Rosmeltirol crystal form and preparation method thereof

Abstract

The invention provides a novel crystal form of rosemeltirome and a preparation method thereof. And the crystal form of the APTI-II and the crystal form of the APTI-III are as follows. The crystal forms are easy to prepare and high in purity. Particularly, the crystal form APTI-III has good stability and good solubility in a water solvent, and is suitable for industrial large-scale production and preparation of pharmaceutical preparations.

Description

Technical Field

[0001] The present invention specifically relates to a new crystal form of Resmetirom, APTI-II and APTI-III, and a preparation method thereof, and belongs to the field of pharmaceutical crystal chemistry. Background Art

[0002] Metabolic dysfunction-associated steatohepatitis (MASH) is a complex liver disease caused by obesity and diabetes, which may 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. As the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of MASH, Resmetirom has shown significant effects in reducing the formation of liver scar tissue 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, bringing hope to MASH patients.

[0003] Resmetiro is currently mainly administered in the form of resmetiro free base, the chemical structure of which is shown in Formula (I) below.

[0004]

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

[0006] The current research on resmetiro crystal form is as follows:

[0007] Prior art WO2014043706 discloses the crystal form of resmetiro Form I, which is also the drug-delivery crystal form used in the current commercial preparations. However, the preparation method of this crystal form is complicated, and the sample is taken through hydrate, methyl isobutyl ketone solvate and N, N-dimethylacetamide solvate, and is prepared by multiple crystal transformations. In addition, in the final crystal preparation process, the resmetiro MIBK solvate is refluxed and beaten with ethanol at 90°C, and crystals are transformed to form Form I. The inventors of the present application repeated the preparation process of the crystal and found that there is a risk of forming resmetiro ethanol solvate during the beating and crystal transformation process. According to the ICH requirements, the ethanol content is not higher than 5000ppm. Once the ethanol solvate is formed, the residual solvent will be much higher than this standard and cannot be used as a raw material.

[0008] The prior art WO2020010068 discloses a variety of anhydrous crystalline forms and solvates of resmetirole, but the residual solvents of all solvates cannot meet the pharmaceutical requirements, and the various anhydrous crystalline forms are obtained by desolvation of the solvates. The inventors of the present application have studied the ethyl acetate solvate and found that the temperature required for desolvation of the solvate is relatively high and cannot be used for large-scale industrial production. In addition, high-temperature desolvation usually makes it difficult to solve the problem of residual solvents.

[0009] The prior art WO2022086894 and CN114907327A also disclose various solvates of resmetirole, but these solvates also cannot meet the pharmaceutical requirements due to the problem of residual organic solvents.

[0010] The prior art CN119019375A discloses a method for preparing resmetiro crystal form APTI-I, which includes the steps of salt formation and then freeing. The final product is prone to residual inorganic salts, resulting in excessive residue on ignition of the final drug, making it unusable as a raw material for medicinal use.

[0011] The prior art CN119143733A discloses resmetirome crystal form K3. After the crystal form is prepared, it needs to be baked at 120°C, which poses hidden dangers to engineering safety and material stability, and has high production requirements.

[0012] Therefore, it is necessary to develop a better crystal form of resmetiro to facilitate large-scale industrial production and improve its existing physical and chemical properties to make it more suitable for the preparation of pharmaceutical preparations. Summary of the invention

[0013] In view of the defects of the resmetiro crystal form in the prior art, the present invention provides new crystal forms of resmetiro (crystal form APTI-II and crystal form APTI-III), which are suitable for large-scale industrial production, have high yield, high purity, stable physical and chemical properties under high temperature conditions, and better solubility in aqueous solvents of different pH values ​​than the crystal forms in the prior art, and are suitable as new crystal forms for preparations.

[0014] The resmetirole crystal form APTI-II provided by the present invention uses Cu-Kα radiation, and its X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 5.7°±0.2°, 7.6°±0.2°, 9.5°±0.2°, 11.5°±0.2°, and 20.0°±0.2°.

[0015] In another preferred embodiment, the resmetirome crystal form APTI-II, using Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, and has characteristic peaks at any one or more of 5.9°±0.2°, 6.3°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 18.5°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 23.4°±0.2°, 24.6°±0.2°, 25.5°±0.2°, 29.4°±0.2°, 31.0°±0.2°, and 32.4°±0.2°.

[0016] In another preferred embodiment, the X-ray powder diffraction pattern of the resmetirol crystal form APTI-II is substantially as follows Figure 4 shown.

[0017] In another preferred embodiment, the differential scanning calorimetry diagram of the resmetirome crystal form APTI-II has an exothermic peak at 215.01°C±5°C (peak) and an endothermic peak at 337.03°C±5°C (peak).

[0018] In another preferred embodiment, the differential scanning calorimetry analysis diagram of the resmetiro crystal form APTI-II is substantially as follows Figure 5 shown.

[0019] In another preferred embodiment, the thermogravimetric analysis chart of the resmetirome crystal form APTI-II shows a weight loss of about 0.8% at 30° C. to 120° C.

[0020] In another preferred embodiment, the thermogravimetric analysis diagram of the resmetiro crystal form APTI-II is substantially as follows Figure 6 shown.

[0021] The present invention also provides a method for preparing the above-mentioned resmetirome crystal form APTI-II, and the preparation method comprises the following steps:

[0022] (1) adding resmetirol to ethylene glycol dimethyl ether and stirring until the solution is clear;

[0023] (2) Methyl tert-butyl ether was added dropwise to the ethylene glycol dimethyl ether solution of resmetirole, and the mixture was stirred until a white solid was precipitated. The solid was filtered and dried to obtain crystalline form APTI-IB.

[0024] (3) The crystal form APTI-IB obtained in step (2) is added to n-heptane for slurrying, and then dried at 40-60° C. to obtain the crystal form APTI-II.

[0025] In another preferred embodiment, in step (1), the weight-to-volume ratio of resmetirox to ethylene glycol dimethyl ether is 1 g / 5 to 20 mL, more preferably 1 g / 8 to 12 mL.

[0026] In another preferred embodiment, in step (1), the stirring process for obtaining clarification is carried out at 0-40°C, more preferably 4-30°C.

[0027] In another preferred embodiment, in step (2), the volume ratio of methyl tert-butyl ether to ethylene glycol dimethyl ether is 6 to 2:1, more preferably 5 to 3:1.

[0028] In another preferred embodiment, in step (2), the process of adding methyl tert-butyl ether and stirring is carried out at 0 to 35°C, more preferably 4 to 25°C.

[0029] In another preferred embodiment, in step (2), the drying temperature is 40 to 70° C., and the drying time is 1 to 9 hours, more preferably 1 to 3 hours.

[0030] In another preferred embodiment, in step (3), the weight volume ratio of crystalline APTI-IB to n-heptane is 1 g / 5 to 20 mL, more preferably 1 g / 8 to 12 mL.

[0031] In another preferred embodiment, in step (3), the beating temperature in n-heptane is 4 to 40° C., and the beating time is 1 to 24 hours, more preferably 2 to 10 hours.

[0032] In another preferred embodiment, in step (3), the drying time is 2-4 hours.

[0033] In another preferred embodiment, in step (3), the drying temperature is 50° C. and the drying time is 3 hours.

[0034] The present invention also provides a resmetirole crystal form APTI-III, which uses Cu-Kα radiation, and its X-ray powder diffraction pattern represented by 2θ angles has characteristic peaks at 6.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 9.2°±0.2°, and 11.1°±0.2°.

[0035] In another preferred embodiment, the resmetiro crystal form APTI-II, using Cu-Kα radiation, has an X-ray powder diffraction pattern expressed in 2θ angles, and has characteristic peaks at any one or more of 5.2°±0.2°, 5.4±0.2°, 10.3°±0.2°, 12.0°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 21.9°±0.2°, 23.5°±0.2°, and 25.2°±0.2°.

[0036] In another preferred embodiment, the X-ray powder diffraction pattern of the resmetirol crystal form APTI-III is substantially as follows Figure 7 shown.

[0037] In another preferred embodiment, the differential scanning calorimetry graph of the resmetirome crystal form APTI-III has an exothermic peak at 218.71°C±5°C (peak) and an endothermic peak at 336.87°C±5°C (peak).

[0038] In another preferred embodiment, the differential scanning calorimetry analysis diagram of the resmetiro crystal form APTI-III is substantially as follows Figure 8 shown.

[0039] In another preferred embodiment, the thermogravimetric analysis chart of the resmetirome crystal form APTI-III shows a weight loss of about 0.1% at 30-140°C.

[0040] In another preferred embodiment, the thermogravimetric analysis diagram of the resmetiro crystal form APTI-III is substantially as follows Fig. 9 shown.

[0041] The present invention also provides a method for preparing the above-mentioned resmetirome crystal form APTI-III, and the preparation method comprises the following steps:

[0042] (1) adding resmetirol to the clear solution of ethylene glycol dimethyl ether and stirring until the solution is clear;

[0043] (2) Methyl tert-butyl ether was added dropwise to the ethylene glycol dimethyl ether solution of resmetirole, and the mixture was stirred until a white solid was precipitated. The solid was filtered and dried to obtain crystalline form APTI-IB.

[0044] (3) The crystal form APTI-IB obtained in step (2) is added to n-heptane for slurrying, and then dried at 70-110° C. to obtain the crystal form APTI-II.

[0045] In another preferred embodiment, in step (1), the weight-to-volume ratio of resmetirox to ethylene glycol dimethyl ether is 1 g / 5 to 20 mL, more preferably 1 g / 8 to 12 mL.

[0046] In another preferred embodiment, in step (1), the stirring process for obtaining clarification is carried out at 0-40°C, more preferably 4-30°C.

[0047] In another preferred embodiment, in step (2), the volume ratio of methyl tert-butyl ether to ethylene glycol dimethyl ether is 6 to 2:1, more preferably 5 to 3:1.

[0048] In another preferred embodiment, in step (2), the process of adding methyl tert-butyl ether and stirring is carried out at 0-35°C, more preferably 4-25°C.

[0049] In another preferred embodiment, in step (2), the drying temperature is 40 to 70° C., and the drying time is 1 to 9 hours, more preferably 1 to 3 hours.

[0050] In another preferred embodiment, in step (3), the weight volume ratio of crystalline APTI-IB to n-heptane is 1 g / 5 to 20 mL, more preferably 1 g / 8 to 12 mL.

[0051] In another preferred embodiment, in step (3), the temperature for pulping in n-heptane is 4 to 40° C., and the pulping time is 1 to 24 hours, more preferably 2 to 20 hours.

[0052] In another preferred embodiment, in step (3), the drying time is greater than 3 hours, for example, 5-48 hours. In another more preferred embodiment, in step (3), the drying temperature is 70° C. and the drying time is 10 hours.

[0053] In another aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned resmetirome crystalline form APTI-II and / or crystalline form APTI-III. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is a typical XRPD pattern of resmetirol crystalline form APTI-IB;

[0055] Figure 2 This is a typical DSC spectrum of resmetirol crystalline form APTI-IB;

[0056] Figure 3 This is a typical TGA spectrum of resmetirome crystal form APTI-IB;

[0057] Figure 4 This is a typical XRPD pattern of resmetirol crystalline form APTI-II;

[0058] Figure 5 This is a typical DSC spectrum of resmetirol crystalline form APTI-II;

[0059] Figure 6 This is a typical TGA spectrum of resmetirol crystalline form APTI-II;

[0060] Figure 7 This is a typical XRPD pattern of resmetirol crystalline form APTI-III;

[0061] Figure 8 This is a typical DSC spectrum of resmetirol crystalline form APTI-III;

[0062] Fig. 9 This is a typical TGA spectrum of resmetirol crystalline form APTI-III;

[0063] Fig.10 It is an overlay of the XRPD spectrum of the product obtained by repeating the process of obtaining Form I in the prior art WO2014043706;

[0064] Fig.11 It is an overlay of the XRPD pattern of the ethyl acetate solvate of resmetirole obtained by repeating the prior art WO2020010068 and the XRPD pattern of the crystalline form Form F obtained by desolvation thereof;

[0065] Fig.12 It is a DSC graph of resmetiro ethyl acetate solvate obtained by repeating the prior art WO2020010068;

[0066] Fig.13 This is the XRPD overlay of Resmetirol crystal form APTI-II before and after grinding;

[0067] Fig.14 This is the XRPD overlay of Resmetirol crystal form APTI-III before and after grinding;

[0068] Fig.15 This is the XRPD overlay of the high temperature stability of Resmetirol crystal form APTI-III;

[0069] Fig.16 It is the XRPD overlay of the moisture sorption stability of Resmetirol crystalline form APTI-III;

[0070] Fig.17 This is the XRPD overlay of the constant temperature and humidity stability of Resmetirol crystal form APTI-III;

[0071] Fig.18 It is an XRPD overlay of Resmetirol crystalline form APTI-II and crystalline form APTI-III; DETAILED DESCRIPTION

[0072] The inventors of the present application have obtained a new crystal form of resmetirox, crystal form APTI-II, through extensive and in-depth research. Unexpectedly, the crystal form APTI-II exhibits the advantages of high stability, low hygroscopicity, high purity, high solubility, etc., and the production method is simple, the quality is stable, and it is suitable for large-scale industrial production.

[0073] Resmetirol crystal form APTI-II .

[0074] The resmetirole crystal form APTI-II provided by the present invention uses Cu-Kα radiation, and its X-ray powder diffraction (XRPD) spectrum represented by 2θ angles has characteristic peaks at 5.7°±0.2°, 7.6°±0.2°, 9.5°±0.2°, 11.5°±0.2°, and 20.0°±0.2°.

[0075] Furthermore, the resmetirole crystal form APTI-II provided by the present invention uses Cu-Kα radiation, and its XRPD spectrum expressed in 2θ angles has characteristic peaks at 5.7°±0.2°, 5.9°±0.2°, 6.3°±0.2°, 7.6°±0.2°, 9.5°±0.2°, 11.5°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 18.5°±0.2°, 20.0°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 23.4°±0.2°, 24.6°±0.2°, 25.5°±0.2°, 29.4°±0.2°, 31.0°±0.2°, and 32.4°±0.2°.

[0076] Furthermore, the resmetirole crystal form APTI-II provided by the present invention uses Cu-Kα radiation, and its XRPD spectrum expressed in 2θ angles has characteristic peaks as shown in Table 1 below:

[0077] Table 1

[0078]

[0079]

[0080] Furthermore, the resmetirol crystal form APTI-II provided by the present invention uses Cu-Kα radiation, and its XRPD pattern expressed in 2θ angles is Figure 4 Be consistent.

[0081] Furthermore, the differential scanning calorimetry (DSC) diagram of the resmetirol crystal form APTI-II provided by the present invention has an exothermic peak at 215.01°C±5°C (peak) and an endothermic peak at 337.03°C±5°C (peak);

[0082] Furthermore, the DSC diagram of the resmetirol crystal form APTI-II provided by the present invention is Figure 5 Be consistent.

[0083] Furthermore, the thermogravimetric analysis (TGA) graph of the resmetirole crystal form APTI-II provided by the present invention shows a weight loss of about 0.8% at 30-120°C.

[0084] Furthermore, the TGA diagram of the resmetirol crystal form APTI-II provided by the present invention is Figure 6 Be consistent.

[0085] The resmetirole crystal form APTI-III provided by the present invention uses Cu-Kα radiation, and its X-ray powder diffraction (XRPD) spectrum represented by 2θ angles has characteristic peaks at 5.4±0.2°, 6.4°±0.2°, 7.7°±0.2°, 9.2°±0.2°, and 11.1°±0.2°.

[0086] Furthermore, the resmetirole crystal form APTI-III provided by the present invention uses Cu-Kα radiation, and its XRPD spectrum expressed in 2θ angles has characteristic peaks at 5.4±0.2°, 5.2°±0.2°, 6.2°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 9.2°±0.2°, 10.3°±0.2°, 11.1°±0.2°, 12.0°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 21.9°±0.2°, 23.5°±0.2°, and 25.2°±0.2°.

[0087] Furthermore, the resmetirole crystal form APTI-III provided by the present invention uses Cu-Kα radiation, and its XRPD spectrum expressed in 2θ angles has characteristic peaks as shown in Table 2 below:

[0088] Table 2

[0089]

[0090]

[0091] Furthermore, the resmetirol crystal form APTI-III provided by the present invention uses Cu-Kα radiation, and its XRPD pattern expressed in 2θ angles is Figure 7 Be consistent.

[0092] Furthermore, the differential scanning calorimetry (DSC) diagram of the resmetirol crystal form APTI-III provided by the present invention has an exothermic peak at 218.71°C±5°C (peak) and an endothermic peak at 336.87°C±5°C (peak);

[0093] Furthermore, the DSC diagram of the resmetirol crystal form APTI-III provided by the present invention is Figure 8 Be consistent.

[0094] Furthermore, the thermogravimetric analysis (TGA) graph of the resmetirol crystal form APTI-III provided by the present invention shows a weight loss of about 0.1% at 30-160°C.

[0095] Furthermore, the TGA diagram of the resmetirol crystal form APTI-III provided by the present invention is Fig. 9 Be consistent.

[0096] Preparation method of resmetiro crystal form APTI-II and resmetiro crystal form APTI-III

[0097] In the preparation method of the resmetiro crystal form APTI-II and the resmetiro crystal form APTI-III of the present invention, the crystal form APTI-IB is first prepared, and then slurried in n-heptane, and dried at different temperatures to obtain the crystal form APTI-II and the crystal form APTI-III, respectively. For example, in a preferred embodiment of the present invention, the crystal form APTI-IB is dried at 50°C for 3 hours to obtain the crystal form APTI-II. At a lower temperature (e.g., 40 to 60°C), the drying time is extended, for example, for 8 hours, and a portion of the crystal form APTI-II in the final product is converted into the crystal form APTI-III. In a preferred embodiment of the present invention, the crystal form APTI-IB is dried at 70°C for more than 6 hours to obtain the crystal form APTI-III, and the drying time is extended, for example, drying for 16 hours, and the crystal form APTI-III is still obtained, and there is no other crystal form. In addition, the drying temperature is increased, for example, APTI-IB is dried at 102°C for 5 hours to obtain the crystal form APTI-III, and there is no other crystal form. Therefore, the crystal form APTI-III is a very stable crystal form.

[0098] The XRPD pattern of the crystal form APTI-IB obtained by the present invention is as follows Figure 1 shown.

[0099] In the description of the present invention, "room temperature" refers to 0°C to 40°C, more preferably, 4°C to 25°C.

[0100] Compared with the prior art, the beneficial effects of the resmetirome crystal form APTI-II or APTI-III of the present invention are:

[0101] (1) Compared with the crystal forms disclosed in the prior art (including Form I disclosed in the original research (WO2014043706A1)), the resmetirol crystal form APTI-II and the resmetirol crystal form APTI-III of the present invention have a simpler preparation method, more stable product quality, and high purity and yield of the obtained products.

[0102] (2) The resmetirol crystal form APTI-II of the present invention exhibits good grinding stability, especially the resmetirol crystal form APTI-III exhibits good high temperature stability, grinding stability and packaging stability, and is suitable for long-term storage.

[0103] (3) In the pH solubility evaluation, the resmetirol crystal form APTI-III of the present invention exhibits higher solubility in aqueous solvents of different pH values ​​than the Form I disclosed in the original research (WO2014043706 A1). Since resmetirol has poor water solubility, the crystal form APTI-III of the present invention can improve the solubility of resmetirol, which is very important for the efficacy of resmetirol.

[0104] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only intended to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on normal conditions. Unless otherwise indicated, percentages and parts are weight percentages and parts by weight.

[0105] Materials and general method:

[0106] 1. XRPD pattern determination method

[0107] X-ray powder diffraction instrument: 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; Scanning range: 3.0~40.0°.

[0108] 2.DSC measurement method

[0109] METTLEER DSC1 differential scanning calorimeter temperature program: 30℃~360℃, 20℃ per minute.

[0110] 3. TGA determination method

[0111] Instrument model: METTLEER TGA / DSC1 thermogravimetric analyzer. Heating program: 30℃~400℃, 10℃ per minute.

[0112] The crude resmetirol used in the following comparative examples and examples is commercially available, and its HPLC purity is about 97.6%.

[0113] Comparative Example 1: Form I prepared according to prior art WO2014043706

[0114] Weigh 5 g of crude resmetiro, add 25 mL of methyl isobutyl ketone (MIBK) at room temperature, heat from 20-25 ° C to 50 ° C, keep warm for 1 hour, naturally cool to 20-25 ° C, keep warm for 2.5 hours, filter the product to a nearly dry state, and obtain 6.4 g of wet MIBK solvate.

[0115] The wet product of the MIBK solvate was added to 32 mL of ethanol, heated to 80 ± 5 °C in a three-necked flask, refluxed and slurried, and sampled for testing after 2 hours. XRPD testing confirmed that the product was Form I (see Fig.10 , the bottom XRPD spectrum), reflux beating for 4 hours and sampling for testing, XRPD testing confirmed that the product was Form I (see Fig.10 , XRPD spectrum in the middle). The system refluxed for 4 hours was cooled naturally to 20°C (for a system of about 35 mL, it is difficult to control the temperature to 20°C in 45 minutes), and stirred for 15 minutes and filtered. The obtained product was confirmed to be an ethanol solvate by XRPD detection (see Fig.10 , the top XRPD pattern, which is consistent with WO2020010068 Figure 3 The XRPD patterns of the ethanol solvate of Compound A (resmetirole) shown are consistent.) The purity of the ethanol solvate was 98.5% as determined by HPLC.

[0116] from Fig.10 It can be seen that when the MIBK solvate is slurried in ethanol for 2h to 4h, the crystal form changes to form Form 1, but when the reflux system is naturally cooled to 20°C, the crystal form obtained by filtration changes again to form an ethanol solvate.

[0117] In large-scale workshop production, technicians prepared Form I by reflux slurrying resmetiro MIBK solvate in ethanol. Even if the reflux system was strictly controlled to cool to 20°C within 45 minutes, most batches obtained Form I products, but a small number of batches obtained ethanol solvate of resmetiro. The batches that obtained ethanol solvate of resmetiro were failed batches. This shows that Form I can easily undergo crystal transformation into ethanol solvate in the ethanol system. This is disadvantageous in industrial scale-up production.

[0118] Comparative Example 2: Form F prepared according to prior art WO2020010068

[0119] Weigh 200 mg of resmetiro, add 2 mL of ethyl acetate, stir magnetically at 50°C for 24 h, filter, and XRPD test confirms that the obtained product is ethyl acetate solvate (see Fig.11 , the bottom XRPD spectrum), the ethyl acetate solvate was dried under vacuum at 80°C for 12 h, and XRPD detection revealed that the solvate did not crystallize (see Fig.11 , XRPD pattern in the middle). The ethyl acetate solvate was heated to 150°C and kept at this temperature for 3 min, then the solvent was removed to obtain Form F (see Fig.11 , the top XRPD pattern). The ethyl acetate solvate was subjected to DSC detection, and the results are shown in Fig.12 ,from Fig.12 It can be seen that the solvate desolvates at 148±5°C.

[0120] Form F can only be obtained by heating the ethyl acetate solvate to 150°C, indicating that the temperature required for the method of desolvation of the solvate to obtain the new crystal form is too high to meet the requirements of industrial large-scale production. In addition, the NMR spectrum of the product obtained after heating and desolvation showed that there was still 0.04 eq of ethyl acetate remaining, which exceeded the standard.

[0121] Example 1: Preparation of Resmetirol Crystal Form APTI-IB

[0122] Add 5 g of crude resmetiro and 50 mL of ethylene glycol dimethyl ether to the reaction bottle, stir at room temperature to dissolve and filter, slowly drop 200 mL of methyl tert-butyl ether into the clear solution, the solution becomes clear, and after continuing to stir for 1 to 2 hours, it becomes turbid, and a large amount of solid precipitates overnight, which is filtered and dried in a vacuum drying oven at 50°C for 3 hours to obtain crystalline form APTI-IB. XRPD shows Figure 1 , its DSC diagram is shown in Figure 2 , its TGA diagram can be found in Figure 3 .

[0123] Example 2: Preparation of Resmetiro Crystal Form APTI-II

[0124] 5.3 g of crystalline APTI-IB solid was added to 50 mL of n-heptane and stirred at room temperature for 3 h, filtered, and dried in a 50°C vacuum oven for 3 h to obtain 4.8 g of off-white solid crystalline APTI-II, with a yield of 96% and a HPLC purity of 99.88%. Its XRPD spectrum can be found in Figure 4 , its DSC diagram is shown in Figure 5 , its TGA diagram can be found in Figure 6 .

[0125] Example 3-1: Preparation of Resmetirol Crystal Form APTI-III

[0126] 5.3 g of crystalline APTI-IB solid was added to 50 mL of n-heptane and stirred at room temperature for 18 h, filtered, and dried in a 70°C vacuum oven for 10 h to obtain 4.8 g of off-white solid crystalline APTI-III, with a yield of 96% and a HPLC purity of 99.92%. Its XRPD spectrum can be found at Figure 7 , its DSC diagram is shown in Figure 8 , its TGA diagram can be found in Fig. 9 .

[0127] Example 3-2: Preparation of Resmetirol Crystal Form APTI-III

[0128] 5.0 g of crystalline APTI-IB solid was added with 60 mL of n-heptane, stirred at room temperature for 20 h, filtered, and dried in a vacuum drying oven at 80° C. for 10 h to obtain 4.5 g of an off-white solid, which was confirmed to be crystalline APTI-III by XRPD with a HPLC purity of 99.91%.

[0129] Example 3-3: Preparation of Resmetiro Crystalline APTI-III

[0130] 5.0 g of crystalline APTI-IB solid was added to 60 mL of n-heptane and stirred at room temperature for 15 h, filtered, and dried in a 70°C vacuum oven for 6 h to obtain 4.5 g of an off-white solid. XRPD detection showed that it was crystalline APTI-III with an HPLC purity of 99.91%.

[0131] Example 3-4: Preparation of Resmetirol Crystal Form APTI-III

[0132] 5.0 g of crystalline APTI-IB solid was added with 40 mL of n-heptane and stirred at room temperature for 30 h, filtered, and dried in a 90° C. vacuum drying oven for 6 h to obtain 4.4 g of an off-white solid. XRPD detection showed that it was crystalline APTI-III with an HPLC purity of 99.89%.

[0133] Example 3-5: Preparation of Resmetirol Crystal Form APTI-III

[0134] 5.0 g of crystalline APTI-IB solid was added with 40 mL of n-heptane, stirred at room temperature for 25 h, filtered, and dried in a vacuum drying oven at 102° C. for 5 h to obtain 4.4 g of an off-white solid, which was confirmed to be crystalline APTI-III by XRPD with a HPLC purity of 99.92%.

[0135] Example 4: Grinding stability study

[0136] 4.1 Grinding stability test of resmetirol crystal form APTI-II

[0137] Weigh 200 mg of resmetirol crystal form APTI-II (HPLC purity 99.86%) and grind it manually in an agate grinder for 30 min. The ground product was detected by XRPR. The results are shown in Fig.13 (Shown is an overlay of the XRPD patterns of the starting material (Form APTI-II) and the product obtained after manual dry grinding in an agate grinder for 30 min.) Fig.13 It can be seen that the crystal form of APTI-II did not undergo crystal transformation before and after grinding. The purity of the ground product was 99.86% as determined by HPLC, with no significant change in purity compared to the starting material.

[0138] 4.2 Grinding stability test of resmetirol crystal form APTI-III

[0139] Weigh 200 mg of resmetirol crystal form APTI-III (HPLC purity 99.92%) and grind it manually in an agate grinder for 30 min. The ground product was tested by XRPR. The results are shown in Fig.14 (Shown is an overlay of the XRPD patterns of the starting material (Form APTI-II) and the product obtained after manual dry grinding in an agate grinder for 30 min.) Fig.14 It can be seen that the crystal form of APTI-III did not undergo crystal transformation before and after grinding. The purity of the ground product was 99.89% as determined by HPLC, with no significant change in purity compared to the starting material.

[0140] Example 5: High temperature stability evaluation of resmetirol crystal form APTI-III

[0141] Take 1g of resmetiro crystal form APTI-III (HPLC purity is 99.92%), place it in an oven at 80°C for 24h, then take a sample and detect its crystal form by XRPD. The results are shown in Fig.15 (It shows an overlay of the XRPD patterns of the starting material (form APTI-III) and the product obtained after being placed in an oven at 80°C for 24 hours). Fig.15 It can be seen that the crystal form of APTI-III did not change after being heated at 80° C. for 24 h. The purity of the product after being heated at 80° C. for 24 h was 99.90% as determined by HPLC, which was not significantly different from the starting material.

[0142] Example 6: Evaluation of hygroscopicity of resmetiro crystal form APTI-III

[0143] Accurately weigh 1136.3 mg of solid resmetiro crystal APTI-III (HPLC purity 99.92%) and spread it evenly in a 100 mm glass dish. After the product was left in a constant temperature and humidity chamber at 25°C / 80%RH for 24 hours, the peeled weight was 1147.5 mg, with a weight gain of 11.2 mg and a weight gain of 0.98%. According to the guidelines for the hygroscopicity test of pharmacopoeia drugs, the weight gain due to moisture is less than 2% but not less than 0.2%, indicating that crystal APTI-III is slightly hygroscopic. XRPD was used to detect the product after being left in a constant temperature and humidity chamber at 25°C / 80%RH for 24 hours. The results are shown in Table 1. Fig.15 (which shows an overlay of the XRPD patterns of the starting material (crystalline APTI-III) and the product obtained after being exposed in a constant temperature and humidity chamber at 25°C / 80%RH for 24 hours). Fig.16It can be seen that the crystal form of APTI-III did not change after being placed at 25°C / 80% RH for 24 hours. The purity of the product after being placed at 25°C / 80% RH for 24 hours was 99.92% by HPLC, which was not significantly different from the starting material.

[0144] Example 7: Evaluation of Temperature and Humidity Stability of Resmetirol Crystal Form APTI-III

[0145] Resmetiro crystal form APTI-III 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°C / 60%RH and 40°C / 70%RH respectively. After being placed for 1 week, samples were taken for XRPD detection and purity detection. The XRPD pattern of the obtained product was shown in the overlay diagram. Fig.17 (The starting material (crystalline APTI-III) is shown. The purity of the product is shown in Table 3 below. Fig.17 As can be seen from Table 2, after the resmetiro crystal form APTI-II8I was packaged in PE bags and aluminum foil bags and placed at 25°C / 60% RH and 40°C / 70% RH for 1 week, there was no obvious change in the crystal form and purity, indicating that the resmetiro crystal form APTI-III was stable under 25°C / 60% RH and 40°C / 70% RH conditions after being packaged in PE bags and aluminum foil bags, and was suitable for storage.

[0146] The evaluation conditions of Examples 5-7 and the crystal forms and purities of the products obtained after the experiments are summarized in Table 3 below.

[0147] Table 3

[0148]

[0149]

[0150] Example 8: Evaluation of the solubility of resmetiro crystal form APTI-III in aqueous solutions at different pH values

[0151] The method for preparing aqueous media with different pH values ​​(all aqueous media with different pH values ​​have a uniform ion concentration of 50 mM) is as follows:

[0152] Preparation of pH 1.2 buffer: add 167 μL (2 mmoL) of 36.5% hydrochloric acid to 80 mL of water, then add 0.223 g KCl (3 mmoL), dissolve by ultrasonication, adjust the pH of the system to 1.2 ± 0.1 with hydrochloric acid (mass concentration of 10%) or / and NaOH aqueous solution (mass concentration of 15%), and then calibrate to 100 mL;

[0153] Preparation of pH 4.5 buffer: add 2.75mmoL of acetic acid to 80mL of water, then add 2.25mmoL 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 100mL;

[0154] Preparation of pH 6.8 buffer: 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 (mass concentration of 10%) or / and sodium hydroxide aqueous solution (mass concentration of 15%), and then titrate to 100 mL;

[0155] Water: deionized water.

[0156] 2. Solubility test

[0157] Four portions (100 mg each) of Form I and four portions (100 mg each) of crystalline APTI-III were weighed, and 10 mL of pH 1.2 buffer, pH 4.5 buffer, pH 6.8 buffer and water were added, respectively, and magnetic stirring was performed at 37°C. Samples were taken and filtered at 1 hour and 24 hours, and diluted 2 times. The concentration results were detected by HPLC, and the solubility was calculated. The solubility data are summarized in Table 4 below. As can be seen from Table 4, the 1h solubility data results show that the solubility of crystalline APTI-III in all aqueous solvents is 1.2 to 1.6 times that of Form I, and the 24h solubility results show that the solubility of crystalline APTI-III and Form I in pH 1.2 buffer and pH 4.5 buffer is reduced, and the solubility is similar. In water, the 1h and 24h solubility results show that the solubility of crystalline APTI-III is nearly 3 times that of Form I, and the solubility of crystalline APTI-III in pH 6.8 buffer is also significantly higher than that of Form I. Therefore, in terms of solubility, crystalline APTI-III shows obvious advantages.

[0158] Table 4

[0159]

[0160]

[0161] In summary, the resmetirole crystal forms APTI-II and APTI-III obtained in the present invention are new crystal forms different from the crystal forms disclosed in the prior art. Compared with the original Form I, these crystal forms have a simpler preparation method, the target product has high purity and high yield, and can be prepared more stably in production. In particular, APTI-III exhibits good high temperature resistance, grinding stability, and packaging stability, and is suitable for storage. In the solubility evaluation in aqueous solvents of different pH values, especially in deionized water, the solubility of the crystal form APTI-III is unexpectedly increased by nearly 3 times compared to the original Form I solubility. It can be seen that the crystal form APTI-III provided by the present invention shows obvious advantages in production and preparation, storage and transportation, and potential drug use.

[0162] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A resmetirome crystal form APTI-II, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles is at 5.7°±0.2°, 7.6°±0.2°, 9.5°±0.2°, 11.5°±0.2°, and 20.0°±0.2°.

2. The resmetirome crystal form APTI-II according to claim 1, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles also has characteristic peaks at any one or more of 5.9°±0.2°, 6.3°±0.2°, 14.5°±0.2°, 15.5°±0.2°, 18.5°±0.2°, 20.4°±0.2°, 22.3°±0.2°, 23.4°±0.2°, 24.6°±0.2°, 25.5°±0.2°, 29.4°±0.2°, 31.0°±0.2°, and 32.4°±0.2°.

3. The resmetirome crystal form APTI-II according to claim 1 or 2, characterized in that: The resmetirol crystal form APTI-II also has one or more of the following characteristics: (i) Its X-ray powder diffraction pattern is basically as shown in Figure 4, (ii) Its differential scanning calorimetry analysis chart has an exothermic peak at 215.01℃±5℃(peak) and an endothermic peak at 337.03℃±5℃(peak), (iii) Its differential scanning calorimetry analysis diagram is basically as shown in FIG5 , (iv) Its thermogravimetric analysis shows a weight loss of about 0.8% at 30°C to 120°C. (v) Its thermogravimetric analysis diagram is basically as shown in Figure 6.

4. The method for preparing the resmetirome crystal form APTI-II according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: (1) adding resmetirol to ethylene glycol dimethyl ether and stirring until the solution is clear; (2) adding methyl tert-butyl ether dropwise to the ethylene glycol dimethyl ether solution of resmetirol, stirring until a white solid precipitates, filtering, and drying to obtain crystalline form APTI-IB; (3) adding the crystal form APTI-IB obtained in step (2) into n-heptane for slurrying, and drying at 40-60° C. to obtain the crystal form APTI-II. Preferably, the drying time is 2-4 hours.

5. A resmetirol crystal form APTI-III, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at any one or more of 5.4±0.2°, 6.4°±0.2°, 7.7°±0.2°, 9.2°±0.2°, and 11.1°±0.2°.

6. The resmetirome crystal form APTI-III according to claim 5, characterized in that: Using Cu-Kα radiation, its X-ray powder diffraction pattern expressed in 2θ angles also has characteristic peaks at any one or more of 5.2°±0.2°, 6.2°±0.2°, 10.3°±0.2°, 12.0°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 18.5°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 21.9°±0.2°, 23.5°±0.2°, and 25.2°±0.2°.

7. The resmetirome crystal form APTI-III according to claim 5 or 6, characterized in that: The resmetirol crystal form APTI-III also has one or more of the following characteristics: (i) Its X-ray powder diffraction pattern is basically as shown in Figure 7, (ii) Its differential scanning calorimetry analysis chart has an exothermic peak at 218.71℃±5℃(peak) and an endothermic peak at 336.87℃±5℃(peak), (iii) Its differential scanning calorimetry analysis diagram is basically as shown in FIG8 , (iv) Its thermogravimetric analysis shows a weight loss of about 0.1% at 30°C to 140°C. (v) Its thermogravimetric analysis diagram is basically as shown in FIG9 .

8. The method for preparing the resmetirome crystal form APTI-III according to any one of claims 5 to 7, characterized in that: The preparation method comprises the following steps: (1) adding resmetirol to ethylene glycol dimethyl ether and stirring until the solution is clear; (2) Methyl tert-butyl ether was added dropwise to the resmetirole glycol dimethyl ether solution, and the mixture was stirred until a white solid was precipitated. The solid was filtered and dried to obtain crystalline form APTI-IB. (3) The crystal form APTI-IB obtained in step (2) is added to n-heptane for slurrying, and then dried at 70-110° C. to obtain the crystal form APTI-III.

9. The preparation method according to claim 8, characterized in that: In step (1), the mass volume ratio of resmetirol to ethylene glycol dimethyl ether solution is 1 g / 5 to 20 mL, preferably 1 g / 8 to 12 mL; and / or The stirring process of step (1) to obtain clarification is carried out at 0 to 40° C., more preferably 4 to 30° C.; and / or In step (2), the volume ratio of methyl tert-butyl ether to ethylene glycol dimethyl ether is 6 to 2:1, more preferably 5 to 3:1; and / or In step (2), the process of adding methyl tert-butyl ether and stirring is carried out at 0 to 35° C., preferably 4 to 25° C.; and / or In step (2), the drying temperature is 40 to 70° C., and the drying time is 1 to 9 hours, preferably 1 to 3 hours; and / or In step (3), the weight volume ratio of crystalline form APTI-IB to n-heptane is 1 g / 5 to 20 mL, more preferably 1 g / 8 to 12 mL; and / or In step (3), the beating temperature in n-heptane is 4 to 40° C., and the beating time is 1 to 24 hours, preferably 2 to 20 hours; and / or In step (3), the drying time is 3-48 hours.

10. A pharmaceutical composition comprising the resmetirol crystalline form APTI-II according to any one of claims 1 to 3 and / or the resmetirol crystalline form APTI-III according to any one of claims 5 to 7.

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