WO2023165501A1 - Crystal form of azd5305, preparation method therefor, and use therefor - Google Patents

Abstract

The present application relates to the field of chemical synthesis of pharmaceutics. Specifically, the present application relates to a crystal form of AZD5305, a preparation method therefor, and use thereof. The crystal form provided by the present application has at least one of the following improved features: good stability, low hygroscopicity, good solubility, good dissolution performance, high purity, good fluidity, good druggability such as good compressibility and higher stability in tablet formulations after tableting, good crystal morphology, good stress resistance, and stability in storage that can avoid the crystal transition of drugs in the development process and storage. The prevent invention features a simple and reliable preparation method and has great development value.

Description

Crystal form of AZD5305 and its preparation method and use technical field

This application relates to the field of chemical synthesis of medicines. Specifically, the application relates to the crystal form of AZD5305 and its preparation method and use.

Background technique

AZD5305 is a second-generation PARP inhibitor developed by AstraZeneca. It is a selective PARP1 inhibitor and is clinically used as a single drug or in combination with other anti-tumor drugs to treat solid tumors. The chemical name of AZD5305 is: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide, The structure is as shown in formula (I):

WO2021013735A1 discloses Form A, the crystalline form of AZD5305. The inventors of the present application have found through research that Form A cannot maintain the original crystal form in water at room temperature, and that the DVS weight gain of Form A is about 5.7% under the environment of 0%RH to 80%RH. %, it can be seen that the Form A of the prior art has poor stability, high hygroscopicity, and low drug development value.

Therefore, it is still necessary to carry out systematic and comprehensive crystal form screening of AZD5305 to find the advantageous crystal form suitable for pharmaceutical use.

Contents of the invention

The present application provides a crystal form of AZD5305, which has at least one of the following improved characteristics: good stability, low hygroscopicity, good solubility, good dissolution, high purity, good fluidity, good processability such as good compressibility 1. The tablet after tableting is more stable, has good crystal morphology, good compression resistance, can be stored stably, and avoids crystal transformation of the drug during the development process and storage. The preparation method is simple and reliable, and has a large development value. value.

One aspect of the present application is to provide a crystal form 2 of AZD5305, using Cu-Kα radiation, the X-ray powder diffraction (XRPD) spectrum of the crystal form 2 expressed at 2θ angle is at 9.1°±0.2°, 19.1° At least one of ±0.2°, 19.5°±0.2° and 20.3°±0.2° has a characteristic peak; preferably at least three have characteristic peaks.

In the solution of the preferred technology of the present application, the XRPD pattern of the crystal form 2 further has a characteristic peak at least one of 12.3°±0.2°, 18.9°±0.2°, 20.8°±0.2° and 21.1°±0.2°2θ .

In the preferred technical solution of the present application, the XRPD pattern of the crystal form 2 is further at 22.6°±0.2°, 16.6°±0.2°, 18.5°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 25.0° At least one of ±0.2° and 26.5°±0.2° 2θ has a characteristic peak.

In the preferred technical solution of the present application, the XRPD pattern of the crystal form 2 has characteristics at 9.1°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 20.3°±0.2° and 20.8°±0.2°2θ peak.

In the preferred technical solution of the present application, the XRPD pattern of the crystal form 2 is further at 12.3°±0.2°, 16.6°±0.2°, 18.5°±0.2°, 19.5°±0.2° and 21.1°±0.2°2θ At least one characteristic peak.

In the preferred technical solution of the present application, the XRPD pattern of the crystal form 2 is further at 22.6°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 25.0°±0.2° and 26.5°±0.2°2θ At least one characteristic peak.

In the preferred technical solution of the present application, the XRPD pattern of the crystal form 2 has a diffraction peak at the position of the following table at 2θ:

Without limitation, the crystalline form 2 has an XRPD pattern substantially as shown in FIG. 1 .

In the preferred technical solution of the present application, the Fourier transform infrared spectrum (FT-IR) of the crystal form 2 is at 3414cm ^-1 ±2cm ^-1 , 1570cm ^-1 ±2cm ^-1 , 1527cm ^-1 ±2cm ^-1 , 932cm ^-1 ±2cm ^-1 , 922cm ^{-1 ±} 2cm ^-1 and 634cm ^-1 ±2cm ^-1 at least one ^has a characteristic peak; more preferably at 1647cm ^-1 ±2cm ^-1 , 1583cm ^-1 ±2cm ^-1 , 1249cm ^-1 ±2cm ^-1 , 1230cm ^-1 ±2cm ^-1 , 675cm ^{-1 ±} 2cm ^-1 and 626cm ^-1 ±2cm ^-1 at least one of the characteristic diffraction peaks.

Without limitation, the FT-IR characterization of the crystal form 2 is basically shown in FIG. 4 .

Without limitation, the TGA characterization of the crystal form 2 is basically shown in Figure 2, and there is about 2.2% weight loss before heating to 120°C.

Without limitation, the DSC characterization of the crystal form 2 is basically shown in FIG. 3 .

Without limitation, the DVS characterization of the crystal form 2 is basically shown in Figure 5, and the weight gain is about 1.2% under the environment of 0% RH to 80% RH.

Without limitation, the crystal form 2 is a hydrate.

In some embodiments, the number of water molecules in the hydrate is 0.1-2;

In some embodiments, the number of water molecules in the hydrate is 0.1-1;

In some embodiments, the Form 2 is a hemihydrate.

The AZD5305 crystal form 2 described in this application has the following beneficial effects:

1) Good stability. The AZD5305 crystal form 2 of the present application keeps the crystal form unchanged for 5 months under accelerated (40°C/75%RH, open) and high humidity (room temperature/97%RH, open) conditions, and has good crystal stability and the AZD5305 Form A of the prior art is transformed into a mixed crystal of Form A and Form 2 in 5 months under accelerated (40°C/75%RH, exposure) conditions, indicating that the AZD5305 Form 2 of the present application has more Good stability is conducive to drug storage, ensures the controllable quality of raw materials and preparations, minimizes the quality change of drugs caused by crystal form changes, and ensures the efficacy of drugs.

2) Dissolution is good. The tablet made of the AZD5305 crystal form 2 of the present application has a cumulative dissolution rate of more than 85% in pH4.5 acetate buffer solution for 120 minutes, which is comparable to the tablet made by the prior art Form A.

3) Good solubility. The AZD5305 crystal form 2 of the present application and the prior art have considerable solubility in water, and the solubility after 24 hours is >25ug/mL; the AZD5305 crystal form 2 of the present application and the Form A of the prior art are acetate at pH 4.5 It also has a considerable solubility in the buffer, and the solubility is >200ug/mL after 24 hours.

4) Low hygroscopicity. The AZD5305 crystal form 2 of the present application has a weight gain of about 1.2% under the environment of 0%RH to 80%RH, while the Form A of the prior art has a weight gain of about 5.7% under the same conditions, indicating that the crystal form 2 has Lower hygroscopicity. Hygroscopicity may affect the stability, processability, and quality uniformity of the drug, and ultimately affect the quality of the pharmaceutical preparation, as well as the preparation, post-processing and storage of the drug. Crystal forms with low hygroscopicity do not have strict requirements on storage conditions. It reduces the cost of material storage and quality control, and has high economic value.

5) Good compressibility. The AZD5305 crystal form 2 of the present application has better compressibility, and good compressibility can effectively improve problems such as unqualified hardness/friability and splitting in the tableting process. The preparation has good processability and improves the appearance of the tablet. Improve the quality of tablets, expand the selection of excipients, and reduce costs.

6) Good stability in water. The Form A of the prior art and the AZD5305 crystal form 2 of the present application compete for magma in water and aqueous solvents, and all turn into the crystal form 2 of the present application within 24 hours, indicating that the crystal form 2 of the present application has a better performance in water. stability.

7) Good crystallinity. The AZD5305 crystal form 2 of the present application has good crystallinity.

8) Uniform particle size distribution. The AZD5305 crystal form 2 of the present application has a uniform particle size distribution, can be directly applied to the preparation process, avoids the complicated pretreatment process of the raw material drug, simplifies the process, reduces the production cost, improves the uniformity of the pharmaceutical preparation, and makes the quality of the pharmaceutical preparation better. controllable.

9) The preparation method is simple and suitable for industrial production. In this application, the preparation method of AZD5305 crystal form 2 mainly uses crystal slurry, which is the most common crystal form, which is very easy to realize in industrialization, and the solvent used at the same time contains a lot of water, and water is the cheapest and most environmentally friendly Solvent, low preparation cost.

10) Good chemical stability. After mixing the AZD5305 crystal form 2 of the present application with the excipients, conduct an oxidation test for 10 days (40°C±2°C, carbamide peroxide condition, open), and perform HPLC detection, compared with 0 days, the chemical purity of crystal form 2 The decrease is <0.4%, indicating that the crystal form 2 has good chemical stability.

Another aspect of the present application provides a method for preparing crystal form 2 of AZD5305, the preparation method comprising any one of the following methods:

1) AZD5305 is prepared in solvent 1 as a suspension, crystal slurry, and separated to obtain crystal form 2; or

2) Prepare a solution of AZD5305 in solvent 2, volatilize at a certain temperature, and separate to obtain crystal form 2;

Preferably, in method 1), the solvent 1 is water or a water-containing mixed solvent, and the water-containing mixed solvent is selected from nitriles, alcohols, acetone, tetrahydrofuran, 1,4-dioxane, DMSO, DMF The mixing of any one or combination thereof with water; more preferably the mixing of acetonitrile and/or tetrahydrofuran and water;

Preferably, in method 1), the alcohols are selected from any one of methanol, ethanol, propanol or a combination thereof;

Preferably, in method 1), the mass volume ratio (mg/mL) of said AZD5305 to solvent 1≥ 5; More preferably 10:1-50:1, most preferably 15:1-30:1;

Preferably, in method 1), the water content of the solvent 1 calculated by volume ratio is ≥5%; more preferably ≥50%;

Preferably, in method 1), the temperature of the crystal slurry is room temperature;

Preferably, in method 1), the number of days of the magma slurry is ≥ 2 days; more preferably 2-10 days;

Preferably, in method 1), vacuum drying after separation, the drying temperature is 10°C-50°C, and the time is 1h-48h;

In some embodiments, the drying temperature is 30° C., and the drying time is 24 hours.

Preferably, in method 2), the solvent 2 is water or a water-containing mixed solvent, and the water-containing mixed solvent is selected from methanol, ethanol, propanol, acetone, tetrahydrofuran, 1,4-dioxane, tetrahydrofuran, Any one or combination of acetonitrile mixed with water,

Preferably, the solvent 2 is a mixed solvent of methanol and water;

Preferably, in method 2), the water content of the solvent 2 is ≥5%;

Preferably, in method 2), the volatilization temperature is ≥15°C, more preferably 20-50°C; most preferably 30-50°C.

Another aspect of the present application is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of the AZD5305 crystal form 2 described in the present application, and at least one pharmaceutically acceptable carrier.

Without limitation, the pharmaceutically acceptable carrier is an excipient commonly used in preparations in the art, including but not limited to binders, surfactants, diluents, anti-adhesive agents, hydrophilic or hydrophobic polymers Any of polymers, stabilizers or stabilizers, disintegrants, antioxidants, defoamers, fillers, glidants/lubricants, adsorbents, preservatives, plasticizers, sweeteners, and A mixture of two or more.

Without limitation, when the preparation is an oral solid preparation, the filler or diluent is selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, mannitol Any one or a combination thereof; the disintegrating agent is selected from any one of sodium carboxymethyl starch, cross-linked carmellose sodium, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone or Its combination; the lubricant/glidant is selected from one or a combination of magnesium stearate, talcum powder, micronized silica gel.

Without limitation, the pharmaceutical composition may also include one or more pH adjusters or buffers, for example: acids such as acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, apple Any one of acid, lactic acid, phosphoric acid, hydrochloric acid or a combination thereof; or a base such as any one of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris, or composition; or buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride, and the like; such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, and other counterions ions; and other amounts necessary to maintain the pH of a component within an acceptable range, solutions or solids comprising such acids, bases and buffers.

Without limitation, the pharmaceutical composition can be prepared using techniques known in the art. When preparing the pharmaceutical composition, the crystal form 2 of AZD5305 of the present application is mixed with at least one pharmaceutically acceptable carrier, or by Prepare dosage forms by direct mixing, granulating, tableting or dissolving processes.

Without limitation, the administration routes of the pharmaceutical composition include oral administration, subcutaneous injection, intravenous administration, intramuscular injection, transdermal administration, rectal administration and nasal cavity administration.

Another aspect of the present application is to provide a preparation prepared from the above pharmaceutical composition, and the preparation form is selected from oral solid preparations, external preparations and injections.

In the preferred technical solution of the present application, the preparation forms are tablets, capsules, pills, suppositories, granules, fine granules, powder/powder, sustained-release preparations, quick-release preparations, solutions, suspensions, elixirs, Aerosol etc.

In the preferred technical solution of the present application, the preparation form is a tablet.

Another aspect of the present application is also to provide a use of the AZD5305 crystal form 2 described in the present application or the pharmaceutical composition described in the present application in the preparation of pharmaceutical preparations for treating cancer.

In the preferred technical solution of the present application, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, blood cancer, digestive tract cancer, lung cancer, bladder cancer, cervical cancer and endometrial cancer; preferably, the prostate cancer It is selected from metastatic prostate cancer, the digestive tract is selected from colorectal cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, and the lung cancer is selected from non-small cell lung cancer and small cell lung cancer.

In the preferred technical solution of the present application, the cancer is BRCA1 or BRCA2 deficient phenotype.

In the preferred technical solution of the present application, the cancer is a PARP inhibitor-related cancer, especially a PARP1 inhibitor-related cancer.

Another aspect of the present application is to provide a method for treating or preventing diseases, which includes administering to the patient an effective amount of the AZD5305 crystal form 2 described in the present application or any one of the pharmaceutical compositions described herein or combination; preferably, the disease is cancer.

In the preferred technical solution of the present application, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, blood cancer, digestive tract cancer, lung cancer, bladder cancer, cervical cancer and endometrial cancer; preferably, the prostate cancer It is selected from metastatic prostate cancer, the digestive tract is selected from colorectal cancer, gastric cancer, cholangiocarcinoma, pancreatic cancer, and the lung cancer is selected from non-small cell lung cancer and small cell lung cancer.

In the preferred technical solution of the present application, the cancer is BRCA1 or BRCA2 deficient phenotype.

In the preferred technical solution of the present application, the cancer is a PARP inhibitor-related cancer, especially a PARP1 inhibitor-related cancer.

In the preferred technical scheme of the present application, the method can be administered once a day, twice a day, three times a day or more; a single dose can be 0.1mg-500mg/kg/day, and the specific dosage will be determined according to the actual situation of the patient .

In the preferred technical scheme of the present application, the method is administered twice a day, and the single dose is oral administration of 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg of the crystal form 2 of AZD5305 ; more preferably 300 or 400 mg.

Another aspect of the present application is to provide a combination of the AZD5305 crystal form 2 described in the present application or the pharmaceutical composition described in the present application and other drugs.

In the preferred technical solution of the present application, the other drugs are selected from antitumor drugs.

In the preferred technical solution of the present application, the other drugs are selected from Paclitaxel, Carboplatin, T-Dxd and Dato-DXd.

Unless otherwise specified, "room temperature" in this application refers to a temperature of 10-30°C.

The "separation" can use conventional methods in the art, such as centrifugation or filtration. Wherein, vacuum filtration is generally carried out with suction filtration at a pressure less than atmospheric pressure at room temperature.

The "drying" can be accomplished by conventional techniques in the art, such as drying at room temperature, air blowing or reduced pressure, or under reduced pressure or without reduced pressure. The drying apparatus and method are not limited, and can be fume hood, blast oven, spray dryer, fluidized bed drying or vacuum oven; it can also be carried out under reduced or no reduced pressure.

The "relative intensity (I%)" is expressed as a specific value in a specific XRPD pattern. Based on the anisotropic characteristics of crystals and the principle of X-ray powder diffraction, the relative intensity value of the diffraction peaks of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be regarded as accepted by those skilled in the art.

Unless otherwise specified, the ratios involved in this application are mass-volume ratios between liquids and solids, and volume ratios between liquids and liquids.

Description of drawings

Figure 1 is the XRPD pattern of AZD5305 crystal form 2 prepared in Example 1 of the present application;

Fig. 2 is the TGA diagram of the AZD5305 crystal form 2 prepared in Example 1 of the present application;

Fig. 3 is the DSC diagram of AZD5305 crystal form 2 prepared in Example 1 of the present application;

Fig. 4 is the FT-IR diagram of AZD5305 crystal form 2 prepared in Example 1 of the present application;

Figure 5 is the DVS diagram of AZD5305 crystal form 2 prepared in Example 1 of the present application;

Fig. 6 is an XRPD comparison chart of AZD5305 crystal form 2 prepared in Example 1 of the present application placed under accelerated conditions for 14 days;

Figure 7 is the XRPD comparison chart of AZD5305 crystal form 2 prepared in Example 1 of the present application placed under accelerated and high humidity conditions for 5 months;

Fig. 8 is the XRPD comparison chart of prior art Form A placed under accelerated and high-humidity conditions for 5 months;

Fig. 9 is an XRPD comparison chart of AZD5305 crystal form 2 prepared in Example 1 of the present application during solubility investigation;

Fig. 10 is the XRPD comparison chart of Form A in the prior art during solubility investigation;

Figure 11 is the XRPD comparison chart of the transformation of Form A to AZD5305 crystal form 2 in water;

Figure 12 is the XRPD comparison chart of the transformation of Form A to AZD5305 crystal form 2 in 20% water;

Figure 13 is the XRPD comparison chart of the AZD5305 crystal form 2 of the present application mixed with auxiliary materials before and after tableting (the upper part is after tableting, and the lower part is before tableting).

Detailed ways

The following examples will help to further understand the present application, but are not intended to limit the content of the present application.

Testing instruments and methods:

X-ray powder diffraction (XRPD) data were collected from a Bruker D8 Advance diffractometer. The parameters are as follows: Cu target; wavelength is Current and voltage: 40KV, 40mA; angle range: 3-40°2θ.

Fourier transform infrared spectroscopy (FT-IR) data were collected from Bruker Tensor 27. The parameters are as follows: detection method: ATR method; acquisition range: 600cm ^-1 -4000cm ^-1 ; resolution: 4.0cm ^-1 .

Differential thermal analysis (DSC) data were collected from TA Instruments Q200 DSC. The parameters are as follows: heating rate: 10°C/min; protective gas: N2; sample tray: aluminum crucible with a cover and perforated holes.

Thermogravimetric analysis (TGA) data were collected from TA Instruments Q500 TGA. The parameters are as follows: mode: high resolution mode; heating rate: 10°C/min; protective gas: N2; sample plate: platinum crucible.

Dynamic moisture sorption analysis (DVS) data and isothermal adsorption analysis data were collected from TA Instruments Q5000 TGA. The parameters are as follows: temperature: 25°C; relative humidity range: 0%RH-80%RH; dm/dt=0.001%/min; equilibration time: 90min; protective gas: N2; sample tray: platinum crucible.

Polarized light microscopy (PLM) data were collected from XP-500E. The parameters are as follows: eyepiece 10 times; objective lens 4 times.

HPLC determination method: chromatograph model: Ultimate3000, chromatographic column: C18 3μm (150*4.6mm), column temperature: 30°C, flow rate 1.0mL/min, detection wavelength: 315nm, injection volume: 10μL, running time: 25min, Mobile phase: mobile phase A: 0.1% TFA aqueous solution, mobile phase B: pure acetonitrile, the operating gradient is as follows:

Table 1 HPLC running gradient

In this application, the starting material AZD5305 can be obtained commercially, or can be prepared by existing techniques, such as the method mentioned in WO2021013735A1.

Example 1: Preparation of AZD5305 Form 2

Weigh about 20mg of AZD5305, add an equal volume of water/acetonitrile (v:v=1:1) mixture 1.0mL to make a suspension, slurry at room temperature for 3 days, centrifuge, and vacuum dry at 30°C for 24h to obtain crystal form 2 .

After testing, its XRPD data is shown in the table below:

Its X-ray powder diffraction pattern is shown in Figure 1.

Its TGA spectrum is shown in Figure 2. Before heating to 120°C, there is a weight loss of about 2.2%, which is consistent with the theoretical water content of the hemihydrate.

Its DSC spectrum is shown in Figure 3.

Its FT-IR spectrum is shown in Figure 4.

Its DVS spectrum is shown in Figure 5, and the weight gain is about 1.2% under the environment of 0% RH to 80% RH.

Example 2: Preparation of AZD5305 Form 2

Weigh about 15 mg of AZD5305, add 0.7 mL of water and 0.7 mL of tetrahydrofuran to make a suspension, slurry at room temperature for 2 days, centrifuge, and vacuum dry at 30°C for 24 hours to obtain Form 2.

After testing, its XRPD data is shown in the table below:

Example 3: Preparation of AZD5305 Form 2

Weigh about 15 mg of AZD5305, add 1.0 mL of methanol to dissolve, filter, then add 0.1 mL of water, mix well, place at 40°C to volatilize, and a solid precipitates to obtain Form 2.

Embodiment 4: investigation of crystal form stability

Take 5 mg of the crystal form 2 sample of AZD5305 of the present application, and place it under accelerated (40° C., 75% RH, open) conditions. The results showed that the crystal form 2 remained unchanged for 14 days after the acceleration, and its XRPD pattern is shown in FIG. 6 .

In addition, take the AZD5305 crystal form 2 sample of the present application and the Form A of the prior art, and place them under accelerated (40°C/75%RH, open) and high humidity (room temperature/97%RH, open) conditions respectively, The results show that the crystal form 2 remains unchanged for 5 months under accelerated and high-humidity conditions, and its XRPD pattern is shown in Figure 7; it transforms into a mixed crystal of Form A and crystalline form 2 after 5 months under accelerated conditions , and its XRPD pattern is shown in Figure 8.

The results show that the AZD5305 crystal form 2 of the present application has better crystal form stability than the Form A of the prior art.

Embodiment 5: Solubility investigation

Take the AZD5305 crystal form 2 of the present application, add water and pH4.5 acetate buffer respectively at room temperature (Preparation method: put 2.99g of sodium acetate trihydrate in a 1000mL volumetric flask, add 14.0mL of 2N acetic acid solution, and dilute to the mark with water), mix well, take a sample to determine its crystal form and solubility after 24 hours, and the results show :

In water: the AZD5305 crystal form 2 of the present application and the Form A of the prior art have considerable solubility, and the solubility in water after 24 hours is >25ug/mL; the crystal form of the AZD5305 crystal form 2 of the present application remains unchanged before and after the solubility measurement, Its XRPD spectrum is shown in Figure 9, while the Form A of the prior art is converted to the crystal form 2 of the present application, and its XRPD spectrum is shown in Figure 10;

In pH4.5 acetate buffer: the AZD5305 crystal form 2 of the present application and the Form A of the prior art have considerable solubility, and the solubility in the pH4.5 acetate buffer after 24 hours is >200ug/mL; The applied AZD5305 crystal form 2 remains unchanged before and after the solubility measurement, and its XRPD spectrum is shown in Figure 11, while the Form A of the prior art is converted to the crystal form 2 of the present application, and its XRPD spectrum is shown in Figure 12 .

Embodiment 6: magma competition experiment

Weigh about 20 mg of the Form A sample of the prior art, add 1 mL of water to make a suspension, then add 1 mg of the crystal form 2 seed crystal of the present application, place the crystal slurry at room temperature, take regular samples for testing, and take the solid to measure XRPD, the result is It was shown that Form A was slurried in water, turned into mixed crystals in 8 hours, and completely turned into Form 2 in 24 hours, and its XRPD pattern is shown in Figure 11.

Weigh about 10 mg of the Form A sample of the prior art, and about 10 mg of the crystal form 2 of the present application, add 0.4 mL of acetonitrile and 0.1 mL of water to make a suspension, 18 hours at room temperature, take the solid to measure XRPD, the results show that Form A and crystalline form 2 were slurried in 20% water, and completely transformed into crystalline form 2 of the present application within 18 hours, and its XRPD pattern is shown in FIG. 12 .

Embodiment 7: the preparation of tablet

According to the prescription in the table below, the components were mixed, granulated and compressed to prepare tablets.

Table 2: Tablet Prescription

Embodiment 8: Examination of compressibility

Weigh about 6mg of API, 16.5mg of microcrystalline cellulose, 13.5mg of anhydrous lactose, 0.75mg of crospovidone and 0.75mg of silicon dioxide, mix well and press it under an infrared tablet press for 10S at 2MPa pressure, and take samples before and after Perform XRPD detection. The results show that the crystal form 2 of the present application remains unchanged before and after tableting, and the crystallinity remains unchanged, and its XRPD spectrum is shown in Figure 13 (the upper part is after tableting, the lower part is before tableting), indicating that The applied crystal form 2 has good compressibility and formulation processability.

Embodiment 9: the chemical stability investigation of tablet

Weigh about 2.4mg of the crystal form 2 of the present application, 6.6mg of microcrystalline cellulose, 5.4mg of anhydrous lactose, 0.3mg of crospovidone and 0.3mg of silicon dioxide, mix well and then oxidize (40°C±2°C, Carbamide peroxide condition) 10 days, regular detection. The results showed that compared with 0 day, the chemical purity of the crystal form 2 of the present application decreased by <0.4% after 10 days, indicating that the crystal form 2 has good chemical stability.

Embodiment 10: Dissolution investigation of tablet

Take the tablet of the crystal form 2 prepared in Example 7; according to the tablet prescription in Example 7, replace the crystal form 2 with Form A to prepare the tablet of Form A; respectively prepare the tablet of the crystal form 2 and Tablets of Form A are tested for dissolution according to the following method:

Dissolution medium: pH4.5 acetate buffer

Medium volume: 900mL

Dissolution method: slurry method

Medium temperature: 37°C

Speed: 75rpm

The dissolution results of 120min are shown in Table 3 below.

Table 3: Dissolution results of tablets (120min)

The results show that: the tablet of the present application crystal form 2 and the tablet of the prior art Form A have a cumulative dissolution rate of 120 minutes in pH4.5 acetate buffer solution exceeding 85%, and the cumulative dissolution rate in 60 minutes All ≥ 80%, indicating that the tablet made by the crystal form 2 of the present application and the tablet made by the prior art Form A have a considerable dissolution rate.

The above is only a specific embodiment of the application, but the scope of protection of the application is not limited thereto, any person familiar with the art within the technical scope disclosed in this application may Changes or substitutions thought of by sex labor should be covered within the scope of protection of this application. Therefore, the protection scope of the present application should be determined by the protection scope defined in the claims.

Claims (15)

1. A crystal form 2 of AZD5305 whose structural formula is shown in formula (I),
   

   It is characterized in that, using Cu-Kα radiation, the XRPD spectrum of the crystal form 2 expressed in 2θ angle is at least one of 9.1°±0.2°, 19.1°±0.2°, 19.5°±0.2° and 20.3°±0.2° There are characteristic peaks; preferably at least three characteristic peaks.
2. The crystal form 2 according to claim 1, wherein the XRPD spectrum of the crystal form 2 is further at 12.3°±0.2°, 18.9°±0.2°, 20.8°±0.2° and 21.1°±0.2°2θ At least one of the characteristic peaks.
3. The crystal form 2 according to claim 1 or 2, wherein the XRPD spectrum of the crystal form 2 is further at 22.6°±0.2°, 16.6°±0.2°, 18.5°±0.2°, 23.2°±0.2° , 24.4°±0.2°, 25.0°±0.2° and 26.5°±0.2°2θ have at least one characteristic peak.
4. The crystal form 2 of AZD5305 according to any one of claims 1-3, wherein the XRPD spectrum of the crystal form 2 is at 9.1°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 20.3 There are characteristic peaks at °±0.2° and 20.8°±0.2°2θ.
5. The crystal form 2 according to claim 4, wherein the XRPD spectrum of the crystal form 2 is also 12.3°±0.2°, 16.6°±0.2°, 18.5°±0.2°, 19.5°±0.2° and 21.1° At least one of °±0.2°2θ has a characteristic peak.
6. The crystal form 2 according to claim 4, wherein the XRPD spectrum of the crystal form 2 is also 22.6°±0.2°, 23.2°±0.2°, 24.4°±0.2°, 25.0°±0.2° and 26.5° At least one of °±0.2°2θ has a characteristic peak.
7. The crystal form 2 according to any one of claims 1-6, wherein the XRPD spectrum of the crystal form 2 has a diffraction peak at the position of the following table at 2θ:
   
   
   
8. The crystal form 2 according to any one of claims 1-7, characterized in that, the crystal form 2 has an XRPD spectrum substantially as shown in FIG. 1 .
9. The crystal form 2 according to any one of claims 1-8, characterized in that, the Fourier transform infrared spectrum of the crystal form 2 is at 3414cm ^-1 ±2cm ^-1 , 1570cm ^-1 ±2cm ^-1 , 1527cm ^-1 At least one of ¹ ±2cm ^-1 , 932cm ^-1 ±2cm ^-1 , 922cm ^-1 ±2cm ^-1 and 634cm ^-1 ±2cm ^-1 has a characteristic peak; further at 1647cm ^-1 ±2cm ^-1 , 1583cm ^- At least one of ¹ ±2cm ^-1 , 1249cm ^-1 ±2cm ^-1 , 1230cm ^-1 ±2cm ^-1 , 675cm ^-1 ±2cm ^-1 and 626cm ^-1 ±2cm ^-1 has a characteristic diffraction peak.
10. The crystal form 2 according to any one of claims 1-9, wherein the crystal form 2 is a hydrate; preferably, the number of water molecules in the hydrate is 0.1-2; more preferably 0.1 -1.
11. The preparation method of the crystal form 2 of AZD5305 according to any one of claims 1-10, characterized in that the preparation method comprises any one of the following methods:

    1) AZD5305 is prepared in solvent 1 as a suspension, crystal slurry, and separated to obtain crystal form 2; or

    2) Prepare a solution of AZD5305 in solvent 2, volatilize at a certain temperature, and separate to obtain crystal form 2;

    Preferably, in method 1), the solvent 1 is water or a water-containing mixed solvent, and the water-containing mixed solvent is selected from nitriles, alcohols, acetone, tetrahydrofuran, 1,4-dioxane, DMSO, DMF The mixing of any one or combination thereof with water; more preferably the mixing of acetonitrile or tetrahydrofuran and water;

    Preferably, in method 1), the mass volume ratio (mg/mL) of the AZD5305 to solvent 1 is ≥5; more preferably 10:1-50:1, most preferably 15:1-30:1;

    Preferably, in method 1), the water content of the solvent 1 calculated by volume ratio is ≥5%; more preferably ≥50%;

    Preferably, in method 1), the temperature of the crystal slurry is room temperature;

    Preferably, in method 1), the number of days of the magma slurry is ≥ 2 days; more preferably 2-10 days;

    Preferably, in method 1), vacuum drying after separation, the drying temperature is 10°C-50°C, and the time is 1h-48h;

    Preferably, in method 2), the solvent 2 is water or a water-containing mixed solvent, and the water-containing mixed solvent is selected from methanol, ethanol, propanol, acetone, tetrahydrofuran, 1,4-dioxane, tetrahydro furfur Any one of furan, acetonitrile or their combination mixed with water,

    Preferably, the solvent 2 is a mixed solvent of methanol and water;

    Preferably, in method 2), the water content of the solvent 2 is ≥5%;

    Preferably, in method 2), the volatilization temperature is ≥15°C, more preferably 20-50°C; most preferably 30-50°C.
12. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form 2 of AZD5305 according to any one of claims 1-10, and at least one pharmaceutically acceptable carrier;

    Preferably, the pharmaceutical composition is a tablet or a capsule.
13. A use of the crystal form 2 of AZD5305 selected from any one of claims 1-10 or the pharmaceutical composition of claim 12 in the preparation of pharmaceutical preparations for treating cancer.
14. A method for treating or preventing a disease, comprising administering to a patient an effective amount of any one of the crystal form 2 of AZD5305 described in any one of claims 1-10 or any one of the pharmaceutical composition described in claim 12 or its combination; preferably, the disease is cancer.
15. The combined application of the crystal form 2 of AZD5305 described in any one of claims 1-10 or the pharmaceutical composition described in claim 12 and other drugs;

    Preferably, the other drugs are selected from antitumor drugs;

    Preferably, said other drug is selected from Paclitaxel, Carboplatin, T-Dxd and Dato-DXd.