Quantitative detection method for crystal of cap-dependent endonuclease inhibitor and crystal form of cap-dependent endonuclease inhibitor

Abstract

The present invention provides a crystal form of a cap-dependent endonuclease inhibitor. The crystal form has low hygroscopicity and excellent stability. In addition, the present invention provides a high-accuracy and high-sensitivity method for determining the content of crystal form A in a cap-dependent endonuclease inhibitor sample using a powder X-ray diffraction method.

Description

Quantitative Detection Method and Crystal Forms of Cap-Dependent Nucleotide Inhibitors

[0001] This application claims priority to the following prior patent application: the application filed by the applicant with the China National Intellectual Property Administration on December 31, 2024, with patent application number 202411986929.6 and entitled "Quantitative Detection Method for Crystal Form of Cap-Dependent Nucleotide Endonuclease Inhibitor and Crystal Form Thereof"; the entire contents of the aforementioned prior patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceuticals, specifically relating to a method for quantitative detection of cap-dependent nuclease inhibitor crystals and their crystal forms. Background Technology

[0003] PCT international patent application WO2019 / 144089A1 discloses an anti-influenza heterocyclic compound A, [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazophen-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyridino[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate. This heterocyclic compound exists in various solid forms, and different solid forms may affect the bioequivalence and bioavailability of the oral drug. Therefore, there is an urgent need to develop new solid forms with good stability, such as crystalline forms, to provide better options for the development of this drug.

[0004] Furthermore, the inventors discovered during the formulation process that after preparing a solid dispersion formulation using a stable crystal form, there is a risk of transformation into a different crystal form, affecting drug solubility. Therefore, detecting the content of crystal form A in the formulation is essential. Currently, the main methods for quantitative determination of drug crystal forms include powder X-ray diffraction, micro-Raman spectroscopy, and solid-state NMR, with powder X-ray diffraction being the most commonly used. However, conventional quantitative detection methods have low sensitivity, making accurate quantification difficult when the content of the analyte is too small. To address this issue, it is necessary to develop a method using powder X-ray diffraction for highly sensitive and accurate quantitative determination of the crystal form in cap-dependent nuclease inhibitor capsules. Summary of the Invention

[0005] This invention provides a cap-dependent endonuclease inhibitor crystal form, wherein the crystal form is crystal form A of compound A, and compound A is [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolin-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyrido[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate;

[0006] The X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 18.02°±0.2°, 21.02°±0.2°, 21.62°±0.2°, 22.88°±0.2°, and 24.62°±0.2°.

[0007] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 11.22°±0.2°, 12.54°±0.2°, 13.00°±0.2°, 26.26°±0.2°, and 28.18°±0.2°.

[0008] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 18.88°±0.2°, 22.54°±0.2°, 24.36°±0.2°, 26.56°±0.2°, 27.74°±0.2°, 29.28°±0.2°, and 30.98°±0.2°.

[0009] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 9.58°±0.2°, 19.62°±0.2°, 29.04°±0.2°, 31.98°±0.2°, 34.36°±0.2°, 36.62°±0.2°, and 42.98°±0.2°.

[0010] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 22.54°±0.2°, 26.26°±0.2°, 28.18°±0.2°.

[0011] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 11.22°±0.2°, 12.54°±0.2°, 13.00°±0.2°, 18.88°±0.2°, 27.74°±0.2°.

[0012] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 24.36°±0.2°, 26.56°±0.2°, 29.04°±0.2°, 29.28°±0.2°, 30.98°±0.2°, 42.98°±0.2°.

[0013] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 16.38°±0.2°, 16.62°±0.2°, 19.34°±0.2°, 19.62°±0.2°, 31.98°±0.2°, 33.42°±0.2°, 34.36°±0.2°, 35.44°±0.2°, 36.62°±0.2°, 39.90°±0.2°, 41.10°±0.2°.

[0014] According to an embodiment of the present invention, the analytical data of the X-ray powder diffraction pattern of crystal form A are shown in Table 1, wherein the error range of 2θ for each characteristic diffraction peak is ±0.2°. According to an embodiment of the present invention, crystal form A has an X-ray powder diffraction pattern basically as shown in Figure 5.

[0015] According to an embodiment of the present invention, the differential scanning calorimetry (DSC) chart of crystal form A is essentially as shown in Figure 6. According to an embodiment of the present invention, the DSC chart of crystal form A shows an endothermic peak at 234±5℃. According to an embodiment of the present invention, the thermogravimetric analysis (TGA) chart of crystal form A is essentially as shown in Figure 7. According to an embodiment of the present invention, the TGA chart of crystal form A shows a weight loss of 0.2% at the initial heating to 246±5℃.

[0016] The present invention also provides a method for preparing the above-mentioned crystal form, which includes the following steps: stirring or suspending and stirring compound A in a solvent to crystallize and obtain crystal form A;

[0017] Compound A is [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazopyro-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyrido[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate.

[0018] According to an embodiment of the present invention, the solvent is one or more combinations of anhydrous methanol, benzyl alcohol, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, acetone, 2-butanone, methyl isobutyl ketone, methyl tert-butyl ether, 1,4-dioxane, dichloromethane, anhydrous ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-heptane, n-hexane, cyclohexane, anhydrous diethyl ether, isopropyl ether, petroleum ether, toluene, water, or ethylene glycol dimethyl ether.

[0019] According to an embodiment of the present invention, the crystallization includes the following steps: compound A is dissolved in one or more combined solvents of ethyl acetate, acetonitrile or acetone at a temperature of 45°C-75°C, and then rapidly evaporated to obtain crystal form A.

[0020] The present invention also provides a pharmaceutical composition comprising the above-described crystal form, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0021] According to an embodiment of the present invention, the pharmaceutical composition is used to combat influenza viruses. According to an embodiment of the present invention, the influenza includes influenza A, influenza B, or influenza A and B. According to an embodiment of the present invention, the influenza includes adult influenza A, adult influenza B, adult influenza A and B, and uncomplicated acute infection of uncomplicated influenza A and B in individuals aged 12 years and older.

[0022] The present invention also provides the use of the above-described crystal form and pharmaceutical composition in the preparation of a medicament for use against influenza viruses. According to embodiments of the present invention, the influenza includes influenza A, influenza B, and influenza A and B. According to embodiments of the present invention, the influenza includes adult influenza A, adult influenza B, adult influenza A and B, and uncomplicated acute infection of uncomplicated influenza A and B in individuals aged 12 years and older.

[0023] The present invention also provides a method for treating influenza virus, the method comprising administering to a patient an effective amount of the above-described crystalline form and pharmaceutical composition.

[0024] According to an embodiment of the present invention, the influenza includes influenza A, influenza B, or influenza A and influenza B.

[0025] According to an embodiment of the present invention, the influenza includes adult influenza A, adult influenza B, adult influenza A and B, and uncomplicated acute influenza A and B infection in individuals aged 12 years and older.

[0026] This invention also provides a method for quantitative detection of the crystal form in a cap-dependent nuclease inhibitor sample, wherein the crystal form is crystal form A of compound A, and compound A is [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolin-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyridino[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate. The quantitative detection method uses a powder X-ray diffractometer to measure the sample and performs quantification based on a standard curve.

[0027] According to an embodiment of the present invention, the quantitative detection method uses any one, two or more of 2θ = 12.6°±0.2°, 13.1°±0.2°, and 18.0°±0.2° as the quantitative characteristic peak of crystal form A.

[0028] According to an embodiment of the present invention, the sample includes a solid dispersion sample and a capsule sample.

[0029] According to an embodiment of the present invention, when the sample is a solid dispersion sample, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 17°-18.6°.

[0030] According to an embodiment of the present invention, when the sample is a solid dispersion sample, 13.1°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 12°-13.5°.

[0031] According to an embodiment of the present invention, when the sample is a solid dispersion sample, 12.6°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 12°-13.5°.

[0032] According to an embodiment of the present invention, when the sample is a capsule sample, 12.6°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 12°-13.5°.

[0033] According to an embodiment of the present invention, when the sample is a capsule sample, 13.1°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 12°-13.5°.

[0034] According to an embodiment of the present invention, when the sample is a capsule sample, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A; preferably, the 2θ angle scanning range is 17°-18.6°.

[0035] According to an embodiment of the present invention, during the standard curve establishment process, solid dispersions containing different proportions of crystal form A are prepared; preferably, the proportion of crystal form A in the indicated amount is 0.1%-30.0%; for example: 0.5%, 1.0%, 2.0%, 5.0%, 10.0%, 15.0% and 20.0%.

[0036] According to an embodiment of the present invention, during the standard curve establishment process, capsule standard samples containing different proportions of crystal form A are prepared; preferably, the proportion of crystal form A in the labeled amount is 0.1%-40.0%; for example: 5.0%, 7.5%, 10.0%, 15.0%, 20.0% and 30.0%.

[0037] According to an embodiment of the present invention, the quantitative detection method includes the following steps:

[0038] (1) Prepare standard samples of crystal form A, solid dispersion standard samples and capsule standard samples;

[0039] (2) The standard sample was measured using a powder X-ray diffractometer to establish a standard curve and to determine the content of crystal form A in the sample to be tested.

[0040] According to an embodiment of the present invention, the solid dispersion sample comprises: compound A and a support. According to an embodiment of the present invention, the support is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0041] According to an embodiment of the present invention, the capsule sample comprises: compound A and excipients. According to an embodiment of the present invention, the excipients comprise: Microcrystalline cellulose, croscarmellose sodium, etc.

[0042] According to the embodiment of the present invention, in the process of establishing the standard curve in step (2), any one, two or more of 2θ = 12.6°±0.2°, 13.1°±0.2°, and 18.0°±0.2° are used as the quantitative characteristic peaks of crystal form A.

[0043] According to an embodiment of the present invention, in step (2) of establishing the standard curve of the solid dispersion sample, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A. According to an embodiment of the present invention, in step (2) of establishing the standard curve of the solid dispersion sample, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 17°-18.6°.

[0044] According to an embodiment of the present invention, in step (2) of establishing the standard curve of the capsule sample, 13.1°±0.2 is selected as the quantitative characteristic peak of crystal form A. According to an embodiment of the present invention, in step (2) of establishing the standard curve of the capsule sample, 13.1°±0.2 is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 12°-13.5°.

[0045] According to an embodiment of the present invention, Kα rays from a copper target are used as the diffraction source, the working voltage is 40kV-45kV, the working current is 40mA, the scanning time is 2000-5000s, and the number of scans is 1-3.

[0046] According to an embodiment of the present invention, when determining the content of crystal form A in a solid dispersion sample, the 2θ angle scan range is 17°-18.6°.

[0047] According to an embodiment of the present invention, when determining the content of crystal form A in a capsule sample, the 2θ angle scanning range is 12°-13.5°.

[0048] According to an embodiment of the present invention, the operating voltage is 40kV or 45kV.

[0049] According to an embodiment of the present invention, the scanning time is 2000s, 3000s, 4000s or 5000s.

[0050] According to an embodiment of the present invention, the number of scans is 1, 2, or 3.

[0051] According to an embodiment of the present invention, the method for determining the content of crystal form A in a solid dispersion sample uses Kα rays from a copper target as a diffraction source, sets the working voltage to 45kV, the working current to 40mA, the scanning time to 3000s, the number of scans to 2, the scanning range to 17°-18.6°, the step size to 0.026°, the divergence slit to 1 / 4°, and the anti-scattering slit to 7.5mm.

[0052] According to an embodiment of the present invention, the method for determining the content of crystal form A in a capsule sample uses Kα rays from a copper target as a diffraction source, sets the working voltage to 45kV, the working current to 40mA, the scanning time to 3000s, the number of scans to 2, the scanning range to 12°-13.5°, the step size to 0.026°, the divergence slit to 1 / 4°, and the anti-scattering slit to 7.5mm.

[0053] According to an embodiment of the present invention, before the determination, the sample to be tested and the standard sample are mixed by vortex mixing or sieving. Sieving is preferred, specifically mixing through a 200-mesh sieve.

[0054] According to an embodiment of the present invention, before the determination, a mixed crystal form A standard sample is sieved, specifically sieved through a 200-mesh sieve.

[0055] According to an embodiment of the present invention, the solid dispersion sample is mixed by passing it through a 200-mesh sieve before sampling and testing.

[0056] According to an embodiment of the present invention, the capsule sample is ground, passed through a 200-mesh sieve, and then sampled and tested.

[0057] According to an embodiment of the present invention, step (1) of preparing solid dispersion standard samples specifically involves preparing solid dispersions with different proportions of crystal form A; preferably, the proportion of crystal form A in the indicated amount is 0.1%-30.0%; for example: 0.2%, 0.5%, 1.0%, 2.0%, 5.0%, 10.0%, 15.0% and 20.0%.

[0058] According to an embodiment of the present invention, solid dispersion standard samples with different proportions of crystal form A were prepared, and a standard curve was established: seven standard samples were prepared, with crystal form A accounting for 0.5%, 1.0%, 2.0%, 5.0%, 10.0%, 15.0%, and 20.0% of the labeled amount. The selected 2θ position was 18.0°±0.2° as the quantitative characteristic peak, and the linear equation was y=729687x-2243.4, with a correlation coefficient r=0.9910.

[0059] According to an embodiment of the present invention, step (1) of preparing capsule standard samples specifically involves preparing capsule standard samples with different proportions of crystal form A; preferably, the proportion of crystal form A in the labeled amount is 0.1%-40.0%; for example: 2.0%, 3.0%, 5.0%, 7.5%, 10.0%, 15.0%, 20.0% and 30.0%.

[0060] According to an embodiment of the present invention, capsule standard samples with different proportions of crystal form A were prepared, and a standard curve was established: Six standard samples were prepared, with crystal form A accounting for 5.0%, 7.5%, 10.0%, 15.0%, 20.0%, and 30.0% of the labeled amount. The selected 2θ position was 13.1°±0.2 as the quantitative characteristic peak, y=58738x-1507.2, and the correlation coefficient r=0.9952.

[0061] The present invention also provides a solvate, wherein the solvate is a solvate formed with dichloromethane, and the mass percentage of compound A with dichloromethane is 3.45%-10.01%, preferably 7.73%.

[0062] According to an embodiment of the present invention, the solvate satisfies one or more of the following conditions:

[0063] (1) The X-ray powder diffraction pattern of the solvate, expressed in terms of a 2θ angle, is basically shown in Figure 8.

[0064] (2) The differential scanning calorimeter of the solvate is basically as shown in Figure 9.

[0065] (3) The thermogravimetric analysis diagram of the solvate is basically shown in Figure 10. Beneficial effects

[0066] This invention provides a crystal form of a cap-dependent endonuclease inhibitor, which exhibits low hygroscopicity and excellent stability. Furthermore, this invention provides a highly accurate and sensitive method for determining the content of crystal form A in a cap-dependent endonuclease inhibitor sample using powder X-ray diffraction. Attached Figure Description

[0067] Figure 1 shows the XRPD overlay patterns of crystal form A, blank excipient, and support (Soluplus);

[0068] Figure 2 shows the XRPD pattern of a horizontal solid dispersion with crystal form A accounting for 0.2% of the indicated amount;

[0069] Figure 3 shows the XRPD spectra of the solid dispersion at a level where crystal form A accounts for 0.5% of the indicated amount and at a voltage of 40 kV;

[0070] Figure 4 shows the XRPD spectra of the solid dispersion at a level where crystal form A accounts for 0.5% of the indicated amount and at a voltage of 45 kV;

[0071] Figure 5 shows the XRPD diagram of crystal form A;

[0072] Figure 6 shows the DSC diagram of crystal form A;

[0073] Figure 7 shows the TGA diagram of crystal form A;

[0074] Figure 8 shows the XRPD pattern of the solvate;

[0075] Figure 9 shows the DSC diagram of the solvate;

[0076] Figure 10 shows the TGA graph of the solvate:

[0077] Figure 11 shows the amorphous XRPD plot;

[0078] Figure 12 shows an amorphous DSC diagram;

[0079] Figure 13 shows the amorphous TGA diagram;

[0080] Figure 14 shows the XRPD diagram of the solvate obtained by evaporation at room temperature;

[0081] Figure 15 shows the TGA graph of the solvate obtained by evaporation at room temperature;

[0082] Figure 16 shows the XRPD of the solubilized compound after being left exposed at room temperature for 3 days.

[0083] Figure 17 shows the TGA graph of the solubilized compound after being left exposed at room temperature for 3 days.

[0084] Figure 18 shows the XRPD of the solvate after drying at 70℃ for 1 h 40 min;

[0085] Figure 19 is the TGA graph of the solvate after drying at 70℃ for 1 h 40 min;

[0086] Figure 20 shows the drying time of the solvate at 70℃ for 1 hour and 40 minutes. 1 H-NMR spectrum;

[0087] Figure 21 shows the PXRD patterns of crystal form A before and after DVS;

[0088] Figure 22 shows the PXRD patterns of the solvate before and after DVS;

[0089] Figure 23 shows the PXRD patterns of the amorphous DVS before and after;

[0090] Figure 24 shows the experimental results of the stability of crystal form A;

[0091] Figure 25 shows the experimental results of the stability of the solvate;

[0092] Figure 26 shows the results of the stability test for amorphous materials. Detailed Implementation

[0093] This invention is intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this invention. This invention is by no means limited to the methods and materials described herein.

[0094] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0095] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0096] Example 1: Preparation and testing of compound A and its crystal form A

[0097] 1.1 Preparation of Compound A

[0098] Compound A, a cap-dependent endonuclease inhibitor, chemically named [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazopyro-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyrido[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate, was prepared according to the synthetic route and scheme disclosed in patent WO2019 / 144089A1. The mass spectrometry (MS) and nuclear magnetic resonance (NMR) data of compound A are as follows: MS: m / z 541.0 (M++1); 1 H NMR (CDCl3) δ7.31 (d, 1H), 7.06-7.00 (m, 4H), 6.85-6.84 (m, 1H), 6.73 (d, 1H), 6.03 (d, 1H), 5.96 (d, 1H), 5.80 (d, 1H), 5.49 (d, 1 H), 5.15 (s, 1H), 4.13 (d, 1H), 4.05 (d, 1H), 3.87 (s, 3H), 2.91 (d, 1H), 1.95-1.90 (m, 1H), 1.49-1.48 (m, 1H), 0.88-0.76 (m, 2H).

[0099] 1.2 Preparation of Crystal Form A, Solvate, and Amorphous Form

[0100] The reaction product of compound A, prepared by the above synthetic route and scheme, was purified by conventional methods such as filtration to remove impurities and obtain crude product. An appropriate amount of good solvent was added to dissolve the crude product, and an evaporation experiment was conducted.

[0101] Preparation method of crystal form A of compound A: Dissolve compound A in acetone and evaporate rapidly to obtain crystal form A.

[0102] The crystal form A of compound A, PXRD pattern is shown in Figure 5. Its characteristic diffraction peaks are located at 2θ values ​​of 9.58, 11.22, 12.54, 13.00, 13.78, 14.38, 16.38, 16.62, 18.02, 18.88, 19.34, 19.62, 20.39, 21.02, 21.62, 22.54, 22.88, 24.36, 24.62, 25.54, 26.26, 26.56, 27.74, and 28. The X-ray powder diffraction data, expressed as 2θ angles, are shown in Table 1 below. The DSC characterization results (Figure 6) show that the melting point of crystal form A is 234.86 °C (Tonset). The TGA characterization results (Figure 7) show that crystal form A begins to decompose after 246.63℃, and the weight loss before the decomposition temperature is only 0.2029%, indicating that crystal form A is a solvent-free crystal form. The characterization data of crystal form A are as follows: 1H NMR (400MHz, Chloroform-d): δ7.28 (d, J=7.8Hz, 1H), 7.10-6.99 (m, 3H), 6.96 (dd, J=8.9, 4.6Hz, 1H), 6.81 (tt, J=8.7, 3.9Hz, 1H), 6.71 (d, J=7.7Hz, 1H), 5.93 (dd, J=11.9, 7.1Hz, 2H), 5.75 (d, J=6.5Hz, 1H), 5.48 (dd, J=13.7, 2.6Hz, 1H), 5 .12 (s, 1H), 4.11 (d, J = 14.7Hz, 1H), 4.01 (d, J = 13.7Hz, 1H), 3.83 (s, 3H), 2.89 (d, J = 14.7Hz, 1H), 1.89 (ddd, J = 10.6, 7. 2, 2.9Hz, 1H), 1.45 (ddd, J=10-3, 6.9, 3.6Hz, 1H), 0.81 (td, J=8.1, 7.0, 3.6Hz, 1H), 0.74 (ddd, J=9.5, 6.9, 2.9Hz, 1H).

[0103] Table 1 X-ray powder diffraction data for crystal form A

[0104] The specific preparation process of the solvate is as follows: Compound A is dissolved in dichloromethane, cooled, and crystallized to obtain the solvate. Its PXRD pattern is shown in Figure 8, DSC pattern in Figure 9, and TGA pattern in Figure 10. Thermal analysis shows that the solvate exhibits an endothermic desolvation peak at 70-75℃, corresponding to a desolvation weight loss step of 10.23%. As the temperature increases, a melting endothermic peak appears at 232.86℃, with a melting point of 233.72℃. Decomposition begins after 241.69℃.

[0105] The specific preparation process of the amorphous form is as follows: Compound A is dissolved in tetrahydrofuran, the solvent is evaporated, and the mixture is dried to obtain the amorphous form. Its PXRD pattern is shown in Figure 11, DSC pattern in Figure 12, and TGA pattern in Figure 13. DSC and TGA characterization results show that the amorphous form exhibits a crystallization peak at 147.54℃, and with increasing temperature, a melting endothermic peak appears at 230.72℃. This temperature is close to the melting peak of crystalline form A (233.24℃), suggesting that the amorphous form transforms into crystalline form A upon heating, and finally begins to decompose after 243.89℃.

[0106] 1.3 Solubility

[0107] The solubility of crystal form A was tested. Approximately 10 mg of sample was taken, added to solvent, and subjected to thorough ultrasonic agitation. The dissolution phenomenon was observed, and the results of the preliminary solubility test are as follows:

[0108] Solvents with solubility >12 mg / mL: nitromethane, DMF, DMSO, N-methylpyrrolidone;

[0109] Solvents with solubility in the range of 2.5 mg / mL to 10 mg / mL: anhydrous methanol, benzyl alcohol, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, acetone, 2-butanone, methyl isobutyl ketone, methyl tert-butyl ether, 1,4-dioxane, and dichloromethane.

[0110] Solvents with solubility <2.5 mg / mL: anhydrous ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-heptane, n-hexane, cyclohexane, anhydrous diethyl ether, isopropyl ether, petroleum ether, toluene, water, and ethylene glycol dimethyl ether.

[0111] 1.3 Solvent Desolventization Test

[0112] The solvent was removed by a solvent removal experiment. The sample was obtained by dissolving dichloromethane and then evaporating it at room temperature. The PXRD results are shown in Figure 14 and the TGA results are shown in Figure 15. The solvent content was determined to be 10.01%.

[0113] After being left exposed at room temperature for three days, PXRD analysis was performed. At this time, the powder had become a mixed crystal state of crystal form A and solvate. The PXRD results are shown in Figure 16. The solvent content was determined by TGA, and a significant decrease in solvent content of 3.453% was observed. The TGA results are shown in Figure 17.

[0114] The sample was incubated at 70℃ for 1 hour and 40 minutes to remove the solvent, and then subjected to PXRD analysis. The results showed that the powder transformed into crystal form A at this point, as shown in Figure 18. The solvent content was determined using TGA, and almost no solvent residue was observed, as shown in Figure 19. This sample was then subjected to… 1 H-NMR analysis showed that the chemical structure of the sample remained unchanged. 1 The H-NMR spectrum results are shown in Figure 20.

[0115] Experimental results show that the dichloromethane solvate can be desolventized by heating to obtain crystal form A. Under the above conditions, it is shown that crystal form A of compound A is stable.

[0116] 1.4 Suspension Competition Experiment

[0117] The relative stability of crystalline form A, solvate, and amorphous form at room temperature in different solvents (including ethanol, ethyl acetate, methyl tert-butyl ether, acetone, isopropyl ether, and butyl acetate) was investigated using a suspension competition experiment. The results are shown in Table 2.

[0118] Table 2 Results of the competitive suspension experiment

[0119] The solvent-mediated suspension competition experiment results of pairwise combinations of crystal form A, solvate and amorphous form show that in all solvents shown in Table 2, pairwise combinations all transform into crystal form A, which is a more thermodynamically stable solid form.

[0120] 1.5 Hygroscopicity Test

[0121] The hygroscopic behavior of crystalline form A, solvate and amorphous forms was analyzed using a dynamic moisture adsorption analyzer (DVS).

[0122] Crystal form A absorbs 0.0195% moisture in the relative humidity (RH) range of 40-80%; combined with the PXRD detection spectra before and after DVS, crystal form A did not undergo crystal form transformation. The PXRD results are shown in Figure 21.

[0123] The solvate absorbs 0.346% moisture within a relative humidity (RH) range of 40-80%. Based on the PXRD spectra before and after DVS, the solvate did not undergo a crystal transformation. The PXRD results are shown in Figure 22.

[0124] The amorphous form absorbs 0.355% moisture within a relative humidity (RH) range of 40-80%. Based on the PXRD spectra before and after DVS, the amorphous form transforms into crystalline form A. The PXRD results are shown in Figure 23.

[0125] DVS experimental results show that the order of moisture absorption of crystalline form A, solvate, and amorphous form within a relative humidity (RH) range of 40-80% is: amorphous > solvate > crystalline form A. Furthermore, the amorphous form transforms into crystalline form A after absorbing moisture. Crystalline form A has low hygroscopicity.

[0126] 1.6 Stability Test

[0127] 1.6.1 Crystal form A, solvate, and amorphous samples were placed in accelerated (40℃, 75% RH), high temperature (60℃), high humidity (relative humidity approximately 92.5%), and light (4500 lux) environments. Samples were removed after 5, 10, 20, and 30 days for PXRD testing to examine their physical stability under different conditions. The experimental results are shown in Table 3, and the PXRD results are shown in Figures 24, 25, and 26.

[0128] Table 3. Stability test results

[0129] Stability experiments showed that crystalline form A maintained its crystal structure stability under accelerated, high-temperature, high-humidity, and light-induced (4500 lux) conditions. Under accelerated, high-temperature, and light-induced conditions, the solvate desolventized and transformed into crystalline form A after 5 days; however, under high-humidity conditions, the solvate partially desolventized and transformed into crystalline form A after 5 days, forming a mixed state of crystalline form A and solvate, which remained in this mixed state at 10, 15, and 30 days. The amorphous form transformed into crystalline form A after 5 days under accelerated, high-temperature, and light-induced conditions; under high-humidity conditions, the amorphous form initially only partially transformed into crystalline form A, showing a weak characteristic peak of crystalline form A, but completely transformed into crystalline form A after 15 days. This demonstrates the superior stability of crystalline form A.

[0130] Based on the above research results, it is known that the amorphous form of compound A readily transforms into crystalline form A, especially under accelerated, high-temperature, light-exposed, and high-humidity conditions. When the amorphous form in the formulation transforms into crystalline form A, its solubility decreases, potentially affecting the bioequivalence and bioavailability of the oral drug. Therefore, the presence of crystalline form A may affect the efficacy of oral formulations, making it essential to detect the content of crystalline form A in the formulation. Currently, conventional quantitative detection methods for drug crystalline forms have low sensitivity, making accurate quantification difficult when the content of the analyte is too small. To address this issue, it is necessary to develop a method using powder X-ray diffraction for highly sensitive and accurate determination of the content of crystalline form A in formulations containing compound A.

[0131] Example 2: Determination of Characteristic Peak Selection

[0132] Blank excipients for capsules mainly include Microcrystalline cellulose, croscarmellose sodium, etc.

[0133] The crystal form A and the support of compound A were examined respectively. XRPD wide-angle scanning (4°-40°) was performed on the capsule blank excipients, and it was found that crystal form A was unaffected by the carrier at 12.6°, 13.1° and 18.0°. The characteristic peaks of interference from the blank excipient are shown in Figure 1. Therefore, it is proposed to select these three characteristic peaks and dilute them with the carrier and blank excipient to prepare samples containing different proportions of crystalline raw materials for method development.

[0134] Example 3: Scanning Angle Screening

[0135] 3.1 Solid Dispersions

[0136] Use carrier A series of mixed samples were prepared with crystal form A at the indicated concentration levels of 0.2%, 0.5%, 1.0%, 2.0%, 5.0%, 10.0%, 15.0%, and 20.0%. The linearity and sensitivity of the samples at the three characteristic peaks of 12.6°, 13.1°, and 18.0° were investigated (see Table 4) (for other instrument parameter settings and detection methods, please refer to section 6.1 of Example 6).

[0137] The results showed that at 18.0°, the linear relationship of crystal form A as a percentage of the labeled amount was optimal in the range of 0.2%–20.0% (r = 0.9982), and the S / N ratio at the 0.2% level was >3, resulting in the best peak shape (Figures 2 and 3). The 0.2% level can be used as the detection limit. Therefore, 18.0° was selected as the characteristic peak angle for quantitative determination of crystal forms in solid dispersions.

[0138] Table 4. Linearity and sensitivity at different characteristic peaks of solid dispersions with different proportions of crystal form A (as indicated).

[0139] 3.2 capsules

[0140] A series of mixed samples were prepared using blank excipients and crystal form A at proportions of 2.0%, 3.0%, 5.0%, 7.5%, 10.0%, 15.0%, 20.0%, and 30.0% of the labeled amount. The linearity and sensitivity of the samples at the three characteristic peaks of 12.6°, 13.1°, and 18.0° were investigated (see Table 5) (for other instrument parameter settings and detection methods, please refer to section 6.2 of Example 6).

[0141] The results showed a good linear relationship at 13.1° at the 3.0%–30.0% level (r = 0.9934) and high sensitivity (S / N > 10 at the 5.0% level). The 5.0% level can be used as the limit of quantitation. Furthermore, by examining the repeatability of the doped samples at three angles—12.6°, 13.1°, and 18.0°—the results (see Table 6) showed good repeatability of the peak area at 13.1°. Therefore, 13.1° was selected as the characteristic peak angle for the quantitative determination of crystal form in capsules.

[0142] Table 5. Linearity and sensitivity of capsule samples with different proportions of crystal form A at different characteristic peaks.

[0143] Note: 1. The linear correlation coefficient is calculated based on the proportion of crystal form A in the indicated amount, which is in the range of 2.0%-30.0%.

[0144] 2. The linear correlation coefficient is calculated based on the proportion of crystal form A in the indicated amount, which ranges from 3.0% to 30.0%.

[0145] 3. The linear correlation coefficient is calculated based on the proportion of crystal form A in the indicated amount, which ranges from 7.5% to 30.0%.

[0146] Table 6. Repeatability results of the contents of the crystal-doped capsules at different characteristic peaks.

[0147] Example 4: Optimization and Screening of Detection Methods

[0148] 4.1 Scan duration and number of scans

[0149] A comparative study was conducted on the same spiked solid dispersion sample with different scan durations and scan counts (see section 6.1 of Example 6 for other instrument parameter settings and detection methods). The results showed that increasing both the scan duration and the number of scans improved the S / N ratio (see Tables 7 and 8), but the detection time also increased accordingly. The scan duration and number of scans were optimized to balance sample detection time and sensitivity, and parameters with similar total running time (such as scan times of 3000 s / 2 scans and 2000 s / 3 scans) were selected.

[0150] The results showed that the peak area increased with a scan time of 3000 s / 2 scans, and the S / N ratio improved slightly (see Table 9). The results indicate that the sensitivity is optimal with a scan time of 3000 s and 2 scans.

[0151] Table 7. Detection results of samples at the 1.0% level with different scan durations and scan numbers.

[0152] Table 8. Detection results of different scan numbers for samples at the 0.5% level.

[0153] Table 9. Detection results of samples at the 0.5% level with different scan times and scan numbers.

[0154] 4.2 Voltage

[0155] The method of this invention uses a Malvern Pacona X-ray diffractometer. The effects of two parameters, 40 kV and 45 kV, on the detection sensitivity were investigated separately (for other instrument parameter settings and detection methods, please refer to section 6.1 of Example 6). The results show (see Table 10) that when the voltage is 45 kV, the peak shape and sensitivity are significantly improved.

[0156] Table 10. Test results of 0.5% level solid dispersion standard samples under different voltages

[0157] Example 5: Preparation and Screening of Standard Samples

[0158] 5.1 Investigation of the mixing method and sampling uniformity of solid dispersions

[0159] The mixing method and sampling uniformity of the solid dispersion were investigated (for other instrument parameter settings and detection methods, please refer to section 6.1 of Example 6). By comparing vortex mixing and sieving mixing, it was found that during vortex mixing, the material adhered to the wall and easily agglomerated, resulting in uneven mixing and poor parallelism of peak areas for mixed samples of the same concentration, making it impossible to fit a linear relationship (see Table 11). However, when using sieving mixing, the linear relationship was good (see Table 12). Therefore, sieving mixing was selected as the mixing method for solid dispersions.

[0160] Therefore, when testing solid dispersion samples, in order to ensure the uniformity of sampling, the material should first be passed through a 200-mesh sieve to break up any agglomerates before sampling and testing.

[0161] Table 11 Results of vortex mixing test for samples with different proportions of crystal form A in the solid dispersion

[0162] Table 12 Results of sieve mixing test of solid dispersion samples with different proportions of crystal form A as indicated.

[0163] 5.1 Investigation of capsule mixing method and sampling uniformity

[0164] Referring to the solid dispersion mixing method, the capsule samples were sieved and mixed (for other instrument parameter settings and detection methods, please refer to section 6.2 of Example 6). The results showed a good linear relationship (see Table 13). Therefore, sieving and mixing were selected as the mixing method for the finished product.

[0165] Since the contents of the capsule samples were white powder and granules, the finished product was ground and passed through a 200-mesh sieve for testing to ensure sampling uniformity.

[0166] Table 13 Results of sieve mixing and testing of capsule standard samples with different proportions of crystal form A as indicated.

[0167] Example 6 Quantitative Determination Method

[0168] 6.1 Quantitative Determination Method for Crystal Form A in Solid Dispersions

[0169] 6.1.1 Instrument parameters are shown in Table 14

[0170] Table 14 Instrument parameters for quantitative determination of crystal form A in solid dispersions

[0171] 6.1.2 Detection Limit (Crystal Form A accounts for 0.2% of the labeled amount, equivalent to 0.08% of the total solid dispersion) Sample Preparation

[0172] Take the materials that have been ground through a 200-mesh sieve. For crystal form A, a detection limit sample at a level of 0.2% of the labeled amount was prepared using a doubling-increment method. Approximately 170 mg was weighed and placed in a background-free silicon wafer sample dish. The surface was gently pressed flat with a glass slide, and residual powder at the edges was wiped away.

[0173] 6.1.3 Limit of Quantitation (Crystal form A accounts for 0.5% of the labeled amount, equivalent to 0.2% of the total solid dispersion) Sample Preparation

[0174] Take the materials that have been ground through a 200-mesh sieve. For crystal form A, a quantitation limit sample at a level of 0.5% of the labeled amount was prepared using a doubling-increment method. Approximately 170 mg was weighed and placed in a background-free silicon wafer sample dish. The surface was gently pressed flat with a glass slide, and residual powder at the edges was wiped away.

[0175] 6.1.4 Preparation of Standard Samples for Solid Dispersions

[0176] Take an appropriate amount of solid dispersion, pass it through a 200-mesh sieve, weigh about 170 mg and place it in a background-free silicon wafer sample dish. Gently press the surface with a glass slide to flatten it, and wipe away any residual powder from the edges.

[0177] The method of this invention, after screening and optimization, adjusted the voltage from 40kV to 45kV, narrowed the scanning range from a wide angle range of 4-40° / 2θ to a narrow angle range of 17°-18.6°, and adjusted the scanning time to approximately 3000s, thereby improving the detection sensitivity of crystal form A. After optimization, the sensitivity of the quantitative determination method for crystal form A in solid dispersions is 0.2% of that of standard samples (equivalent to 0.5% of the labeled amount, an improvement of 120 times).

[0178] 6.2 Quantitative Determination Method of Crystal Form A in Capsules

[0179] 6.2.1 Instrument parameters are shown in Table 15

[0180] Table 15 Instrument parameters for quantitative determination of crystal form A in capsules

[0181] 6.2.2 Detection Limit (Crystal Form A accounts for 3% of the labeled amount, equivalent to approximately 0.2% of the total capsule contents) Sample Preparation

[0182] Blank excipients and crystal form A, ground through a 200-mesh sieve, were used to prepare a detection limit sample at a level where crystal form A accounted for 3% of the labeled amount using a doubling-increment method. Approximately 150 mg was weighed and placed in a background-free silicon wafer sample dish. The surface was gently pressed flat with a glass slide, and residual powder at the edges was wiped away.

[0183] 6.2.3 Limit of Quantitation (5% of the labeled amount of active pharmaceutical ingredient, equivalent to approximately 0.33% of the total contents of the capsule) Sample Preparation

[0184] Blank excipients and crystal form A, ground through a 200-mesh sieve, were used to prepare a quantitation limit sample at a level where crystal form A accounted for 5% of the labeled amount using a doubling-increment method. Approximately 150 mg was weighed and placed in a background-free silicon wafer sample dish. The surface was gently pressed flat with a glass slide, and residual powder at the edges was wiped away.

[0185] 6.2.4 Preparation of capsule standard samples

[0186] Take 4 capsule samples, mix the contents, grind them, and pass them through a 200-mesh sieve. Weigh about 150mg and place it in a background-free silicon wafer sample dish. Gently press the surface with a glass slide to flatten it, and wipe away any residual powder from the edges.

[0187] The method of this invention has been screened and optimized, adjusting the voltage from 40kV to 45kV, adjusting the scanning range from a wide angle range of 4-40° / 2θ to a narrow angle range of 12°-13.5°, and adjusting the scanning time to about 3000s, thereby improving the detection sensitivity of crystal form A.

[0188] Before optimization, the sensitivity of the quantitative determination method for crystal form A was 4% of that of the capsule standard sample (4% for both solid dispersion and capsules, equivalent to 60% of the labeled amount). After optimization, the sensitivity for detecting crystal form A in capsules was 0.33% of the standard (equivalent to 5.0% of the labeled amount, a 12-fold improvement). Therefore, as shown in Table 16, the method of this invention can achieve highly sensitive determination and monitoring of crystal form A in cap-dependent endonuclease inhibitor capsules.

[0189] Table 16 Comparison of old and new methods for determining and monitoring crystal form A in capsules.

[0190] Note: LOQ is 5.0%.

[0191] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A cap-dependent endonuclease inhibitor crystal form, wherein the crystal form is crystal form A of compound A, and compound A is [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolin-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyridino[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate; The X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 18.02°±0.2°, 21.02°±0.2°, 21.62°±0.2°, 22.88°±0.2°, and 24.62°±0.2°.

2. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A also includes one, two or more characteristic diffraction peaks at the 2θ angle: 11.22°±0.2°, 12.54°±0.2°, 13.00°±0.2°, 26.26°±0.2°, 28.18°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form A further includes one, two, or more characteristic diffraction peaks at the 2θ angle: 18.88°±0.2°, 22.54°±0.2°, 24.36°±0.2°, 26.56°±0.2°, 27.74°±0.2°, 29.28°±0.2°, 30.98°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 9.58°±0.2°, 19.62°±0.2°, 29.04°±0.2°, 31.98°±0.2°, 34.36°±0.2°, 36.62°±0.2°, and 42.98°±0.2°.

3. The crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A also includes one, two or more characteristic diffraction peaks at the 2θ angle: 22.54°±0.2°, 26.26°±0.2°, 28.18°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 11.22°±0.2°, 12.54°±0.2°, 13.00°±0.2°, 18.88°±0.2°, 27.74°±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A further includes one, two or more characteristic diffraction peaks at the 2θ angle: 24.36°±0.2°, 26.56°±0.2°, 29.04°±0.2°, 29.28°±0.2°, 30.98°±0.2°, and 42.98°±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A further includes one, two, or more characteristic diffraction peaks at the 2θ angle: 16.38°±0.2°, 16.62°±0.2°, 19.34°±0.2°, 19.62°±0.2°, 31.98°±0.2°, 33.42°±0.2°, 34.36°±0.2°, 35.44°±0.2°, 36.62°±0.2°, 39.90°±0.2°, and 41.10°±0.2°.

4. The crystal form according to any one of claims 1-3, characterized in that, The X-ray powder diffraction pattern analysis data of crystal form A are shown in Table 1, where the error range of 2θ for each characteristic diffraction peak is ±0.2°. And / or, the crystal form A has an X-ray powder diffraction pattern basically as shown in Figure 5; And / or, the differential scanning calorimetry (DSC) of crystal form A is basically as shown in Figure 6; And / or, the differential scanning calorimetry of crystal form A has an endothermic peak at 234±5℃; And / or, the thermogravimetric analysis diagram of crystal form A is basically as shown in Figure 7; And / or, the thermogravimetric analysis of crystal form A shows a weight loss of 0.2% at the initial heating to 246±5°C.

5. A pharmaceutical composition comprising the crystal form according to any one of claims 1-4, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

6. The use of the crystal form according to any one of claims 1-4, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for use against influenza virus.

7. A method for quantitative detection of the crystal form in a cap-dependent nuclease inhibitor sample, wherein the crystal form is crystal form A of compound A according to any one of claims 1-4, and compound A is [[1′-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiazolin-11yl]-1′,2′,4′,6′-tetrahydro-4′,6′-dioxospiro(cyclopropane-1,3′-[3H]pyridino[1,2-b]pyridazine)-5′-yl)oxy)methyl carbonate, wherein the quantitative detection method uses a powder X-ray diffractometer to measure the sample and performs quantification based on a standard curve; The quantitative detection method uses any one, two or more of 2θ = 12.6°±0.2°, 13.1°±0.2°, and 18.0°±0.2° as the quantitative characteristic peaks of crystal form A.

8. The method according to claim 7, characterized in that, The samples include solid dispersion samples and capsule samples; Preferably, the Kα rays from the copper target are used as the diffraction source, the working voltage is 40kV-45kV, the working current is 40mA, the scanning time is 2000-5000s, and the number of scans is 1-3. Preferably, Kα rays from a copper target are used as the diffraction source, the operating voltage is 45 kV, the operating current is 40 mA, the scanning time is 3000 s, and the number of scans is 2. Preferably, before the determination, the sample to be tested and the standard sample are mixed by vortex mixing or sieving. Preferably, before the determination, the sample to be tested and the standard sample are sieved and mixed.

9. The method according to claim 7 or 8, characterized in that, When the sample is a solid dispersion, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 17°-18.6°; Preferably, when the sample is a solid dispersion, 13.1°±0.2 is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 12°-13.5°; Preferably, when the sample is a solid dispersion, 12.6°±0.2° is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 12°-13.5°; Preferably, during the establishment of the standard curve, solid dispersions with different proportions of crystal form A are prepared; preferably, the proportion of crystal form A in the indicated amount is 0.1%-30.0%; Preferably, the solid dispersion sample comprises: compound A and a support; preferably, the support is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; Preferably, the solid dispersion sample is mixed by passing it through a 200-mesh sieve before sampling and testing.

10. The method according to claim 7 or 8, characterized in that, When the sample is a capsule sample, 13.1°±0.2 is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 12°-13.5°; Preferably, when the sample is a capsule sample, 12.6°±0.2° is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 12°-13.5°; Preferably, when the sample is a capsule sample, 18.0°±0.2° is selected as the quantitative characteristic peak of crystal form A, and the 2θ angle scanning range is 17°-18.6°; Preferably, during the standard curve establishment process, capsule standard samples with different proportions of crystal form A are prepared; preferably, the proportion of crystal form A in the labeled amount is 0.1%-40.0%; Preferably, the capsule sample includes: compound A and excipients; preferably, the excipients include: Soluplus, microcrystalline cellulose, and croscarmellose sodium; Preferably, the capsule samples are ground, passed through a 200-mesh sieve, and then sampled and tested.

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