A new crystalline form of resminostat and a process for its preparation

Abstract

The present application provides a new crystal form of resmetirom, crystal form APTI-I, using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 5.0°±0.2°, 6.3°±0.2°, 7.8°±0.2°, 12.2°±0.2°, 20.0°±0.2°. The crystal form is easy to prepare, high in purity, good in stability, good in solubility in different pH buffer and deionized water solvent, and suitable for industrial scale production and preparation of pharmaceutical preparations.

Description

Technical Field

[0001] This invention specifically relates to a new crystal form of resmetirom, APTI-I, and its preparation method, belonging to the field of pharmaceutical crystal chemistry. Background Technology

[0002] Metabolic dysfunction-associated steatohepatitis (MASH) is a complex liver disease caused by obesity and diabetes, which can lead to liver fibrosis, liver failure, and even liver cancer. According to the latest epidemiological studies, approximately 5% of adults worldwide are affected by MASH. Resmetirom, the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of MASH, has shown significant efficacy in reducing liver scar tissue formation and improving other hallmark symptoms of the disease. By enhancing the liver's response to thyroid hormones, resmetirom stimulates the liver to metabolize fatty acids, thereby reducing inflammation and fat accumulation, offering hope to MASH patients.

[0003] Resmetrol is currently mainly administered in the form of resmetrol free base, the chemical structure of which is shown in Figure (I).

[0004]

[0005] As is well known, different spatial arrangements of drug molecules will form different crystal forms, and different crystal forms will exhibit different physicochemical properties such as stability, solubility, and hygroscopicity.

[0006] Current research on the crystal forms of resimeltiro is as follows:

[0007] Prior art WO2014043706A1 discloses resimetidine crystal form Form I, which is the crystal form currently used in commercially available resimetidine drug formulations. This prior art discloses three methods for preparing crystal form Form I: The first method involves preparing resimetidine as a MIBK solvate, then refluxing and slurrying the MIBK solvate in ethanol, and finally cooling to room temperature to obtain crystal form Form I; the second method involves preparing resimetidine as an N,N-dimethylacetamide (DMAC) solvate, then refluxing the N,N-dimethylacetamide solvate in ethanol, and finally cooling to room temperature to obtain crystal form Form I; the third method involves heating a mixture of the N,N-dimethylacetamide solvate and the dihydrate of resimetidine in MIBK to 80°C, and then cooling to room temperature to obtain crystal form Form I. The inventors of this application repeated the first method described above and discovered that during the preparation of Form I crystals from the MIBK solvate by slurrying with ethanol and cooling to room temperature, there is a risk of forming resimemetiro ethanol solvate. According to ICH requirements, the ethanol content should not exceed 5000 ppm. Once ethanol solvate is formed, the solvent residue will far exceed this standard, making it unsuitable for use as a pharmaceutical raw material.

[0008] Prior art WO2020010068A1 discloses various amorphous forms and solvates of resimemetiro. However, the solvent residue in all solvates fails to meet pharmaceutical requirements. Furthermore, the various amorphous forms are obtained through solvent removal from the solvates. The inventors of this application have studied the ethyl acetate solvate and found that the solvent removal temperature required for this solvate is too high for large-scale industrial production. In addition, high-temperature solvent removal typically fails to address the solvent residue problem.

[0009] Existing technologies WO2022086894A1 and CN114907327A also disclose various solvates of resimetiro, but these solvates cannot meet pharmaceutical requirements due to the problem of residual organic solvents.

[0010] Therefore, it is necessary to develop a superior crystal form of resimeltiro to facilitate large-scale industrial production and improve its existing physicochemical properties, making it more suitable for preparing pharmaceutical formulations. Summary of the Invention

[0011] To address the shortcomings of existing resimetidine crystal forms, this invention provides a new resimetidine crystal form (crystal form APTI-I). This new crystal form is suitable for large-scale industrial production, exhibiting high yield, high purity, stable physicochemical properties under high temperature conditions, and good solubility in aqueous solvents of different pH values, making it suitable as a crystal form for preparing pharmaceutical formulations.

[0012] The resmetrol crystal form APTI-I provided by the present invention, using Cu-Kα radiation, has characteristic peaks in its X-ray powder diffraction pattern expressed in 2θ angles at 5.0°±0.2°, 6.3°±0.2°, 7.8°±0.2°, 12.2°±0.2°, and 20.0°±0.2°.

[0013] In another preferred embodiment, the resimetidine crystal form APTI-I is a bulk crystal.

[0014] In another preferred embodiment, the D90 of the resimetidine crystal form APTI-I is about 5.0 to 7.5 μm. In another more preferred embodiment, the D90 of the resimetidine crystal form APTI-I is about 5.4 to 7.0 μm. In yet another more preferred embodiment, the D90 of the resimetidine crystal form APTI-I is about 6.2 μm.

[0015] In another preferred embodiment, the repose angle of the resimetidine crystal form APTI-I is 33 to 36 degrees.

[0016] In another preferred embodiment, the resmetiro crystal form APTI-I, using Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles that also has characteristic peaks at any one or more of the following: 8.5°±0.2°, 10.1°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 16.5°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 22.0°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 25.3°±0.2°, and 26.4°±0.2°.

[0017] In another preferred embodiment, the X-ray powder diffraction pattern of the retrimetrol crystal form APTI-I is essentially as follows: Figure 6 As shown.

[0018] In another preferred embodiment, the differential scanning calorimetry (DSC) of the resimetidine crystal form APTI-I shows an exothermic peak at 237±5℃ and an endothermic peak at 330±5℃.

[0019] In another preferred embodiment, the differential scanning calorimetry (DSC) chromatogram of the resimemetiro APTI-I crystal form is essentially as follows: Figure 7 As shown.

[0020] In another preferred embodiment, the thermogravimetric analysis of the resimetidine crystal form APTI-I showed a weight loss of approximately 2.7% at temperatures ranging from 40°C to 160°C.

[0021] In another preferred embodiment, the thermogravimetric analysis (TGA) plot of the resimemetiro crystal form APTI-I is essentially as follows: Figure 8 As shown.

[0022] In another preferred embodiment, the polarized light micrograph of the retrimetrol crystal form APTI-I is essentially as follows: Figure 9a As shown.

[0023] In another preferred embodiment, the differential scanning calorimetry (DSC) curve of the resmetidine APTI-I crystal form shows an exothermic peak at 221±5℃ and an endothermic peak at 336.2±5℃.

[0024] In another preferred embodiment, the differential scanning calorimetry (DSC) chromatogram of the resimemetiro APTI-I crystal form is essentially as follows: Figure 14b As shown.

[0025] In another preferred embodiment, the polarized light micrograph of the retrimetrol crystal form APTI-I is essentially as follows: Figure 14c As shown.

[0026] In another preferred embodiment, the aspect ratio of the bulk crystal is 1 to 3:1. In yet another more preferred embodiment, the resimetidine crystal form APTI-I is a bulk crystal with an aspect ratio of 1 to 2:1.

[0027] This invention also provides a method for preparing the above-mentioned resmetidine crystal form APTI-I, the preparation method comprising the following steps:

[0028] (1) Mix rismetrol with a first organic solvent, add alkali to the mixture to form rismetrol salt and dissolve it, filter, concentrate the filtrate to dryness, and obtain the amorphous form of rismetrol salt.

[0029] (2) The amorphous form of resmetrol salt is mixed with a second organic solvent, acid is added to the mixture to release the resmetrol salt, the mixture is filtered, and the resulting filter cake is dried to obtain resmetrol crystal form APTI-I.

[0030] In another preferred embodiment, the first organic solvent is a hydrophilic organic solvent. In another preferred embodiment, the second organic solvent is an ether-based organic solvent. In another preferred embodiment, the base is an aqueous solution of an inorganic base. In another preferred embodiment, the acid is an aqueous solution of an inorganic acid.

[0031] In another preferred embodiment, the hydrophilic organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof, more preferably, tetrahydrofuran.

[0032] In another preferred embodiment, the ether organic solvent is selected from methyl tert-butyl ether, isopropyl ether, cyclopentyl methyl ether or a combination thereof, more preferably methyl tert-butyl ether.

[0033] In another preferred embodiment, the inorganic base is selected from sodium hydroxide, potassium hydroxide, ammonia, or combinations thereof, more preferably sodium hydroxide.

[0034] In another preferred embodiment, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, or combinations thereof, more preferably hydrochloric acid.

[0035] In another preferred embodiment, the weight-to-volume ratio of resmetrol to the hydrophilic organic solvent is 1 g / 3 mL to 15 mL, more preferably 1 g / 4 mL to 6 mL.

[0036] In another preferred embodiment, the weight-to-volume ratio of resmetiro salt to ether organic solvent is 1 g / 4 mL to 20 mL, more preferably 1 g / 8 mL to 12 mL.

[0037] In another preferred embodiment, the molar ratio of resmetiro to the hydroxide ions provided by the inorganic base is 1:1.0 to 2.0, more preferably 1:1.0 to 1.2, and most preferably 1:1.1.

[0038] In another preferred embodiment, the molar ratio of hydrogen ions provided by the inorganic acid to hydroxide ions provided by the base is 1:0.8 to 1.2, more preferably 1:1.

[0039] In another preferred embodiment, the molar concentration of the aqueous solution of the inorganic base is 1 mol / L to 3 mol / L.

[0040] In another preferred embodiment, the molar concentration of the aqueous solution of the inorganic acid is 1 mol / L to 3 mol / L.

[0041] In another preferred embodiment, in step (2), the drying temperature is 40℃~85℃ and the drying time is 10h~24h. More preferably, the drying temperature is 50℃~70℃ and the drying time is 12h~20h.

[0042] In another preferred embodiment, in step (1), resmetiro is mixed with the first organic solvent and stirred at 35°C to 65°C for 0.5h to 2.0h, then alkali is added, and the filtration temperature is 0 to 40°C.

[0043] In another preferred embodiment, in step (2), the amorphous form of resmetrol salt is mixed with the second organic solvent and stirred at 35°C to 65°C for 0.5h to 2.0h, then acid is added, and the filtration temperature is 0 to 40°C.

[0044] In another preferred embodiment, step (1) further includes the steps of: concentrating the filtrate to dryness to obtain the amorphous form of resimetiro salt, slurrying the amorphous form in a third organic solvent, and concentrating the slurry to dryness to obtain the amorphous form of powdered resimetiro salt, wherein the third organic solvent is selected from methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, or combinations thereof.

[0045] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned resmetiro crystal form APTI-I. Attached Figure Description

[0046] Figure 1 It is a superimposed image of the XRPD pattern of the product obtained in the process of obtaining crystal form Form I by repeating the existing technology WO2014043706;

[0047] Figure 2 It is a superimposed image of the XRPD pattern of the ethyl acetate solvate of resimetiro obtained by repeating the prior art WO2020010068 and the XRPD pattern of the crystal form Form F obtained by desolventizing it;

[0048] Figure 3 It is a DSC diagram of the ethyl acetate solvate of resimemetiro obtained by repeating the existing technology WO2020010068;

[0049] Figure 4 The image shows the amorphous XRPD pattern of resimetiro sodium salt obtained in Example 1.

[0050] Figure 5 The 1H NMR spectrum (solvent DMSO) of resimetiro sodium salt obtained in Example 1 is shown.

[0051] Figure 6 This is a typical XRPD pattern of resimetirol crystal form APTI-I;

[0052] Figure 7 This is a typical DSC pattern of resimetirol crystal form APTI-I;

[0053] Figure 8 This is a typical TGA pattern of resimetiro crystal form APTI-I;

[0054] Figure 9a This is a typical PLM diagram of resimetiro crystal form APTI-I;

[0055] Figure 9b This is the 1H NMR spectrum of resmetidine crystal form APTI-I (solvent DMSO);

[0056] Figure 10 This is an XRPD overlay of the starting material (crystal form APTI-I) and the product obtained after manual dry grinding in agate grinding for 30 minutes during the grinding stability test of crystal form APTI-I.

[0057] Figure 11This is a superimposed image of the XRPD spectra of the starting material (crystal form APTI-I) and the product obtained after being placed in an 80°C oven for 24 hours during the high-temperature stability test of the APTI-I crystal form.

[0058] Figure 12 This is a superimposed image of the XRPD spectra of the starting material (crystal form APTI-I) and the product obtained after being placed open in a constant temperature and humidity chamber at 25℃ / 80%RH for 24 hours during the hygroscopicity test of the APTI-I crystal form.

[0059] Figure 13 This is a superimposed XRPD image of the product obtained during the isothermal and humidity stability test of resimeltiro APTI-I crystal form. The initial material (crystal form APTI-I) was packaged in PE bags and aluminum foil bags (i.e., the product has two layers of packaging, first in PE bags and then in aluminum foil bags) and placed at 25℃ / 60%RH for 1 week. Then, it was packaged in PE bags and aluminum foil bags and placed at 40℃ / 75%RH for 1 week. Finally, it was packaged in PE bags and aluminum foil bags and placed at 25℃ / 60%RH for 2 weeks. Finally, it was packaged in PE bags and aluminum foil bags and placed at 40℃ / 75%RH for 2 weeks.

[0060] Figure 14a This is the XRPD pattern of APTI-I, the crystal form of resmetiro obtained in Example 9.

[0061] Figure 14b This is the DSC spectrum of the APTI-I crystal form of resimetiro obtained in Example 9.

[0062] Figure 14c This is the PLM diagram of the APTI-I crystal form of retrimetiro obtained in Example 9.

[0063] Figure 14d The results are PSD detection results of the APTI-I crystal form of resimetiro obtained in Example 9.

[0064] Figure 15a This is the XRPD pattern of APTI-A, the crystal form of resmetiro obtained in Example 10.

[0065] Figure 15b This is the DSC spectrum of the APTI-A crystal form of resmetiro obtained in Example 10.

[0066] Figure 15c This is the PLM diagram of the APTI-A crystal form of retrimetiro obtained in Example 10.

[0067] Figure 15d The results are PSD detection results of the resmetidine crystal form APTI-A obtained in Example 10.

[0068] Figure 16aThis is the XRPD pattern of the APTI-B crystal form of resimetiro obtained in Example 11.

[0069] Figure 16b This is the DSC spectrum of the APTI-B crystal form of resimetidine obtained in Example 11.

[0070] Figure 16c This is the PLM diagram of the APTI-B crystal form of retrimetiro obtained in Example 11.

[0071] Figure 16d The results are PSD detection results of the APTI-B crystal form of resimetidine obtained in Example 11.

[0072] Figure 17a These are dissolution curves of APTI-I and Form I tablets placed in a pH 1.2 buffer solution.

[0073] Figure 17b These are dissolution profiles of APTI-I and Form I tablets placed in a pH 4.5 buffer solution.

[0074] Figure 17c These are dissolution profiles of APTI-I and Form I tablets placed in a buffer solution at pH 6.8.

[0075] Figure 17d These are the dissolution profiles of APTI-I and Form I tablets placed in water.

[0076] Figure 18a The XRPD spectra of APTI-I tablets after 12 days of open storage under accelerated conditions (40℃ / 75%RH), light conditions, and long-term stability conditions (25℃ / 60%RH) are shown in the figure. (From top to bottom, the XRPD spectra of APTI-I tablets after 12 days of open storage at 40℃ / 75%RH, the XRPD spectra of APTI-I tablets after 12 days of open storage in a light chamber with a light intensity of 8 k lux, the XRPD spectra of APTI-I tablets after 12 days of open storage at 40℃ / 75%RH, and the XRPD spectra of APTI-I tablets on day 0 are shown.)

[0077] Figure 18bThe XRPD spectra of APTI-I tablets after 20 days of open storage under accelerated conditions (40℃ / 75%RH), light conditions, and long-term stability conditions (25℃ / 60%RH) are shown in the figure. (From top to bottom, the XRPD spectra of APTI-I tablets after 20 days of open storage at 40℃ / 75%RH, the XRPD spectra of APTI-I tablets after 20 days of open storage under light intensity of 8 k lux in a light chamber, the XRPD spectra of APTI-I tablets after 12 days of storage at 40℃ / 75%RH, and the XRPD spectra of APTI-I tablets on day 0 are shown.) Detailed Implementation

[0078] Through extensive and in-depth research, the inventors of this application have obtained a new crystal form of resimetidine, crystal form APTI-I. Unexpectedly, this crystal form APTI-I exhibits advantages such as high stability, low hygroscopicity, high purity, and high solubility. Moreover, the production method is simple, the quality is stable, and it is suitable for large-scale industrial production.

[0079] Resimetirol crystal form APTI-I .

[0080] The resmetrol crystal form APTI-I provided by this invention, using Cu-Kα radiation, has characteristic peaks in its X-ray powder diffraction (XRPD) pattern expressed in 2θ angles at 5.0°±0.2°, 6.3°±0.2°, 7.8°±0.2°, 12.2°±0.2°, and 20.0°±0.2°.

[0081] Furthermore, the resmetiro APTI-I crystal form provided by this invention, using Cu-Kα radiation, exhibits characteristic peaks in its XRPD spectrum expressed at 2θ angles at 5.0±0.2°, 6.3±0.2°, 7.8±0.2°, 8.5±0.2°, 10.1±0.2°, 12.2±0.2°, 14.4±0.2°, 15.1±0.2°, 16.5±0.2°, 16.9±0.2°, 17.9±0.2°, 20.0±0.2°, 20.4±0.2°, 20.9±0.2°, 22.0±0.2°, 23.0±0.2°, 23.8±0.2°, 25.3±0.2°, and 26.4±0.2°.

[0082] Furthermore, the resmetiro APTI-I crystal form provided by this invention, using Cu-Kα radiation, has the characteristic peaks shown in Table 1 below in its XRPD spectrum expressed at a 2θ angle:

[0083] Table 1

[0084]

[0085]

[0086] Furthermore, the resmetiro APTI-I crystal form provided by this invention, using Cu-Kα radiation, has an XRPD pattern expressed at a 2θ angle that is essentially the same as... Figure 6 Maintain consistency.

[0087] Furthermore, the differential scanning calorimetry (DSC) chart of the APTI-I crystal form of resmetrol provided by the present invention shows an exothermic peak at 237±5℃ (peak) and an endothermic peak at 330±5℃ (peak).

[0088] Furthermore, the DSC chart of the APTI-I crystal form of resimemetiro provided by this invention is essentially the same as... Figure 7 or Figure 14b Maintain consistency.

[0089] Furthermore, the thermogravimetric analysis (TGA) chart of the resmetidine crystal form APTI-I provided by this invention shows a weight loss of approximately 2.7% at 40–160°C.

[0090] Furthermore, the TGA chart of the APTI-I crystal form of resimemetiro provided by this invention is essentially the same as... Figure 8 Maintain consistency.

[0091] Furthermore, the polarized light microscopy (PLM) results of the APTI-I crystal form of resimetidine provided by the present invention show that the crystal morphology is rod-shaped and uniformly distributed.

[0092] Furthermore, the PLM diagram of the APTI-I crystal form of resimemetiro provided by this invention is essentially the same as... Figure 9a Or keep it consistent with 14c.

[0093] Preparation of Resmetiro crystal form APTI-I

[0094] The preparation method of resmetidine crystal form APTI-I of the present invention includes the following steps:

[0095] (1) Mix rismetrol with a first organic solvent, add alkali to the mixture to form rismetrol salt and dissolve it, filter, concentrate the filtrate to dryness, and obtain the amorphous form of rismetrol salt.

[0096] (2) The amorphous form of resmetrol salt is mixed with a second organic solvent, acid is added to the mixture to release the resmetrol salt, the mixture is filtered, and the resulting filter cake is dried to obtain resmetrol crystal form APTI-I.

[0097] Furthermore, the first organic solvent is a hydrophilic organic solvent, the second organic solvent is an ether-based organic solvent, the base is an aqueous solution of an inorganic base, and the acid is an aqueous solution of an inorganic acid.

[0098] Furthermore, the hydrophilic organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, or combinations thereof; the ether organic solvent is selected from methyl tert-butyl ether, isopropyl ether, cyclopentyl methyl ether, or combinations thereof; the inorganic base is selected from sodium hydroxide, potassium hydroxide, ammonia, or combinations thereof; and the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, or combinations thereof.

[0099] Further, in step (1), after resmetiro is mixed with the first organic solvent, it is stirred at 35℃~65℃ for 0.5h~2.0h, then alkali is added, and the filtration temperature is 0~40℃.

[0100] Further, in step (2), after the amorphous resmetiro salt is mixed with the second organic solvent, it is stirred at 35℃~65℃ for 0.5h~2.0h, then acid is added, and the filtration temperature is 0~40℃.

[0101] Furthermore, in step (2), the drying temperature is 40℃~85℃ and the drying time is 10h~24h.

[0102] Further, step (1) also includes the steps of: concentrating the filtrate to dryness to obtain the amorphous form of resimetiro salt, slurrying the amorphous form in a third organic solvent, and concentrating the slurry to dryness to obtain the amorphous form of powdered resimetiro salt, wherein the third organic solvent includes, but is not limited to, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, or combinations thereof.

[0103] In some specific embodiments, Preparation of Resmetiro crystal form APTI-I In step (1), the filtrate is concentrated to dryness to obtain an amorphous form of resimetiro salt with a certain viscosity, forming large solid lumps or adhering to the container wall, or a mixture of solid and oily viscous substances. This mixture is then slurried with a third organic solvent, and the slurry is concentrated to dryness to obtain powdered amorphous resimetiro salt, which is convenient for handling. In some specific embodiments of the present invention, the weight-to-volume ratio of resimetiro to the third organic solvent is 1 g / 4 mL to 20 mL.

[0104] There is no particular limitation on the amount of hydrophilic organic solvent used; it is a commonly used amount in solvent pulping in the art. In some specific embodiments of the present invention, the weight-to-volume ratio of resimetidine to the hydrophilic organic solvent is 1 g / 3 mL to 15 mL. There is no particular limitation on the amount of ether organic solvent used; it is a commonly used amount in solvent pulping in the art. In some specific embodiments of the present invention, the weight-to-volume ratio of resimetidine to the ether organic solvent is 1 g / 4 mL to 20 mL.

[0105] The purpose of the inorganic base is to provide cations to form a salt with resmetiro, which dissolves in the solvent. Therefore, theoretically, the molar ratio of resmetiro to the hydroxide ions provided by the inorganic base is 1:1. In some specific embodiments of the present invention, in order to ensure sufficient salt formation of resmetiro, the molar ratio of resmetiro to the hydroxide ions provided by the inorganic base is 1:1.0 to 1.2.

[0106] The purpose of the inorganic acid is to provide hydrogen ions to neutralize the inorganic base, thereby freeing the resimeltiro salt. Therefore, theoretically, the molar ratio of hydrogen ions provided by the inorganic acid to hydroxide ions provided by the base is 1:1.

[0107] There is no particular limitation on the concentration of the aqueous solution of inorganic base. In some specific embodiments of the present invention, the molar concentration of the aqueous solution of inorganic base is 1 to 3 mol / L.

[0108] There is no particular limitation on the concentration of the aqueous solution of inorganic acid. In some specific embodiments of the present invention, the molar concentration of the aqueous solution of inorganic acid is 1 to 3 mol / L.

[0109] In the description of this invention, "room temperature" refers to 0℃ to 40℃, for example, 4℃, 10℃, 25℃, 35℃, etc.

[0110] Compared with the prior art, the beneficial effects of the resimetidine crystal form APTI-I of the present invention are as follows:

[0111] (1) The preparation method of the retimetirol crystal form APTI-I of the present invention is simpler than that of the crystal form Form I disclosed in the original research (WO2014043706A1), the product quality is more stable in production, and the product has good purity and high yield.

[0112] (2) The retrimetrol crystal form APTI-I of the present invention exhibits good high temperature stability, grinding stability and packaging stability, and is suitable for long-term storage.

[0113] (3) The retimetide crystal form APTI-I of the present invention exhibits higher solubility in water-soluble media at multiple pH levels compared to the crystal form FormI disclosed in the original drug (WO2014043706), and is more conducive to the drug exerting its efficacy as an API.

[0114] The present invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0115] The crude resmetidine used in the following comparative examples and embodiments was commercially available and had an HPLC purity of approximately 97.6%.

[0116] Raw materials and general methods:

[0117] 1. XRPD spectral determination method

[0118] X-ray powder diffractometer: BRUKER AXSD2 PHASER X-ray powder diffractometer; Radiation source: Intensity ratio α1 / α2 is 0.5; Generator kV: 30.0 kV; Generator mA: 10.0 mA; Scan range: 3.0~40.0°.

[0119] 2. DSC Measurement Method

[0120] The METTLEER DSC1 differential scanning calorimeter has a temperature rise program of 20°C per minute, ranging from 30°C to 360°C.

[0121] 3. TGA determination method

[0122] Instrument model: METTLEER TGA / DSC1 thermogravimetric analyzer. Temperature program: 30℃~400℃, 10℃ increase per minute.

[0123] 3. D90 determination method

[0124] The instrument used was a Malvern 3000 laser particle size analyzer.

[0125] Test method: Wet method

[0126] Dispersion medium: water

[0127] Sample preparation method: Take 100mg of sample, add 2 drops of Tween 80, mix and stir repeatedly with the sample, then add 50mL of water and sonicate until evenly dispersed.

[0128] 4. Angle of repose measurement

[0129] The angle of repose typically refers to the maximum angle formed by the free slope of a powder accumulation layer and the horizontal plane. A smaller angle of repose indicates lower friction and better flowability. Generally, θ ≤ 30 degrees is considered good flowability, and θ ≤ 40 degrees is sufficient to meet the flowability requirements during production. The flowability of powders significantly affects the weight variation and normal operation of granules, capsules, tablets, and other formulations. This example uses the GB11986-89 standard test method to determine the angle of repose of crystals.

[0130] Comparative Example 1: Preparation of crystal form Form I according to prior art WO2014043706

[0131] Weigh 5g of crude resmetiro, add 25mL of MIBK at room temperature, heat from 20-25℃ to 50℃ and keep warm for 1 hour, then cool naturally to 20-25℃ and keep warm to grow crystals for 2.5 hours. Filter the product until it is almost dry to obtain 6.4g of wet MIBK solvate.

[0132] The above-mentioned wet MIBK solvate was added to 32 mL of ethanol, heated to 80±5℃ in a three-necked flask, refluxed and stirred, and sampled for testing after 2 hours. XRPD analysis confirmed that the product was of crystal form Form I (see...). Figure 1 (See the XRPD pattern at the bottom). After reflux pulping for 4 hours, samples were taken for testing. XRPD testing confirmed that the product is of crystal form Form I (see...). Figure 1 (The XRPD spectrum in the middle). The system, after reflux and pulping for 4 hours, was naturally cooled to 20°C, stirred for 15 minutes, and then filtered. The obtained product was confirmed by XRPD analysis to be an ethanol solvate (see...). Figure 1 The topmost XRPD image is the same as WO2020010068. Figure 3 The XRPD chromatograms of the ethanol solvate of compound A (resimetiro) shown are consistent. HPLC analysis revealed the purity of the ethanol solvate to be 98.5%.

[0133] The overlay images of the XRPD spectra of the product obtained by reflux and beating in ethanol for 2 hours, the product obtained by reflux and beating in ethanol for 4 hours, and the product obtained by filtration after the reflux system was naturally cooled to 20°C are shown below. Figure 1 .from Figure 1 It can be seen that when the MIBK solvate is slurried in ethanol for 2 to 4 hours, the crystal form changes to form Form I. However, when the reflux system is naturally cooled to 20°C, the crystal form obtained by filtration changes again, and the ethanol solvate is formed.

[0134] During the scaled-up kilogram-scale experiments, when the inventors prepared crystalline Form I by refluxing and pulping the resimetidine MIBK solvate in ethanol, even with strict control of cooling the reflux system to 20°C within 45 minutes, most batches yielded crystalline Form I products. However, a small number of batches still yielded the ethanol solvate of resimetidine. This indicates that crystalline Form I readily transforms into the ethanol solvate in the ethanol system, which is disadvantageous for industrial-scale production.

[0135] Comparative Example 2: Preparation of crystal form Form F according to prior art WO2020010068

[0136] Weigh 200 mg of resimetiro, add 2 mL of ethyl acetate, stir magnetically at 50 °C for 24 h, filter, and XRPD analysis confirms that the product is an ethyl acetate solvate (see...). Figure 2(See the XRPD spectrum at the bottom). The ethyl acetate solvate was vacuum dried at 80℃ for 12 h. XRPD analysis showed that the solvate did not crystallize (see...). Figure 2 (The XRPD spectrum in the middle). The ethyl acetate solvate was analyzed by DSC; the results are shown in [Figure number missing]. Figure 3 ,from Figure 3 It can be seen that the solvate desolventized at 148±5℃. The ethyl acetate solvate was heated to 150℃ and held for 3 min, then desolventized to obtain crystal form Form F (see...). Figure 2 (The topmost XRPD map).

[0137] The crystal form Form F requires heating the ethyl acetate solvate to 150°C, indicating that the method for obtaining the new crystal form by desolventizing the solvate requires too high a temperature, making it difficult to meet the requirements of large-scale industrial production. Furthermore, the NMR spectrum of the product obtained after desolventizing by heating showed that 0.04 eq of ethyl acetate remained, exceeding the standard for residual solvent.

[0138] Example 1: Preparation of Resimetiro crystal form APTI-I

[0139] Add 5g of crude resimetrol and 25mL of tetrahydrofuran solvent to the reaction flask, stir magnetically at 50℃ for 1h to prepare a suspension, stop heating and add 1.1eq of 2mol / L NaOH aqueous solution to the suspension. The suspension gradually dissolves and is stirred continuously for 1h. Filter at room temperature, concentrate the filtrate to dryness, and filter with MTBE (to make the residue powdery for easy removal from the reaction flask) to obtain the amorphous sodium resimetrol. Its XRPD pattern is shown in [Figure number missing]. Figure 4 Its 1H NMR spectrum can be found in [reference needed]. Figure 5 .

[0140] 5g of the above-mentioned resmetiro sodium salt amorphous form was added to 50mL of methyl tert-butyl ether. The mixture was stirred at 50℃ for 30min, then heating was stopped and 1.1eq of concentrated hydrochloric acid was slowly added dropwise. After stirring for 1h, the mixture was filtered at room temperature. The filter cake was washed with 10mL of water and then vacuum dried at 50℃ for 16h to obtain 4.5g of an off-white solid with a purity of 99.8% and a yield of approximately 94.5%. XRPD analysis confirmed that the solid was in the crystalline form APTI-I. Its XRPD spectrum is shown below. Figure 6 See its DSC chart. Figure 7 See its TGA diagram. Figure 8 See its PLM diagram. Figure 9a Its 1H NMR spectrum can be found in [reference needed]. Figure 9b Based on these spectra, it is inferred that the APTI-I crystal form is amorphous.

[0141] Example 2: Preparation of Resimetiro crystal form APTI-I

[0142] Add 5g of crude resimetiro and 25mL of tetrahydrofuran solvent to a reaction flask, stir magnetically at 50°C for 1h to prepare a suspension, stop heating and add 1.1eq of concentrated ammonia solution to the suspension. The suspension gradually dissolves and becomes clear. After stirring continuously for 1h, filter at room temperature and concentrate the filtrate to dryness to obtain the amorphous resimetiro ammonium salt.

[0143] 5g of the above-mentioned resmetiromonium salt amorphous form was added to 50mL of methyl tert-butyl ether. The mixture was stirred at 50℃ for 30min, then heating was stopped, and 1.1eq of concentrated hydrochloric acid was slowly added dropwise. The mixture was stirred for 1h, filtered at room temperature, and the filter cake was washed with 10mL of water and then vacuum dried at 50℃ for 16h to obtain 4.5g of an off-white solid with a purity of 99.86% and a yield of approximately 93.7%. XRPD analysis of this off-white solid yielded results consistent with... Figure 6 The XRPD patterns are consistent.

[0144] Example 3: Preparation of Resimetiro crystal form APTI-I

[0145] Add 5g of crude resimetiro to the reaction flask and 25mL of tetrahydrofuran solvent. Stir magnetically at 50℃ for 1h to prepare a suspension. Stop heating and add 1.1eq of 2mol / L KOH aqueous solution to the suspension. The suspension gradually dissolves. After stirring continuously for 1h, filter at room temperature. Concentrate the filtrate to dryness to obtain the amorphous potassium resimetiro.

[0146] 5g of the above-mentioned resmetiro potassium salt amorphous form was added to 50mL of isopropyl ether. The mixture was stirred at 50℃ for 30min, then heating was stopped, and 0.55eq 2mol / L sulfuric acid was slowly added dropwise. After stirring continuously for 1h, the mixture was filtered at room temperature. The filter cake was washed with 10mL of water and dried under vacuum at 50℃ for 16h to obtain 4.2g of an off-white solid with a purity of 99.84% and a yield of approximately 91.5%. XRPD analysis of the off-white solid yielded results consistent with... Figure 6 The XRPD patterns are consistent.

[0147] Example 4: Grinding stability of resimeltiro crystal form APTI-I

[0148] 200 mg of resimeltiro APTI-I (HPLC purity 99.86%) was weighed and manually dry-ground in an agate mortar for 30 min. The ground product was analyzed by XRPD. The results are shown in the figure. Figure 10 (This shows a superimposed XRPD pattern of the starting material (crystal form APTI-I) and the product obtained after manual dry grinding in an agate mortar for 30 minutes). From Figure 10 It can be seen that the APTI-I crystal form did not undergo a transformation before and after grinding. HPLC analysis showed that the purity of the ground product was 99.86%, with no significant change in purity compared to the starting material.

[0149] Example 5: High-Temperature Stability Assessment of Resimetiro Crystal Form APTI-I

[0150] 1 g of resimemetiro in APTI-I crystal form (HPLC purity 99.86%) was placed in an 80℃ oven for 24 hours, and then sampled. Its crystal form was determined using XRPD. The results are shown below. Figure 11 (This shows a superimposed image of the XRPD patterns of the starting material (crystal form APTI-I) and the product obtained after being placed in an oven at 80°C for 24 hours). From Figure 11 It can be seen that the crystal form of APTI-I remained unchanged after heating at 80℃ for 24 hours. HPLC analysis showed that the purity of the product after heating at 80℃ for 24 hours was 99.84%, which was not significantly different from the starting material.

[0151] Example 6: Evaluation of the hygroscopicity of Resmetiro crystal form APTI-I

[0152] Accurately weigh 1172.5 mg of resimeltiro crystalline form APTI-I (HPLC purity 99.86%) solid into a 100 mm glass dish and spread it evenly. After the product was left open in a 25℃ / 80%RH constant temperature and humidity chamber for 24 hours, the tare weight was 1176.8 mg, a weight gain of 4.3 mg, or 0.37%. According to the pharmacopoeia guidelines for drug hygroscopicity testing, a weight gain due to hygroscopicity should be less than 2% but not less than 0.2%, indicating that crystalline APTI-I has slight hygroscopicity. XRPD was used to analyze the product after 24 hours of open storage in the 25℃ / 80%RH constant temperature and humidity chamber. The results are shown in the figure. Figure 12 (This shows a superimposed XRPD plot of the starting material (crystal form APTI-I) and the product obtained after being left open in a 25°C / 80%RH constant temperature and humidity chamber for 24 hours), from Figure 12 It can be seen that the crystal form of APTI-I did not change after being placed at 25℃ / 80%RH for 24 hours. HPLC analysis showed that the purity of the product after being placed at 25℃ / 80%RH for 24 hours was 99.87%, which was not significantly different from the starting material.

[0153] Example 7: Temperature and humidity stability of Resmetiro crystal form APTI-I

[0154] Resimetirox APTI-I was packaged in PE bags and aluminum foil bags (i.e., the product had two layers of packaging, first in PE bags and then in aluminum foil bags) and then placed at 25℃ / 60%RH and 40℃ / 70%RH respectively. Samples were taken at 1 week and 2 weeks for XRPD and purity testing. The overlay of the XRPD spectra of the obtained product is shown in [reference needed]. Figure 13(The table shows the XRPD spectra of the starting material (crystal form APTI-I), the products obtained after packaging in PE and aluminum foil bags and storing at 25°C / 60%RH for 1 week, packaging in PE and aluminum foil bags and storing at 40°C / 75%RH for 1 week, packaging in PE and aluminum foil bags and storing at 25°C / 60%RH for 2 weeks, and packaging in PE and aluminum foil bags and storing at 40°C / 75%RH for 2 weeks. The XRPD spectra of these products are arranged sequentially from bottom to top.) Product purity is shown in Table 2 below. From... Figure 13 As shown in Table 2, after packaging retrimetrol APTI-I in PE bags and aluminum foil bags and placing it at 25℃ / 60%RH and 40℃ / 70%RH for 1 or 2 weeks respectively, there were no significant changes in crystal form and purity. This indicates that retrimetrol APTI-I is stable under 25℃ / 60%RH and 40℃ / 70%RH conditions after packaging in PE bags and aluminum foil bags, and is suitable for storage.

[0155] The evaluation conditions and the crystal form and purity of the products obtained after the experiments in Examples 5-7 are summarized in Table 2 below.

[0156] Table 2

[0157]

[0158] Example 8: Solubility evaluation of resimemetiro crystal forms APTI-I and Form I in aqueous solutions at different pH values

[0159] The preparation method for water-soluble media with different pH values ​​(all water-soluble media with different pH values ​​have a uniform ion concentration of 50mM) is as follows:

[0160] Preparation of pH 1.2 buffer solution: Add 167 μL (2 mmol) of 36.5% hydrochloric acid to 80 mL of water, then add 0.223 g KCl (3 mmol), sonicate to dissolve, adjust the pH of the system to 1.2 ± 0.1 with hydrochloric acid (10% concentration) and / or NaOH aqueous solution (15% concentration), and then standardize to 100 mL;

[0161] Preparation of pH 4.5 buffer solution: Add 2.75 mmol of acetic acid to 80 mL of water, then add 2.25 mmol of sodium acetate. Adjust the pH of the system to 4.5 ± 0.2 with hydrochloric acid or sodium hydroxide aqueous solution, and then titrate to 100 mL.

[0162] Preparation of pH 6.8 buffer solution: Add 2.45 mmol of disodium hydrogen phosphate and 2.55 mmol of sodium dihydrogen phosphate to 80 mL of water, adjust the pH of the system to 6.8 ± 0.2 with hydrochloric acid (10% by mass) and / or sodium hydroxide aqueous solution (15% by mass), and then titrate to 100 mL.

[0163] Water: Deionized water.

[0164] 2. Solubility test

[0165] Four 100mg portions of crystalline Form I and four 100mg portions of crystalline APTI-I were weighed and added to 10mL of pH 1.2 buffer, pH 4.5 buffer, pH 6.8 buffer, and water, respectively. The solutions were magnetically stirred at 37℃, and samples were taken after 1 hour and 24 hours, filtered, and diluted twice. The filtrates were analyzed by HPLC, and the concentration results are summarized in Table 3 below. Table 3 shows that the 1-hour solubility data indicates that the solubility of crystalline APTI-I in all aqueous media is 1.2–1.6 times that of crystalline Form I. The 24-hour solubility data shows that the solubility of both crystalline APTI-I and crystalline Form I decreases in pH 1.2 and pH 4.5 buffers, while their solubilities are similar. In water, the 24-hour solubility data shows that the solubility of crystalline APTI-I is 1.9 times that of crystalline Form I, and the solubility of crystalline APTI-I in pH 6.8 buffer is also significantly higher than that of crystalline Form I. Therefore, in terms of solubility in water-soluble media at different pH values, the APTI-I crystal form shows a significant advantage over the Form I crystal form.

[0166] Table 3

[0167]

[0168] Example 9: Preparation of Resimetiro crystal form APTI-I

[0169] Weigh 5g of crude resimetiro, add 25mL of THF and dissolve at room temperature (20-30℃). Stir for 15min until the solution becomes turbid. Slowly add 1mol / L NaOH solution (1.1eq) at room temperature until the solution gradually becomes clear. After stirring continuously at 20-30℃ for 1h, filter and evaporate the filtrate to obtain a mixture of solid and oily viscous substance. Add 50mL of ethyl acetate (EA) and slurry at room temperature for 16h. Evaporate the slurry to obtain a solid (amorphous resimetiro sodium salt). Add 50mL of MTBE and slowly add 1.1eq of concentrated hydrochloric acid at room temperature. After the addition is complete, heat the mixture to 50℃ and stir for 5min. Filter and wash the resulting filter cake twice with water (25mL each time). Transfer to a vacuum drying oven and vacuum dry at 50℃ for 18h to obtain the crystalline product. The crystalline product was tested by XRPD, DSC, PLM, and PSD. The test results are shown in [reference to relevant documentation]. Figure 14a , Figure 14b , Figure 14c and Figure 14dThe test results showed that the XRPD pattern of this crystal was similar to that of the aforementioned crystal form APTI-I. Figure 6 The results are basically consistent with those above. DSC results show that the crystal has an exothermic peak at 221℃ and an endothermic peak at 336℃. PLM analysis results show that the crystal is a bulk crystal (as described above). Figure 9a The shape of the medium-sized APTI-I crystal is basically consistent, with an aspect ratio between 1 and 2:1 and a particle size of less than 10 μm. PSD test results show that the D90 of this crystal is 6.2 μm. The angle of repose of this APTI-I crystal is 33 to 36 degrees, and θ ≤ 40 degrees, which can meet the flowability requirements in the production process.

[0170] Example 10: Preparation of Resimetiro crystal form APTI-A

[0171] 3g of resimeltiro Form I was weighed and added to 30mL of EtOH. The mixture was stirred at room temperature (15℃) for 24 hours, filtered to obtain an ethanol solvate, which was then transferred to 30mL of MTBE. The mixture was stirred at room temperature for 5 hours, filtered again, and the resulting product was transferred to a vacuum drying oven and dried under vacuum at 120℃ for 8 hours to obtain a solid product. XRPD, DSC, PLM, and PSD analyses were performed on the solid product. The obtained chromatograms are shown in the attached figures. Figure 15a , Figure 15b , Figure 15c and Figure 15d XRPD testing showed that the solid product was a crystal (named "crystal form APTI-A"), and its XRPD pattern was similar to that of the aforementioned crystal form APTI-I. Figure 6 The results are largely consistent. However, DSC analysis of the APTI-A crystal form shows an exothermic peak at 242℃ and an endothermic peak at 337℃. Furthermore, its PLM plot indicates it is a rod-shaped crystal with an aspect ratio of approximately 5–10:1 and a particle size less than 30 μm. PSD analysis of this APTI-A crystal form shows a D90 of 4.5 μm. The angle of repose of this APTI-A crystal form is 45–48 degrees, indicating poor flowability.

[0172] Example 11: Preparation of crystal form APTI-B

[0173] Weigh 3g of resimeltiro ethyl acetate solvate (see Comparative Example 2), add it to 30mL of MTBE, stir at 16℃ for 3h, filter, and transfer the resulting product to a vacuum drying oven. Dry under vacuum at 25℃ for 0.5h, then transfer to a nitrogen-protected environment, heat to 140℃ at 10℃ / min, and dry for 1h. Cool to room temperature to obtain a solid product. The solid product was analyzed by XRPD, DSC, PLM, and PSD (see [references to be inserted here]). Figure 16a , Figure 16b , Figure 16c and Figure 16dXRPD testing results showed that the solid product was a crystal (named "crystal form APTI-B"), and its XRPD pattern was similar to that of the aforementioned crystal form APTI-I. Figure 6 The results are largely consistent, but DSC analysis of this APTI-B crystal form shows an exothermic peak at 265℃ and an endothermic peak at 336℃. Its PLM plot shows it as needle-like crystals with an aspect ratio of approximately 9–15:1 and a particle size less than 30 μm. PSD analysis of this APTI-B crystal form shows a D90 of 4.9 μm. The angle of repose of this APTI-B crystal form is 51–54 degrees, indicating poor flowability.

[0174] Example 12: Preparation of tablets containing resimemetiro crystal forms APTI-I and Form I

[0175] The composition and preparation process of resmetiro crystal form APTI-I and Form I tablets are shown in Tables 4 and 5 below, respectively.

[0176] Table 4. Components of the tablets:

[0177] 1 API medicinal 100 2 MCC101 medicinal 22 3 Mannitol medicinal 35 4 Cross-linked carboxymethyl cellulose sodium medicinal 9 5 colloidal silica medicinal 2 6 Magnesium stearate ZW-MS-8 medicinal 2

[0178] Table 5 Preparation process

[0179]

[0180] Example 13: Dissolution study of resimeltiro crystal forms APTI-I and From I tablets

[0181] Resimemetiro tablets in crystalline form APTI-I and Form I were placed in different pH buffer solutions (preparation of the buffer solutions is shown in Example 8) (pH 1.2, pH 4.5, pH 6.8) and water. Samples were taken at 10, 15, 20, 30, 45, 60, 90, and 120 min to determine the resimemetiro concentration. The dissolution curves obtained are shown in [reference needed]. Figure 17a , Figure 17b , Figure 17c and Figure 17d These dissolution profiles show that the APTI-I crystalline form tablets exhibit faster dissolution rates in pH 1.2 and pH 6.8 buffers and in water compared to the original Form I tablets. This indicates that the APTI-I crystalline form of this invention is more conducive to drug release.

[0182] Example 14: Stability study of tablets containing resmetiro APTI-I crystal form

[0183] Resimetiro APTI-I tablets were sampled and XRPD analyzed after 12 and 20 days of open storage under 40°C / 75%RH (accelerated conditions) and light exposure, and 25°C / 60%RH (long-term stability conditions). The results are summarized in Table 6. The XRPD overlay for 12-day stability is shown below. Figure 18a 20-day stability XRPD overlay plots are shown below. Figure 18b The results showed no significant change in the crystal form of APTI-I, indicating that the tablet product has stable physicochemical properties.

[0184] Table 6

[0185]

[0186]

[0187] This invention obtains a novel crystalline form, APTI-I, by first preparing resimetidine into a salt and then neutralizing it with acid. This APTI-I differs from existing crystalline forms and exhibits a different crystal shape compared to crystalline forms not prepared with resimetidine salt (APTI-A and APTI-B). Compared to the original crystalline form Form I, APTI-I has a simpler preparation method, is more stable in production, and achieves higher purity and yield. Furthermore, APTI-I exhibits better high-temperature resistance, grinding stability, and packaging stability, making it more suitable for storage. In solubility evaluations in different pH buffers and deionized water solvents, APTI-I unexpectedly showed higher solubility than the original crystalline form Form I, which is more conducive to drug efficacy. Furthermore, compared to the crystalline forms (APTI-A and APTI-B) prepared directly from resmetrol free base using methyl tert-butyl ether as a solvent without salting and re-neutralization, the APTI-I crystalline form of this invention is a blocky crystal with good flowability, is not prone to aggregation, and has a smaller angle of repose. Therefore, the APTI-I crystalline form provided by this invention exhibits significant advantages in production, storage, transportation, and formulation preparation.

[0188] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A retrimetrol crystal form APTI-I, characterized in that, The X-ray powder diffraction pattern obtained by using Cu-Kα radiation is shown in Figure 6.

2. The resimemetiro crystal form APTI-I according to claim 1, characterized in that, It is a bulk crystal.

3. The resimelotirol crystal form APTI-I according to claim 1 or 2, characterized in that, D90 ranges from 5.0μm to 7.5μm.

4. The resimelotirol crystal form APTI-I according to claim 1 or 2, characterized in that, D90 is 5.4~7.0μm.

5. The resimemetiro crystal form APTI-I according to claim 1 or 2, characterized in that, The resimetirol crystal form APTI-I also has one or more of the following characteristics: (i) The differential scanning calorimetry curve shows an exothermic peak at 237±5℃ and an endothermic peak at 330±5℃. (ii) Its differential scanning calorimetry (DSC) curve is basically shown in Figure 7. (iii) Its thermogravimetric analysis results show a weight loss of approximately 2.7% between 40 and 160°C. (iv) Its thermogravimetric analysis diagram is basically shown in Figure 8. (v) Its polarized microscope image is basically shown in Figure 9a.

6. The method for preparing retrimetrol crystal form APTI-I according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: 5g of crude resimetrol and 25mL of tetrahydrofuran solvent are added to a reaction flask, and the mixture is magnetically stirred at 50°C for 1h to form a suspension. Heating is stopped, and 1.1eq of 2mol / L NaOH aqueous solution is added to the suspension. The suspension gradually dissolves and is stirred continuously for 1h. The mixture is then filtered at room temperature, and the filtrate is concentrated to dryness. The filtrate is then filtered through MTBE pulp to make the residue powdery, which is easy to remove from the reaction flask, thus obtaining amorphous resimetrol sodium salt. 5g of the above amorphous resimetrol sodium salt is weighed and added to 50mL of methyl tert-butyl ether. The mixture is stirred at 50°C for 30min, and heating is stopped while 1.1eq of concentrated hydrochloric acid is slowly added dropwise. After stirring for 1h, the mixture is filtered at room temperature, the filter cake is washed with 10mL of water, and then vacuum dried at 50°C for 16h to obtain an off-white solid. or Add 5g of crude resimetiro and 25mL of tetrahydrofuran solvent to a reaction flask, stir magnetically at 50℃ for 1h to prepare a suspension, stop heating and add 1.1eq of concentrated ammonia solution to the suspension. The suspension gradually dissolves and is stirred continuously for 1h. Filter at room temperature, concentrate the filtrate to dryness to obtain amorphous resimetiro ammonium salt; weigh 5g of the above amorphous resimetiro ammonium salt and add 50mL of methyl tert-butyl ether, stir at 50℃ for 30min, stop heating and slowly add 1.1eq of concentrated hydrochloric acid, stir for 1h, filter at room temperature, rinse the filter cake with 10mL of water, and dry under vacuum at 50℃ for 16h to obtain an off-white solid; or Add 5g of crude resmetiro to a reaction flask and 25mL of tetrahydrofuran solvent. Stir magnetically at 50°C for 1h to form a suspension. Stop heating and add 1.1eq of 2mol / L KOH aqueous solution to the suspension. The suspension gradually dissolves. Continue stirring for 1h, then filter at room temperature. Concentrate the filtrate to dryness to obtain amorphous resmetiro potassium salt. Weigh 5g of the above amorphous resmetiro potassium salt and add it to 50mL of isopropyl ether. Stir at 50°C for 30min, then stop heating and slowly add 0.55eq of 2mol / L sulfuric acid. Continue stirring for 1h, then filter at room temperature. Rinse the filter cake with 10mL of water and dry under vacuum at 50°C for 16h to obtain an off-white solid.

7. A pharmaceutical composition comprising resmetidine crystal form APTI-I as described in any one of claims 1-5.

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