Crystalline form of tas-116, methods of making, pharmaceutical compositions, and uses thereof

Abstract

This invention relates to the technical field of drug crystal forms, specifically to a crystal form of TAS-116, its preparation method, pharmaceutical composition, and uses. The TAS-116 crystal form of this invention has advantages such as better solubility, dissolution rate, crystal form stability, and reduced hygroscopicity.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry. Specifically, this application relates to the crystal form of TAS-116, methods for its preparation, pharmaceutical compositions, and uses. Background Technology

[0002] TAS-116 is a selective heat shock protein 90 (HSP90) inhibitor used to treat gastrointestinal cancers such as colon cancer and gastric stromal tumors. Currently, TAS-116 is undergoing clinical trials in patients with gastrointestinal cancers.

[0003] TAS-116's chemical name is 3-ethyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide, also known as THS-1593, with the molecular formula C 25 H 26 N8O, with a molecular weight of 454.53, has the following chemical structural formula:

[0004]

[0005] Patent CN102471335B discloses a general formula structure including the TAS-116 compound.

[0006] Patent CN104710420B discloses the specific structure of TAS-116 and a method for preparing TAS-116 in its free state, mentioning that TAS-116 is a white solid.

[0007] Patent CN107531707B discloses type I crystals (hereinafter referred to as "crystal form I") and type II crystals (hereinafter referred to as "crystal form II") of TAS-116. Crystal form I only has an XRPD spectrum, and there are problems with the oral absorption of crystal form I. Crystal form II is an anhydrous product. The patent also states that crystal form II is a superior crystal form to crystal form I.

[0008] During their research, the inventors discovered that the TAS-116 sample prepared according to Example 102 of patent CN104710420B was crystal form II, and the obtained sample had a high DMSO (dimethyl sulfoxide) residue, with significant residue remaining even after washing with diethyl ether. The inventors also found that the crystal form II sample reverted to crystal form I after being retained in the solvent of Example 102 for more than 2 hours, indicating a stability issue with crystal form II.

[0009] During the research process, the inventors also discovered that TAS-116 crystal form I prepared according to CN107531707B is unstable and easily undergoes a crystal transformation to crystal form II when placed at room temperature (20-30℃). Crystal form I requires more stringent storage conditions to be stable, indicating that its medicinal value is not high.

[0010] During the research process, the inventors also discovered that the stability of TAS-116 crystal form II prepared according to patent CN107531707B has significant limitations. In addition to being unstable in the solvent of Example 102 in CN104710420B, it also undergoes crystal transformation under various other environments, resulting in crystal form I to varying degrees.

[0011] Given the shortcomings of the existing technology, especially the lack of stability, there is a need in the field to develop a more stable solid form of TAS-116 with more advantages. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the present invention aims to provide a TAS-116 crystal form with superior physicochemical properties, along with its preparation method, pharmaceutical composition, and uses. Compared to known TAS-116 compounds, the TAS-116 crystal form of the present invention exhibits better crystal stability. Furthermore, it has been found to possess other unexpected effects, primarily manifested in better solubility and dissolution rate, better particle morphology, higher crystallinity, and superior hygroscopicity. It is further believed that the crystal form of the present invention also possesses better flowability, formulation processability, and bioavailability.

[0013] According to the purpose of the invention, a first aspect of the invention provides a TAS-116 crystal form, hereinafter referred to as crystal form III.

[0014] The crystal form III of this invention is an anhydrous product, and its structural formula is shown in formula (I):

[0015]

[0016] Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form III exhibits characteristic peaks at 2θ values ​​of 6.39°±0.2°, 10.40°±0.2°, 12.94°±0.2°, and 19.48°±0.2°.

[0017] Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form III has characteristic peaks at 2θ values ​​of 3.20°±0.2°, 6.39°±0.2°, 10.40°±0.2°, 11.41°±0.2°, 12.94°±0.2° and 19.48°±0.2°.

[0018] More preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form III has characteristic peaks at 2θ values ​​of 3.20°±0.2°, 6.39°±0.2°, 10.40°±0.2°, 11.41°±0.2°, 12.94°±0.2°, 17.58°±0.2°, 18.26°±0.2°, 19.48°±0.2°, 21.71°±0.2°, 22.69°±0.2°, and 23.65°±0.2°.

[0019] More preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form III exhibits characteristic peaks at the following diffraction angles, and their 2θ values ​​and relative intensities are shown in the table below:

[0020]

[0021]

[0022] Non-limiting, the X-ray powder diffraction (XRPD) pattern of crystal form III is substantially as follows: Figure 4 As shown.

[0023] Non-limiting, the differential scanning calorimetry (DSC) spectrum of crystal form III is as follows: Figure 5 As shown. The melting point onset value of crystal form III is 269℃, and the peak value is 270℃.

[0024] Non-limiting, the thermogravimetric analysis (TGA) spectrum of crystal form III is as follows: Figure 6 As shown. Crystal form III is anhydrous and loses only 0.9% of its weight before 105°C.

[0025] Non-limiting, the Fourier transform infrared spectrum of crystal form III is as follows: Figure 7 As shown. The Fourier transform infrared spectrum of crystal form III at a wavenumber of 1650 cm⁻¹. -1 ±2cm -1 1569cm -1 ±2cm -1 1504cm -1 ±2cm -1 1424cm -1 ±2cm -1 1272cm -1 ±2cm -1 1030cm -1 ±2cm -1 823cm -1 ±2cm -1 812cm -1 ±2cm -1 748cm-1 ±2cm -1 711cm -1 ±2cm -1 668cm -1 ±2cm -1 and 653cm -1 ±2cm -1 It has a characteristic peak.

[0026] Non-limiting, the DVS isotherm curve of crystal form III is as follows: Figure 8 As shown, the crystal form III exhibits only a 0.3% weight change within a humidity range of 0%RH to 80%RH.

[0027] Non-limiting, the polarization-guided microscopy (PLM) image of crystal form III is shown below. Figure 9 As shown. Crystal form III consists of fine granular crystals.

[0028] According to the purpose of this invention, a second aspect of the invention provides a method for preparing TAS-116 crystal form III, comprising any one of the following methods:

[0029] (1) The solid compound TAS-116 was suspended in solvent 1, stirred, the solid was separated, and dried to obtain the crystal form III;

[0030] Preferably, solvent 1 is selected from cyclic ethers; more preferably, it is 1,4-dioxane.

[0031] Preferably, the mass-to-volume ratio of the compound TAS-116 solid to solvent 1 is 10–200:1 (mg:mL), more preferably 30–100:1;

[0032] Preferably, the stirring time is 10 hours to 168 hours; more preferably, it is 16 hours to 72 hours.

[0033] Preferably, the stirring is carried out at room temperature;

[0034] Preferably, after drying, the resulting solid is heated at a temperature of 60°C to 150°C, more preferably at a temperature of 80°C to 130°C, and preferably for a heating time of 5 minutes to 16 hours;

[0035] (2) The solid compound TAS-116 was dissolved in solvent 2, cooled, the solid was separated and dried to obtain crystal form III;

[0036] Preferably, the solvent 2 is selected from halogenated alkanes, alcohols, ketones, furans, cyclic ethers, nitriles, or mixtures thereof; more preferably, it is tetrahydrofuran and chloroform; preferably, the volume ratio of the two solvents in the mixture is 1:4 to 4:1.

[0037] Preferably, the mass-to-volume ratio of solute to solvent 2 in the solution is 5–100:1 (mg:mL), more preferably 40–100:1;

[0038] Preferably, the temperature at which the solution is formed is 60°C to 80°C;

[0039] Preferably, the temperature is lowered to 10°C to 50°C; more preferably, the temperature is lowered to 10°C to 40°C.

[0040] Preferably, TAS-116 crystal type III seed crystals are added during the cooling process;

[0041] Preferably, the amount of seed crystal added is 10% to 30% of TAS-116 solid;

[0042] Preferably, the cooling can be performed simultaneously with stirring or after cooling; more preferably, the stirring time is 2 hours to 24 hours.

[0043] The TAS-116 crystal form III of the present invention has the following advantages compared with known crystal forms:

[0044] 1. The TAS-116 crystal form III of the present invention exhibits better stability. Compared with the known TAS-116 crystal form I, it has better crystal form stability under thermal conditions; compared with the known TAS-116 crystal form II, it has better crystal form stability under aqueous conditions, including but not limited to aqueous solutions, aqueous media, body fluids, and humid environments. Crystal form I cannot withstand heat (40°C), and crystal form II cannot withstand water; under both conditions, it cannot maintain its original crystal form. Thermal conditions and water are very common during API preparation, drying stages, formulation operations, drug shelf life, and in vivo disintegration and dissolution. Therefore, crystal form I and crystal form II of TAS-116 inevitably experience crystal instability during these processes.

[0045] It is well known that changes in crystal form can adversely affect the solubility, dissolution, bioavailability, stability, safety, and compliance of drugs. Therefore, it is necessary to avoid using crystal form I and crystal form II, while crystal form III has greater medicinal value.

[0046] 2. The TAS-116 crystal form III of the present invention has a faster dissolution rate compared with the known TAS-116 crystal forms I and II;

[0047] 3. The TAS-116 crystal form III of the present invention has higher solubility compared with the known TAS-116 crystal forms I and II;

[0048] 4. The TAS-116 crystal form III of the present invention has a moisture absorption of 0.3% in an environment of 0% to 80% RH, and is not prone to moisture absorption.

[0049] The TAS-116 crystal form III of this invention is a uniform and fine powder with better solubility and dissolution rate, which is beneficial to improving the bioavailability of the drug; it has better particle size distribution, making it easier to achieve uniform mixing and content; and it has lower hygroscopicity, making it more stable in humid environments.

[0050] In the preparation method of TAS-116 crystal form III of the present invention:

[0051] Unless otherwise specified, "overnight" means 10 to 16 hours.

[0052] "Room temperature" refers to a temperature between 10 and 30°C.

[0053] "Stirring" can be carried out using conventional methods in the field, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.

[0054] "Separation" can be performed using conventional methods in the art, such as centrifugation or filtration. Preferred method is vacuum filtration, typically performed at room temperature under pressure less than atmospheric pressure, preferably less than 0.09 MPa.

[0055] "Drying" can be accomplished using conventional techniques in the art, such as room temperature drying, forced-air drying, or vacuum drying; it can be carried out under reduced or normal pressure, preferably less than 0.09 MPa. The drying apparatus and methods are not limited and can include fume hoods, forced-air ovens, spray dryers, fluidized bed dryers, or vacuum ovens; it can be carried out under reduced or no pressure, preferably less than 0.09 MPa. The starting material TAS-116 can be prepared according to the method described in Example 102 of patent document CN104710420B, or it can be purchased commercially, which is incorporated herein by reference in its entirety.

[0056] In this invention, "crystal form" refers to the crystal form confirmed by the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that experimental errors depend on instrument conditions, sample preparation, and sample purity. The pattern typically changes with instrument conditions. The relative intensity of peaks may vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor; experimental errors in peak angles should also be taken into account, typically allowing ±0.2°; factors such as sample height can cause overall peak angle shifts, typically allowing a certain degree of shift. Therefore, those skilled in the art will understand that any crystal form with the same or similar characteristic peaks as the X-ray powder diffraction pattern of this invention falls within the scope of this invention. The term "single crystal form" refers to a single crystal form as detected by X-ray powder diffraction.

[0057] The novel crystalline form of TAS-116 of the present invention is pure and singular, substantially free from any other crystalline or amorphous states. In this invention, "substantially free" when referring to a novel crystalline form means that the novel crystalline form contains less than 20% (by weight) of other crystalline or amorphous states, more specifically less than 10% (by weight), particularly less than 5% (by weight), and especially less than 1% (by weight). According to the purpose of the invention, a third aspect provides a pharmaceutical composition comprising a therapeutically effective amount of the TAS-116 crystalline form III or TAS-116 crystalline form III prepared by the method of the present invention, and at least one pharmaceutically acceptable carrier.

[0058] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral (enteral), parenteral (injection), rectal, topical, transdermal, intradermal, intrathecal, subcutaneous (SC), intramuscular (IM), sublingual / buccal, ocular, ear, vaginal, and nasal administration, or inhalation. Typically, an effective amount of the solid form of TAS116 provided herein is administered. The amount of solid form of TAS116 actually administered may be determined by a physician, depending on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0059] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, they are more commonly provided in unit dose form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc., which may be conventional immediate-release formulations, dispersible, chewable, or orally dissolving formulations, or sustained-release formulations, such as enteric-coated tablets.

[0060] For oral dosage, a typical regimen is one to five oral doses daily, particularly one to four oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the solid form of TAS-116 provided by this invention, with preferred doses providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 0.2 to approximately 5 mg / kg, depending on the specific condition being treated, the age and weight of the individual patient, and the individual patient's response to drug treatment. The precise dosage should be determined under the guidance of a physician according to standard medical principles. Specific unit doses may be, for example, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 200 mg, etc.

[0061] The pharmaceutically acceptable carriers or excipients in the pharmaceutical composition are well known to those skilled in the art and may take various well-known forms, including but not limited to: diluents such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, copovidone, etc.; disintegrants such as starch, sodium carboxymethyl starch, sodium glycolate starch, pregelatinized starch, crospovidone, crospovidone, colloidal silica, etc.; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; flow aids such as colloidal silica, etc.; complex forming agents such as cyclodextrins and resins of various grades; and release rate control agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc. Other pharmaceutically acceptable carriers or adjuvants include, but are not limited to, film-forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, and antioxidants. In the case of oral tablets, commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate may also be added; in the case of oral capsules, useful carriers / diluents include lactose, high and low molecular weight polyethylene glycol, and dry corn starch; in the case of gelatin capsules, powdered carriers or adjuvants include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like; when administered orally as a suspension, the active ingredient is mixed with an emulsifier and a suspending agent; if desired, certain sweeteners and / or flavoring agents and / or colorants may be added. Each carrier or adjuvant must be acceptable, compatible with other ingredients in the formulation, and harmless to the patient.

[0062] According to the purpose of this invention, a fourth aspect of the invention provides the use of the TAS-116 crystal form III, the TAS-116 crystal form III obtained by the preparation method of this invention, or the pharmaceutical composition thereof in the preparation of a medicament for treating cancer. Further, the cancers include, but are not limited to, the following specific diseases and conditions: head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder-choleduct cancer, bile duct cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumors, bone-soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumors, mesothelioma, etc.

[0063] According to the objectives of the present invention, a fifth aspect provides a method for treating cancer, the method comprising administering a therapeutically effective amount of the TAS-116 crystal form III or a pharmaceutical composition thereof to a patient in need. The patient includes, but is not limited to, mammals.

[0064] According to the purpose of the invention, a sixth aspect of the invention provides the combined use of the TAS-116 crystal form III or a pharmaceutical composition thereof with other drugs; the other drugs are preferably monoclonal antibody drugs, more preferably PD-1 and PD-L1 inhibitors, such as nivolumab, AB122, etc. Attached Figure Description

[0065] Figure 1 XRPD pattern (crystal form II) of the TAS-116 compound prepared according to the method described in Example 102 of patent document CN104710420B.

[0066] Figure 2 The XRPD pattern of TAS-116 compound crystal form I (type I crystal) prepared according to the method described in Comparative Example 1 of Patent Document CN107531707B.

[0067] Figure 3 The XRPD pattern of TAS-116 compound crystal form II (type II crystal) prepared according to the method described in Example 1 of patent document CN107531707B.

[0068] Figure 4 The image shows the XRPD pattern of TAS-116 crystal form III obtained in Example 1 of this invention.

[0069] Figure 5 The image shows the DSC spectrum of TAS-116 crystal form III obtained in Example 1 of this invention.

[0070] Figure 6 The TGA spectrum of TAS-116 crystal form III obtained in Example 1 of this invention.

[0071] Figure 7 The image shows the IR spectrum of TAS-116 crystal form III obtained in Example 1 of this invention.

[0072] Figure 8 This is the DVS pattern of TAS-116 crystal form III obtained in Example 1 of the present invention.

[0073] Figure 9 This is a PLM diagram of TAS-116 crystal form III obtained in Example 1 of the present invention.

[0074] Figure 10 This is the XRPD diagram of TAS-116 crystal form I under thermal conditions in Experiment 1 of Experiment Example 1.

[0075] Figure 11 This is the XRPD image of TAS-116 crystal form II in water under Experiment 1 of Experiment Example 1.

[0076] Figure 12 The image shows the XRPD diagrams of TAS-116 crystal form II and crystal form III under thermal conditions in Experiment 1 of Experiment Example 1.

[0077] Figure 13 The image shows the XRPD images of TAS-116 crystal form I and crystal form III under aqueous conditions in Experiment 1 of Experiment Example 1.

[0078] Figure 14 The image shows a comparison of XRPD results for the crystal stability experiment of TAS-116 crystal form III in Experiment 2 of Experiment Example 1.

[0079] Figure 15 The image shows a comparison of XRPD values ​​for the 63-day stability test of TAS-116 crystal form III in Experiment 2 of Experiment 1.

[0080] Figure 16 The image shows the particle size distribution (PSD) of TAS-116 crystal form III in Experimental Example 2.

[0081] Figure 17 The solubility curves of crystal form I, crystal form II and crystal form III in buffer solution at pH 6.8 are shown in Experiment 1 of Experiment 3.

[0082] Figure 18 The dissolution curves are for TAS-116 crystal form I, crystal form II and crystal form III tablets in Experiment Example 4. Detailed Implementation

[0083] The following embodiments further illustrate the present invention; however, they do not constitute a limitation or restriction on the scope of the invention. All patent documents and non-patent publications referenced in this specification are incorporated herein by reference in their entirety.

[0084] Testing instruments and methods:

[0085] X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The sample was tested at room temperature. The detection conditions were as follows: angle range: 3–40°2θ, step size: 0.02°2θ, speed: 0.2 seconds / step.

[0086] The polarization microscopy (PLM) images were taken from an XP-500E polarization microscopy microscope. A small amount of powder sample was placed on a glass slide, a small amount of mineral oil was added to disperse the sample, a coverslip was placed on the stage, and the sample was observed and photographed.

[0087] Thermogravimetric analysis (TGA) data were obtained from a TA Instruments Q500 TGA. The detection method was as follows: the sample was heated to 400℃ at a heating rate of 10℃ / min under the protection of dry N2 at a rate of 40mL / min.

[0088] Dynamic moisture adsorption (DVS) and isothermal adsorption analysis data were obtained from SMS Intrinsic PLUS. The detection method was as follows: samples were taken, and the weight change was measured as the relative humidity changed from 0% to 80% and back to 0%.

[0089] Infrared spectral analysis (IR) data were acquired using a Bruker Tensor 27 and an ATR instrument, in the range of 600–4000 cm⁻¹. -1 Infrared absorption spectra were collected within the specified range.

[0090] HPLC purity data were obtained from an Ultimate 3000 high-performance liquid chromatograph. The chromatographic column was C18 (4.6*150mm, 5μm), the detection wavelength was 254nm, the detection column temperature was 30℃, the flow rate was 1mL / min, and the injection volume was 5μL.

[0091] Unless otherwise specified, all examples were performed at room temperature, and all solvent ratios are volume ratios.

[0092] Unless otherwise specified, all reagents used in the examples were commercially available.

[0093] Preparation Example 1: Preparation of TAS-116 in its free state

[0094] TAS-116 free white solid was prepared according to the method described in Example 102 (P77) of patent document CN104710420B.

[0095] Upon testing, its XRPD spectrum is as follows: Figure 1As shown, TAS-116 prepared according to the method described in Example 102 of Patent Document CN104710420B is crystal form II. Preparation Example 2: Preparation of TAS-116 Crystal Form I

[0096] The free TAS-116 sample was prepared according to the method described in Comparative Example 1 of Patent Document CN107531707B.

[0097] Upon testing, its XRPD spectrum is as follows: Figure 2 As shown, the free TAS-116 sample prepared according to the method described in Comparative Example 1 of Patent Document CN107531707B is of crystal form I.

[0098] Preparation Example 3: Preparation of TAS-116 Crystal Form II

[0099] The free TAS-116 sample was prepared according to the method described in Example 1 of patent document CN107531707B.

[0100] Upon testing, its XRPD spectrum is as follows: Figure 3 As shown, the TAS-116 free state sample prepared according to the method described in Example 1 of patent document CN107531707B is of crystal form II.

[0101] Example 1: Preparation of TAS-116 crystal form III

[0102] Take about 500 mg of TAS-116, add 10 mL of 1,4-dioxane to form a suspension, stir overnight at room temperature, centrifuge, vacuum dry overnight at room temperature to obtain a solid, and then heat at 120 °C for 5 minutes to obtain about 401 mg of white solid.

[0103] Upon testing, the obtained solid was identified as TAS-116 crystal form III.

[0104] XRPD map as follows Figure 4 As shown;

[0105] DSC chart as follows Figure 5 As shown, the melting point onset value is 269℃, and the peak value is 270℃;

[0106] TGA chart as follows Figure 6 As shown; it is an anhydrous substance, and it only loses 0.9% of its weight before 105℃;

[0107] IR spectrum as follows Figure 7 As shown;

[0108] DVS diagram as follows Figure 8 As shown, there was only a 0.3% weight change within the humidity range of 0%RH-80%RH;

[0109] PLM diagram as shown Figure 9 As shown, the crystals are fine granular with a particle size much smaller than 50 micrometers. The fine particles are more conducive to improving solubility and dissolution rate.

[0110] Example 2: Preparation of TAS-116 crystal form III

[0111] Take about 1000 mg of TAS-116, add 5 mL of 1,4-dioxane to form a suspension, stir at room temperature for 72 hours, centrifuge, vacuum dry at room temperature overnight to obtain a solid, and then heat at 150 °C for 5 minutes to obtain about 850 mg of white solid.

[0112] Example 3 Preparation of TAS-116 crystal form III

[0113] Take about 200 mg of TAS-116, add 20 mL of 1,4-dioxane to form a solution, and after 0.5 hours it becomes a suspension. Stir at room temperature for 10 hours, centrifuge, and vacuum dry at room temperature overnight to obtain a solid. Then heat at 60℃ for 16 hours to obtain about 100 mg of white solid.

[0114] Example 4: Preparation of TAS-116 crystal form III

[0115] Take about 50 mg of TAS-116 prepared in Example 1, add 1.0 mL of chloroform, form a solution at 60°C, cool to 30°C-40°C to obtain a saturated solution, add 5 mg of crystal type III seed prepared in Example 1, stir for 2 hours, continue to cool to 0°C, centrifuge, and vacuum dry overnight at room temperature to obtain about 47 mg of white solid.

[0116] Example 5: Preparation of TAS-116 crystal form III

[0117] Take about 50 mg of TAS-116 prepared in Example 1, add 1.0 mL of chloroform and 0.25 mL of tetrahydrofuran, form a solution at 60 °C, cool to room temperature to obtain a saturated solution, add 15 mg of crystal type III seed prepared in Example 1, stir for 24 hours, centrifuge, and vacuum dry overnight at room temperature to obtain about 44 mg of white solid.

[0118] Upon testing, the solids obtained in Examples 2-5 were found to be TAS-116 crystal form III, which had the same characterization spectrum as crystal form III prepared in Example 1, and will not be shown again in this invention.

[0119] Experiment Example 1: Stability Comparison Experiment

[0120] Experiment 1

[0121] The crystal form I and II samples disclosed in the present invention and the crystal form III sample of the present invention were taken and the crystal form changes after heating and under water conditions were investigated.

[0122] Thermal conditions include, but are not limited to, forced-air drying at temperatures above 30°C, vacuum drying, factors affecting acceleration (40°C / 75% RH), and heating in solvents at temperatures above 30°C. The thermal conditions of this invention refer to forced-air drying at 40°C.

[0123] Water conditions: including but not limited to environments such as aqueous solutions, aqueous media, body fluids, and humidity. The water conditions for this invention are stirring in an aqueous solution at room temperature for 16 hours.

[0124] The experimental results are shown in Table 1 below. Table 1 shows that crystal form I cannot withstand heat, and crystal form II cannot withstand water; neither can maintain its original crystal form under these two conditions. However, crystal form III of the present invention exhibits good thermal and water stability.

[0125] Table 1

[0126]

[0127] Experiment 2

[0128] Weigh an appropriate amount of the crystal form III sample of the present invention and place it in the open under long-term (25°C / 60%RH), accelerated (40°C / 75%RH), and high-temperature (40°C) conditions, and periodically test the XRPD.

[0129] Experimental results show that crystal form III did not transform into crystals after 15 days under long-term, accelerated, and high-temperature conditions. Its XRPD comparison diagram is shown below. Figure 14 As shown.

[0130] Furthermore, the crystal form of crystal type III remained unchanged after 63 days of long-term (25℃ / 60%RH) and high-temperature (40℃) conditions, as shown in the XRPD comparison diagram. Figure 15 As shown.

[0131] Experiment 3

[0132] Weigh an appropriate amount of the crystal form III sample of the present invention and place it in the open under long-term (25℃ / 60%RH), accelerated (40℃ / 75%RH), high temperature (40℃) and high humidity (97%RH) conditions. Take the crystal form III samples after the initial 0 days, long-term (25℃ / 60%RH) for 63 days, accelerated (40℃ / 75%RH) for 63 days, high temperature (40℃) for 63 days and high humidity (97%RH) for 63 days for HPLC purity detection.

[0133] The HPLC detection methods are shown in Table 2 below.

[0134] Table 2

[0135] Category parameter instrument Ultimate3000 High Performance Liquid Chromatography Column type C18, 4.6×150mm, 5um ultraviolet wavelength UVat254nm Flow rate 1.0 mL / min Column temperature 30℃ Injection volume 5.0uL diluent methanol Mobile phase A Water (0.05% FA) Mobile phase B Methanol (0.05% FA) Mobile phase ratio A:B = 45:55

[0136] The purity test results for crystal form III are shown in Table 3 below. Table 3 shows that crystal form III of this invention exhibits good chemical stability.

[0137] Table 3

[0138]

[0139] Experimental Example 2 Particle Size Distribution

[0140] Appropriate amounts of the crystal form III sample of this invention were taken, dispersed in n-heptane, and then analyzed using a laser particle size analyzer. Particle size distribution (PSD) was collected using a Microtrac S3500 laser particle size analyzer. The method parameters are shown in Table 4 below.

[0141] Table 4

[0142]

[0143]

[0144] The experimental results are shown in Table 5 below. Figure 16 . Figure 16 The PSD of crystal form III is normally distributed.

[0145] Table 5

[0146] Crystal form <![CDATA[D (10) (μm)]]> <![CDATA[D (50) (μm)]]> <![CDATA[D (90) (μm)]]> Crystal form III 5.42 10.75 25.47

[0147] Experiment Example 3: Solubility Experiment

[0148] Experiment 1: Solubility at pH 6.8

[0149] Take approximately 10 mg each of crystal form I, crystal form II, and crystal form III into a bottle, and add 15 mL of pH 6.8 buffer solution to form a suspension. Then, shake all samples at 25℃±2℃. After shaking for 5 min, 30 min, 45 min, and 60 min, respectively, take 1 mL of each crystal form sample from the pH 6.8 buffer solution and filter. Analyze the sample solubility using HPLC. The HPLC detection method is the same as in Table 2.

[0150] Buffer solution with pH = 6.8: Prepare 100 mL of 0.2 mol / L potassium dihydrogen phosphate and adjust the pH to 6.8 with 0.2 mol / L sodium hydroxide.

[0151] The solubility results of crystal forms I, II, and III in a buffer solution at pH 6.8 are shown in Table 6 below, and the solubility curves are as follows. Figure 17 As shown.

[0152] Table 6

[0153]

[0154] Experiment 2: Solubility in Water

[0155] Take about 4 mg of crystal form III sample into a bottle, add 15 mL of water to form a suspension, and then shake at 25℃±2℃. After shaking for 60 min, take 1 mL of sample and filter. Detect the sample solubility by HPLC (method as in Table 6). The solubility is 5.83 μg / mL.

[0156] Experimental Example 4: Tablet Dissolution

[0157] Tablet manufacturing and dissolution test process:

[0158] Take appropriate amounts of crystal form I, crystal form II and crystal form III samples according to the raw materials and excipients weighed in Table 7 and mix them evenly.

[0159] Table 7 Tablet Prescription Table

[0160]

[0161] The raw materials and excipients of the three crystal forms were mixed and pressed into tablets using a single-punch tablet press (pressure 2MPa, time 2min).

[0162] Dissolution medium: pH 6.8 phosphate buffer.

[0163] Dissolution tests were performed on tablets containing crystal form I, crystal form II, and crystal form III, respectively.

[0164] Dissolution method: Temperature 37℃, rotation speed 50 rpm, medium volume 900 mL, slurry method. (Dissolution apparatus: Agilent 708-DS, sampler: Agilent 850-DS)

[0165] Samples were taken and tested at nine time points: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, and 2 h.

[0166] Experimental results:

[0167] Within the same time frame, the dissolution rate of crystal form III was higher than that of crystal forms I and II; after 2 hours, the dissolution rate of crystal form III reached 49%, while the dissolution rates of crystal forms I and II were only 29% and 33%, respectively. The tablet dissolution curves for crystal forms I, II, and III are shown below. Figure 18 The specific dissolution test results for crystal form I, crystal form II, and crystal form III tablets are shown in Table 8 below.

[0168] Table 8

[0169]

[0170]

[0171] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be conceived by those skilled in the art within the technical scope disclosed in the present invention without creative effort should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A crystal form III of a compound TAS-116 with the structural formula shown in formula (I), Formula (I) Its features are, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form III was obtained at a 2θ value of 3.

20. ±0.2 6.39 ±0.2 10.40 ±0.2 11.41 ±0.2 12.94 ±0.2 and 19.48 ±0.2 It has a characteristic peak.

2. The crystal form III according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form III was obtained at a 2θ value of 3.

20. ±0.2 6.39 ±0.2 10.40 ±0.2 11.41 ±0.2 12.94 ±0.2 17.58 ±0.2 18.26 ±0.2 19.48 ±0.2 21.71 ±0.2 22.69 ±0.2 and 23.65 ±0.2 It has a characteristic peak.

3. The crystal form III according to claim 2, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form III exhibits characteristic peaks at the following diffraction angles, and their 2θ values ​​and relative intensities are shown in the table below:

4. Crystal form III according to any one of claims 1 to 3, characterized in that, The X-ray powder diffraction pattern of crystal form III is basically shown in Figure 4.

5. Crystal form III according to any one of claims 1 to 3, characterized in that, The Fourier transform infrared spectrum of crystal form III is at a wavenumber of 1650 cm⁻¹. -1 ±2 cm -1 1569 cm -1 ±2 cm -1 1504 cm -1 ±2 cm -1 1424cm -1 ±2cm -1 1272cm -1 ±2 cm -1 1030cm -1 ±2 cm -1 823cm -1 ±2 cm -1 812 cm -1 ±2 cm -1 748cm -1 ±2cm -1 711cm -1 ±2 cm -1 668 cm -1 ±2 cm -1 and 653 cm -1 ±2 cm -1 It has a characteristic peak.

6. The method for preparing crystal form III according to any one of claims 1 to 4, wherein the preparation method comprises any one of the following methods: (1) The solid TAS-116 compound was suspended in solvent 1, stirred, the solid was separated, and dried to obtain the crystal form III. in, Solvent 1 is selected from dioxane; The mass-to-volume ratio of the solid compound TAS-116 to solvent 1 is 10~200:1; The stirring time is 10 hours to 168 hours; The stirring was carried out at room temperature; After drying, the resulting solid is heated at 60℃~150℃ for 5 minutes to 16 hours. (2) The solid compound TAS-116 was dissolved in solvent 2, cooled, the solid was separated, and dried to obtain crystal form III. Solvent 2 is selected from tetrahydrofuran and chloroform; The mass-to-volume ratio of solute to solvent 2 in the solution is 5~100:1; The temperature at which the solution is formed is 60℃~80℃; Cool down to 10℃~50℃; The stirring time is 2 to 24 hours.

7. The method for preparing crystal form III according to claim 6, wherein, In method (1), The stirring time is 16 hours to 72 hours; After drying, the resulting solid is heated at 80℃~130℃ for 5 minutes to 16 hours.

8. The method for preparing crystal form III according to claim 6, wherein, In method (2), The temperature will drop to 10℃~40℃.

9. The method for preparing crystal form III according to claim 6 or 8, wherein, In method (2), Add TAS-116 crystal type III seed crystals during the cooling process; The amount of seed crystals added is 10% to 30% of TAS-116 solid.

10. A pharmaceutical composition comprising crystal form III as described in any one of claims 1 to 5, or crystal form III prepared by any one of claims 6 to 9, and at least one pharmaceutically acceptable carrier.

11. Use of a crystal form III as described in any one of claims 1 to 5, a crystal form III prepared by any one of claims 6 to 9, or a pharmaceutical composition as described in claim 10 in the preparation of a medicament for treating cancer; wherein the cancer is selected from: esophageal cancer, gastric cancer, colon cancer, and rectal cancer.

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