than crystal form Form C and crystal form 7.

[0115] Experimental Example 3

[0116] Solubility experiment

[0117] Solubility is one of the important properties that affect bioavailability, especially the solubility in a simulated human environment. The crystal form LX-I and the crystal form Form C of the present invention were prepared into saturated solutions using FaSSIF (simulating intestinal fluid in a fasting state) and FeSSIF (simulating intestinal fluid in a fed state). Samples were taken at 1 hour and 24 hours and the content of the sample in the saturated solution was determined by HPLC. The experimental results are as follows:

[0118]

[0119] The results showed that the solubility of the crystal form LX-I in FaSSIF, FeSSIF and water was superior to that of the original crystal form Form C. The solubility was significantly improved, which was beneficial to improve intestinal absorption and thus improve drug utilization.

[0120] Experimental Example 4

[0121] Liquidity Comparison

[0122] Angle of repose measurement: measured using an angle of repose meter in accordance with international standard ISO 4324-1977.

[0123] During the preparation process, the compressibility index or Carr index is usually used to evaluate the fluidity of powders or intermediate particles. The determination method is to gently put a certain amount of powder into a measuring cylinder and measure the initial bulk density. The tapping method is used to make the powder in the most compact state and measure the final volume; calculate the bulk density ρ0 and the tap density ρ r According to the formula c = (ρ r-ρ0) / ρ r Calculate the compressibility coefficient.

[0124] The definition standard of the compressibility coefficient for powder fluidity refers to the United States Pharmacopoeia USP1174, as shown in the following table.

[0125] Compressibility coefficient (%) Liquidity ≤10 Excellent 11-15 good 16-20 generally 21-25 Acceptable 26-31 Difference 32-37 Very bad ＞38 Very bad

[0126] The fluidity evaluation results of Form LX-I and prior art Forms Form 7 and Form C are shown in the table below.

[0127] Crystal form Angle of repose <![CDATA[Bulk density ρ0]]> <![CDATA[Tap density ρ r > Carl coefficient c Form C 37.4° 0.345g / ml 0.365g / ml 5.4％ Crystal form LX-I 30.8° 0.467g / ml 0.514g / ml 7.4％

[0128] The results show that the crystal form LX-I obtained by this method and the crystal form Form C obtained by the original crystal patent have improved fluidity.

Claims

1. A pesidatinib hydrochloride crystal form LX-I, whose chemical formula is shown in formula (I): It is characterized in that The crystal form is an anhydrous crystal form, and its X-ray powder diffraction pattern expressed in 2θ angles has diffraction peaks at 6.6±0.2°, 12.2±0.2°, 16.0±0.2°, 18.4±0.2°, 19.8±0.2° and 20.8±0.2°.

2. The pesidatinib hydrochloride crystal form LX-I according to claim 1, characterized in that The relative intensities of the interplanar spacing and peak heights of its X-ray powder diffraction pattern expressed in 2θ angles are shown below:

3. The pesidatinib hydrochloride crystal form LX-I according to claim 2, characterized in that: It has an X-ray powder diffraction pattern as shown in Figure 1 of the specification.

4. The pesidatinib hydrochloride crystal form LX-I according to any one of claims 1 to 3, characterized in that The differential scanning calorimetry showed an endothermic peak at 234.6±5°C.

5. The pesidatinib hydrochloride crystal form LX-I according to claim 4, characterized in that: It has a differential scanning calorimetry curve as shown in Figure 2 of the specification.

6. The method for preparing the pesidatinib hydrochloride crystal form LX-I according to any one of claims 1 to 3, characterized in that: The following steps are involved: The pemidatinib hydrochloride is dissolved in an ethanol-water mixed solvent at 40-60° C., and an anti-solvent is slowly added dropwise to obtain a solid powder pemidatinib hydrochloride crystal form LX-I, wherein the anti-solvent is selected from one of n-heptane, water or methyl tert-butyl ether.

7. The method for preparing the pesidatinib hydrochloride crystal form LX-I according to claim 6, characterized in that: The volume ratio of ethanol to water is 5:1, the volume ratio of the mixed solvent to the anti-solvent is 1:5, and the mass volume ratio of the pesidatinib hydrochloride to the mixed solvent is 100 mg / mL-150 mg / mL.

8. The method for preparing the pesidatinib hydrochloride crystal form LX-I according to claim 6, characterized in that: The dissolution temperature of pesidatinib hydrochloride is 60°C.

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