Tillatrecol crystal form and preparation method thereof

Abstract

The invention relates to a tilatrocol crystal form and a preparation method thereof, and particularly provides a tilatrocol crystal form C. Compared with the prior art, the tilatrocol crystal form C provided by the invention has more excellent stability, solubility, flowability and compressibility and higher purity, provides a better choice for drug development of tilatrocol, and has good application prospects. And the method has very important significance on drug development.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemical crystal preparation, and particularly relates to telotracort crystal form C and a preparation method thereof. Background Art

[0002] Telotracort is a thyroid hormone analogue, chemically named 3,3',5-triiodothyroacetic acid, with a structure as shown in Formula I. It is used for the treatment of thyroid hormone resistance syndrome and in combination with thyroxine to inhibit the production of thyroid-stimulating hormone in patients with thyroid cancer. It has been studied for reducing goiter and Allan-Herndon-Dudley syndrome and has certain therapeutic effects in aspects such as neurological diseases, genetic diseases, and deformities.

[0003]

[0004] Telotracort also has certain therapeutic effects on thalassemia. Thalassemia is a disease with abnormal hemoglobin and is a genetic disease caused by autosomal gene defects. Due to the deletion or mutation of the gene regulating globin synthesis, the synthesis ratio of α-chain and β-chain globins constituting hemoglobin is imbalanced, resulting in a hemolytic anemia with shortened red blood cell lifespan. The pathogenesis of thalassemia is different from that of ordinary anemia. Ordinary anemia is caused by a lack of iron in the diet, resulting in too few red blood cells and insufficient oxygen delivery by red blood cells, while thalassemia is due to defects in the red blood cells themselves rather than insufficient red blood cell quantity. Carriers of the thalassemia gene do not develop the disease and have the same appearance and physical functions as normal people, and only severe patients will show symptoms.

[0005] Generally, the method for preparing telotracort and its derivatives involves electrophilic substitution of p-acetophenol with iodine, followed by esterification with ethanol, Ullmann coupling, dealkylation, hydrolysis, and iodination, a total of five steps to obtain the target compound.

[0006] As is well known, the crystal polymorphs of a specific drug are closely related to the drug's druggability. The crystal form of a drug affects the stability, solubility, dissolution rate of the preparation, and thus affects the bioavailability of the drug. Studying the crystal form of the active pharmaceutical ingredient and selecting a crystal form with high stability, good safety, and high bioavailability plays an important role in the development of drug preparations.

[0007] In summary, there is an urgent need in this field to develop a new telotracort crystal form with high stability, good safety, and high bioavailability. Summary of the Invention

[0008] The inventor of the present invention has discovered a crystal form of telratricol, which has unique advantages in terms of physicochemical properties, pharmaceutical processing performance, bioavailability, etc. For example, it has advantages in at least one of the aspects such as melting point, solubility, hygroscopicity, purification effect, adhesiveness, compressibility, fluidity, in vitro and in vivo dissolution, and bioavailability, providing a better choice for the drug development of telratricol and having very important significance.

[0009] In the first aspect of the present invention, there is provided a crystal form of a compound of formula 1,

[0010]

[0011] characterized in that the crystal form is crystal form C, which has the following X-ray powder diffraction characteristic peaks: 7.52° ± 0.2°, 9.33° ± 0.2°, 15.17° ± 0.2°, 21.32° ± 0.2°, 21.96° ± 0.2°, 22.87° ± 0.2°, 24.01° ± 0.2°.

[0012] In another preferred example, the crystal form has the following X-ray powder diffraction characteristic peaks: 7.52° ± 0.2°, 9.33° ± 0.2°, 15.17° ± 0.2°, 21.32° ± 0.2°, 21.67° ± 0.2°, 21.96° ± 0.2°, 22.87° ± 0.2°, 24.01° ± 0.2°, 25.65° ± 0.2°, 27.05° ± 0.2°, 29.38° ± 0.2°, 30.35° ± 0.2°, 33.59° ± 0.2°.

[0013] In another preferred example, the crystal form has the following X-ray powder diffraction characteristic peaks: 7.52° ± 0.2°, 9.33° ± 0.2°, 15.17° ± 0.2°, 15.83° ± 0.2°, 18.82° ± 0.2°, 19.19° ± 0.2°, 21.32° ± 0.2°, 21.67° ± 0.2°, 21.96° ± 0.2°, 22.24° ± 0.2°, 22.87° ± 0.2°, 23.37° ± 0.2°, 24.01° ± 0.2°, 25.65° ± 0.2°, 27.05° ± 0.2°, 27.58° ± 0.2°, 27.96° ± 0.2°, 28.43° ± 0.2°, 28.81° ± 0.2°, 29.38° ± 0.2°, 30.35° ± 0.2°, 30.70° ± 0.2°, 33.59° ± 0.2°, 36.29° ± 0.2°, 36.86° ± 0.2°.

[0014] In another preferred example, the DSC pattern of the crystal form has an endothermic peak at 170°C to 180°C.

[0015] In another preferred example, the TG pattern of the crystal form shows no weight loss at 0 to 160 °C.

[0016] In another preferred example, the preparation method includes the steps of:

[0017] 1) Dissolve the compound of formula 1 in a solvent, and leave the solution to stand and volatilize at room temperature until the solvent is completely volatilized to obtain the target crystal form C; preferably, in step 1, the solvent is selected from the following group: methanol, ethanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, ethylene glycol dimethyl ether, acetonitrile, chloroform, or a combination thereof.

[0018] In another preferred example, the molar volume ratio of the compound of formula 1 to the solvent is 1:2 - 4 mol / mL.

[0019] In another preferred example, the reaction temperature of step 1 is 20 to 30 °C.

[0020] In another preferred example, the preparation method includes the steps of:

[0021] 2) Drop the solution of the compound of formula 1 in a good solvent into a poor solvent to crystallize and obtain the target crystal form C; preferably, in step 2, the good solvent is selected from the following group: acetone, ethyl acetate, butyl formate, ethylene glycol dimethyl ether, ethyl formate, methanol, n-propanol, acetone, acetonitrile, isopropanol, 4-methyl-2-pentanone, isopropyl acetate, ethyl formate, or a combination thereof, and the poor solvent is selected from n-heptane, cyclohexane, water, toluene, or a combination thereof.

[0022] In another preferred example, the molar volume ratio of the compound of formula 1 to the good solvent is 1:2 - 4 mol / mL.

[0023] In another preferred example, the molar volume ratio of the compound of formula 1 to the poor solvent is 1:20 - 40 mol / mL.

[0024] In another preferred example, the reaction temperature of step 2 is 20 to 30 °C.

[0025] In another preferred example, the preparation method includes the steps of:

[0026] 3) Drop a poor solvent into the solution of the compound of formula 1 in a good solvent until a solid precipitates, and filter to obtain the target crystal form C; preferably, in method 3, the good solvent is selected from the following group: n-propanol, ethyl formate, acetone, butyl formate, ethanol, isopropanol, ethyl acetate; and the poor solvent is selected from n-heptane, cyclohexane, water, dichloromethane, or a combination thereof.

[0027] In another preferred example, the molar volume ratio of the compound of Formula 1 to the good solvent is 1:2 - 4 mol / mL.

[0028] In another preferred example, the molar volume ratio of the compound of Formula 1 to the poor solvent is 1:4 - 8 mol / mL.

[0029] In another preferred example, the reaction temperature of Step 3 is 20 - 30 °C.

[0030] In another preferred example, the preparation method includes the steps:

[0031] 4) Add the compound of Formula 1 to the poor solvent, heat to 45 - 55 °C, then dropwise add the preheated good solvent until the solution is clear, naturally cool to room temperature, crystallize and filter to obtain the target crystal form C; preferably, in Method 4, the good solvent is selected from the group consisting of ethanol, isopropanol, or a combination thereof, and the poor solvent is water.

[0032] In another preferred example, the molar volume ratio of the compound of Formula 1 to the poor solvent is 1:20 - 40 mol / mL.

[0033] In another preferred example, the molar volume ratio of the compound of Formula 1 to the good solvent is 1:15 - 20 mol / mL.

[0034] In another preferred example, the reaction temperature of Step 4 is 40 - 60 °C.

[0035] In another preferred example, the preparation method includes the steps:

[0036] 5) Suspend the compound of Formula 1 in a solvent, crystallize, and filter to obtain the target crystal form C; preferably, in Step 5), the solvent is selected from the group consisting of a mixed solvent of isopropanol and n - heptane, a mixed solvent of 4 - methyl - 2 - pentanone and n - heptane, a mixed solvent of isopropyl acetate and n - heptane, a mixed solvent of ethyl formate and n - heptane, a mixed solvent of chloroform and n - heptane, a mixed solvent of ethyl acetate and cyclohexane, a mixed solvent of acetone and cyclohexane, a mixed solvent of acetone and water, a mixed solvent of acetonitrile and water, a mixed solvent of methanol and water, a mixed solvent of ethylene glycol dimethyl ether and water, a mixed solvent of tetrahydrofuran and water, isopropyl ether, chloroform, n - heptane, cyclohexane, water, toluene, dichloromethane, or a combination thereof.

[0037] In another preferred example, the molar volume ratio of the compound of Formula 1 to the solvent is 1:10 - 20 mol / mL.

[0038] In another preferred example, the reaction temperature of Step 5 is 20 - 30 °C.

[0039] In another preferred example, the preparation method includes the steps:

[0040] 6) Dissolve the compound of formula (1) in a good solvent, place it in an atmosphere of a poor solvent at room temperature, crystallize, filter, and dry to obtain the target crystal form C.

[0041] In another preferred embodiment, the molar volume ratio of the compound of formula (1) to the good solvent is 1:2 - 4 mol / mL.

[0042] In another preferred embodiment, the reaction temperature in step 6 is 20 - 30 °C.

[0043] In the second aspect of the present invention, there is provided a pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises: (i) the crystal as described in claim 1, and (b) a pharmaceutically acceptable carrier.

[0044] In another aspect of the present invention, there is provided a use of the crystal as described in claim 1, which is characterized in that it is used for preparing a drug or a pharmaceutical composition for thyroid hormone resistance syndrome or thalassemia.

[0045] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 It is the XRPD pattern of teracozole crystal form C;

[0047] Figure 2 It is the DSC and TGA patterns of teracozole crystal form C;

[0048] Figure 3 It is the NMR pattern of teracozole crystal form C;

[0049] Figure 4a It is the DVS curve of teracozole crystal form C, Figure 4b It is the XRPD patterns of teracozole crystal form C before and after DVS test;

[0050] Figure 5 It is the PLM image of teracozole crystal form C;

[0051] Figure 6 It is the XRPD pattern for the stability study of teracozole crystal form C;

[0052] Figure 7 It is the XRPD comparison pattern of the remaining solid after teracozole crystal form C oscillates in the medium for 24 h. DETAILED DESCRIPTION OF THE INVENTION

[0053] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0054] General method

[0055] The present invention provides a method for preparing telaprevir polymorph C, which is characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapor sorption analysis (DVS), and polarized light microscopy analysis (PLM) according to the attached drawings.

[0056] X-ray powder diffraction (XRPD)

[0057] The solid sample obtained from the experiment was analyzed using an X-ray powder diffractometer Panalytical EMPYREAN (PANalytical, UK). The 2θ scanning angle ranged from 3° to 45°, the scanning step was 0.013°, and the total test time was 5 minutes and 8 seconds. The test method was Cu target Kα1 radiation, the voltage was 45 kV, the current was 40 mA, and the sample disk was a zero-background sample disk.

[0058] In-situ variable temperature XRPD testing was carried out using an X-ray powder diffractometer Malvern PANalytical Aeris (MalvernPanalytical, UK). The 2θ scanning angle ranged from 3° to 40°, the scanning step was 0.02°, and the test time was 13 min. When testing the sample, the tube voltage and current were 40 kV and 7.5 mA respectively, and the sample disk was a zero-background sample disk. The sample was placed on a BTS500 hot stage (Anton Paar, AT), and XRPD testing was carried out at room temperature. Subsequently, it was heated to the selected temperature at a rate of 10 °C / min, isothermally maintained for 10 min, and then XRPD testing was carried out at this temperature. Subsequently, it was cooled to room temperature and then XRPD testing was carried out again.

[0059] Thermogravimetric analysis (TGA)

[0060] The model of the thermogravimetric analyzer was TA Discovery 55 (TA, US). 2 - 5 mg of the sample was placed in an open aluminum sample pan that had been balanced and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C / min, the nitrogen purge rate at the sample was 60 mL / min, and the nitrogen purge rate at the balance was 40 mL / min.

[0061] Differential scanning calorimetry (DSC)

[0062] The differential scanning calorimeter model is TA Discovery 2500 (TA, US). After accurately weighing 1 - 2 mg of the sample, it was placed in a punctured DSC Tzero sample pan. After equilibration for 1 min, it was heated to the final temperature at a rate of 10 °C / min, and the nitrogen purge rate in the furnace was 50 mL / min.

[0063] Dynamic vapor sorption (DVS)

[0064] Dynamic vapor sorption analysis was performed using DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes of 0% - 95% - 0%. In the range of 0% to 90%, the humidity change for each gradient was 10%. The gradient endpoint was judged by the dm / dt method, with dm / dt less than 0.002% and maintained for 10 minutes as the gradient endpoint, or each gradient was maintained for a maximum of 180 minutes. After the test, XRPD analysis was performed on the sample to confirm whether the solid form had changed.

[0065] Polarizing light microscopy (PLM)

[0066] The polarizing light microscope model is Nikon Ci-POL (Nikon, JP). A small amount of the sample was placed on a glass slide, and an appropriate lens was selected to observe the sample morphology.

[0067] Example 1: Preparation of telacortide polymorph C (Method 1)

[0068] Weigh 1.0 g of telacortide raw material and dissolve it in 5.0 mL of ethyl acetate. Filter it through a 0.22 μm organic filter membrane. Drop the solution into 50 mL of n-heptane. After stirring for 40 min, filter the suspension by suction. Dry the solid in vacuo at 40 °C overnight to obtain 650 mg of a white powder, which is defined as polymorph C.

[0069] Perform basic characterizations such as XRPD, DSC, TGA, NMR, DVS, and PLM on the product. The characterization results are as Figures 1 to 5 shown. The following table shows the characteristic peaks of telacortide polymorph C. The XRPD results show that polymorph C is a solid with general crystallinity. The TGA results show that polymorph C has no weight loss during heating to 160 °C and may decompose above 230 °C. The DSC results show that polymorph C has an endothermic melting peak at about 178 °C. The NMR results show that the peak positions and integral results of each peak of the sample are the same as those of the reference spectrum Figure 1To, solvent signal peaks of ethyl acetate can be seen at 4.02 ppm, 1.99 ppm and 1.17 ppm, suggesting that there is a small amount of residual ethyl acetate solvent in the sample. The DVS results show that for polymorph C, the weight gain due to adsorption is 0.26% at 95% RH, 0.12% at 80% RH, and the weight loss due to desorption is 0.06% at 0% RH, indicating that polymorph C has almost no hygroscopicity. The XRPD results show that the polymorph of the sample after DVS testing has not changed. The PLM image shows that polymorph C is needle-like particles with a length generally less than 25 μm. Based on the above information, polymorph C is a general crystalline anhydrate with almost no hygroscopicity.

[0070] Characteristic peaks of telacortide polymorph C

[0071]

[0072]

[0073] Example 2: Stability study

[0074] The stability study of polymorph C was carried out under the conditions of high temperature (60 °C), high humidity (25 °C / 92.5% RH), light (25 °C / 4500 Lux), and accelerated (40 °C / 75% RH). Samples were taken at 7 days and 15 days respectively for XRPD characterization and HPLC testing. The results are shown in the following table. The XRPD results are as Figure 6 shown. Polymorph C is stable for 15 days under the conditions of high temperature, high humidity, light, and accelerated conditions, and no polymorphic transformation occurs. Among them, the sample was observed to turn yellow after 15 days under light conditions. The HPLC results show that the chemical purity of polymorph C has no significant change after being placed for 15 days under the above conditions.

[0075] Results of stability study

[0076]

[0077] Example 3: Bio-media and water solubility testing

[0078] The preparation process of the bio-media is shown in the following table. The sample was added to the bio-media and water and shaken at a constant temperature of 37 °C for 24 h. Samples were taken at 0.5 h, 2 h and 24 h respectively. The sampled solutions were filtered through a 0.22 μm aqueous filter membrane. For some samples with higher concentrations, appropriate dilution was carried out with a diluent. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, the pH value of the 24 h supernatant was measured, and the remaining solid was tested by XRPD.

[0079] Preparation process of bio-media

[0080]

[0081] The dynamic solubility of crystalline form C was determined in three biological media (FaSSIF, FeSSIF, and FaSSGF) and water. The corresponding results are shown in the following table and Figure 7 .

[0082] The results showed that the 24-hour solubility of crystalline form C in biological media and water decreased in the order of FeSSIF > FaSSIF >> water > FaSSGF, and the remaining solids in the three biological media and water were all crystalline form C.

[0083] Dynamic solubility test in biological media

[0084]

[0085] *: The lower limit of the standard curve is 0.05 mg / mL.

[0086] Development of the preparation process of crystalline form C

[0087] Example 4: Preparation of telacortide crystalline form C (Method 1)

[0088] Telacortide (2.05 g, 3.29 mmol) was added to 10 mL of ethanol and stirred until dissolved. The solution was evaporated to dryness in an open container, and the solid was collected and dried under vacuum to obtain the title product (2.05 g, yield 100%). It was detected by X-ray powder diffraction, and the product was crystalline form C.

[0089] Example 5: Preparation of telacortide crystalline form C (Method 2)

[0090] Telacortide (2.02 g, 3.24 mmol) was added to 10 mL of acetone and stirred until dissolved. The resulting solution was added dropwise to 100 mL of n-heptane, and crystallization was carried out with stirring for 24 h. Then, the mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.45 g, yield 75%). It was detected by X-ray powder diffraction, and the product was crystalline form C.

[0091] Example 6: Preparation of telacortide crystalline form C (Method 3)

[0092] Telacortide (2.07 g, 3.32 mmol) was added to 10 mL of ethanol and stirred until dissolved. 20 mL of water was added dropwise until solid precipitation occurred, and crystallization was carried out with stirring for 24 h. Then, the mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.41 g, yield 68%). It was detected by X-ray powder diffraction, and the product was crystalline form C.

[0093] Example 7: Preparation of telacortide crystalline form C (Method 4)

[0094] Tiracol (2.05 g, 3.29 mmol) was added to 100 mL of water, heated to 50 °C, and 60 mL of preheated isopropanol was slowly added dropwise until the solution became clear. After naturally cooling to room temperature and crystallizing for 24 h, filtration was carried out, the filter cake was collected, and vacuum drying was performed to obtain the title product (0.99 g, yield 48%). By X-ray powder diffraction detection, this product was polymorph C.

[0095] Example 8: Preparation of Tiracol Polymorph C (Method 5)

[0096] Tiracol (2.00 g, 3.21 mmol) was added to a mixed solvent of 50 mL of isopropyl acetate and n-heptane (v / v, 1:4), and the mixture was suspended at room temperature for 7 days. Filtration was carried out, the filter cake was collected, and vacuum drying was performed to obtain the title product (1.02 g, yield 51%). By X-ray powder diffraction detection, this product was polymorph C.

[0097] Example 9: Preparation of Tiracol Polymorph C (Method 6)

[0098] Tiracol (0.197 g, 0.316 mmol) was added to 1 mL of 4-methyl-2-pentanone, and the resulting solution was placed in an atmosphere of 100 mL of n-heptane. It was allowed to stand at room temperature until a solid formed. Filtration was carried out, the filter cake was collected, and vacuum drying was performed to obtain the title product (0.065 g, yield 33%). By X-ray powder diffraction detection, this product was polymorph C.

[0099] Conclusion

[0100] In the present invention, various crystallization methods were used to obtain tiracol polymorph C. In the systematic evaluation of polymorph C, in addition to basic characterization of the samples, hygroscopicity, solid-state stability, and solubility were also investigated. The evaluation results showed that:

[0101] 1) Polymorph C had almost no hygroscopicity, and no polymorph change occurred after DVS testing.

[0102] 2) In terms of solid-state stability, polymorph C did not undergo polymorphic transformation within 15 days under high temperature, high humidity, light, and accelerated conditions, and the purity did not decrease significantly. Among them, the sample was observed to turn yellow under light conditions for 15 days.

[0103] 3) The 24-hour solubility in biological media and water from high to low was: FeSSIF > FaSSIF >> water > FaSSGF, and the remaining solids in the 3 biological media and water were all polymorph C.

[0104] In summary, the tiracol polymorph obtained in the present invention has unique advantages in terms of physicochemical properties, formulation processing performance, and bioavailability, etc. It has good stability, high bioavailability, and no hygroscopicity, which can provide a better choice for the drug development of tiracol.

[0105] Preparation of Other Tiratricol Polymorphs

[0106] Example 10:

[0107] Preparation of Tiratricol Polymorph A:

[0108] Dissolve tiratricol (1.98 g, 3.18 mmol) in 10 mL of ethyl acetate. At room temperature, add 50 mL of cyclohexane dropwise. After stirring for crystallization for 24 h, filter, collect the filter cake, and dry it under vacuum to obtain the title product (1.28 g, yield 65%). Detected by X-ray powder diffraction, the characteristic peaks are shown in the following table. This product is defined as polymorph A.

[0109] Characteristic Peaks of Tiratricol Polymorph A

[0110]

[0111]

[0112] Example 12: Preparation of Tiratricol Polymorph A

[0113] Add tiratricol (0.196 g, 0.315 mmol) to 10 mL of cyclohexane and heat to 50 °C. Add 1 mL of ethanol dropwise until the solution becomes clear. After naturally cooling to room temperature, evaporate the solvent until it is gone with the container open. Collect the solid and dry it under vacuum to obtain the title product (0.196 g, yield 100%). Detected by X-ray powder diffraction, this product is polymorph A.

[0114] Example 13: Preparation of Tiratricol Polymorph B

[0115] Dissolve tiratricol (2.02 g, 3.24 mmol) in 10 mL of 4-methyl-2-pentanone. At room temperature, add 30 mL of n-heptane dropwise. After stirring for crystallization for 24 h, filter, collect the filter cake, and dry it under vacuum to obtain the title product (1.45 g, yield 72%). Detected by X-ray powder diffraction, this product is defined as polymorph B, and the characteristic peaks are shown in the following table.

[0116] Characteristic Peaks of Tiratricol Polymorph B

[0117]

[0118] Example 14: Preparation of Tiratricol Polymorph D

[0119] Add tiratricol (2.07 g, 3.28 mmol) to 10 mL of dioxane and stir until dissolved. Evaporate the solvent until it is gone with the container open. Collect the solid and dry it under vacuum to obtain the title product (2.07 g, yield 100%). This product is defined as polymorph D, and the characteristic peaks are shown in the following table.

[0120] Characteristic peaks of telithromycin polymorph D

[0121]

[0122]

[0123] Example 15: Preparation of telithromycin polymorph D

[0124] Telithromycin (1.96 g, 3.15 mmol) was added to 5 mL of dioxane, and the mixture was heated to 50 °C. Preheated 100 mL of toluene was slowly added dropwise until the solution became clear. After natural cooling to room temperature and crystallization for 24 h, the mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.02 g, yield 52%). Detection by X-ray powder diffraction showed that the product was polymorph D.

[0125] Example 16: Preparation of telithromycin polymorph D

[0126] Telithromycin (2.01 g, 3.23 mmol) was added to 10 mL of dioxane, and the resulting solution was placed in an atmosphere of 100 mL of cyclohexane. The mixture was allowed to stand at room temperature until a solid formed, then filtered, and the filter cake was collected and dried under vacuum to obtain the title product (0.603 g, yield 30%). Detection by X-ray powder diffraction showed that the product was polymorph D.

[0127] Example 17: Preparation of telithromycin polymorph E

[0128] Telithromycin (2.03 g, 3.26 mmol) was added to 10 mL of tetrahydrofuran and stirred until dissolved. The solution was evaporated to dryness with the mouth open until no solvent remained, and the solid was collected and dried under vacuum to obtain the title product (2.03 g, yield 100%). This product was defined as polymorph E, and its characteristic peaks are shown in the following table.

[0129] Characteristic peaks of telithromycin polymorph E

[0130]

[0131]

[0132] Example 18: Preparation of telithromycin polymorph E

[0133] Telithromycin (2.08 g, 3.34 mmol) was added to 10 mL of tetrahydrofuran and stirred until dissolved. 100 mL of cyclohexane was added dropwise until a solid precipitated, and the mixture was stirred and crystallized for 24 h. Then, it was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.35 g, yield 65%). Detection by X-ray powder diffraction showed that the product was polymorph E.

[0134] Example 19: Preparation of telithromycin polymorph F

[0135] Tiracol (2.07 g, 3.32 mmol) was added to 10 mL of dimethylformamide and stirred until dissolved completely. It was left open to volatilize until the solvent was gone, and the solid was collected and dried under vacuum to obtain the title product (2.07 g, yield 100%). This product was defined as crystal form F, and the characteristic peaks are shown in the following table.

[0136] Characteristic Peaks of Tiracol Crystal Form F

[0137]

[0138] Example 20: Preparation of Tiracol Crystal Form F

[0139] Tiracol (2.02 g, 3.24 mmol) was added to 10 mL of dimethylformamide and stirred until dissolved completely. The resulting solution was added dropwise to 100 mL of water until a solid precipitated. After stirring for crystallization for 24 h, it was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.09 g, yield 54%). By X-ray powder diffraction detection, this product was crystal form F.

[0140] Example 21: Preparation of Tiracol Crystal Form G

[0141] Tiracol (2.07 g, 3.32 mmol) was added to 130 mL of methyl tert-butyl ether and stirred until dissolved completely. It was left open to volatilize until the solvent was gone, and the solid was collected and dried under vacuum to obtain the title product (2.07 g, yield 100%). This product was defined as crystal form G, and the characteristic peaks are shown in the following table.

[0142] Characteristic Peaks of Tiracol Crystal Form G

[0143]

[0144] Example 22: Preparation of Tiracol Crystal Form G

[0145] Tiracol (2.01 g, 3.23 mmol) was added to 130 mL of methyl tert-butyl ether and stirred until dissolved completely. The resulting solution was added dropwise to 650 mL of n-heptane until a solid precipitated. After stirring for crystallization for 24 h, it was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.16 g, yield 58%). By X-ray powder diffraction detection, this product was crystal form G.

[0146] Example 23: Preparation of Tiracol Crystal Form H

[0147] Tiracol (2.05 g, 3.29 mmol) was added to a mixed solvent of 100 mL of methyl tert-butyl ether and n-heptane (v / v, 1:1), and it was suspended at 10 °C for 7 days. Then it was filtered, and the filter cake was collected and dried under vacuum to obtain the title product (1.53 g, yield 75%). This product was defined as crystal form H, and the characteristic peaks are shown in the following table.

[0148] Characteristic peaks of telithromycin polymorph H

[0149]

[0150] Example 24: Preparation of telithromycin polymorph H

[0151] Telithromycin (2.02 g, 3.24 mmol) was added to 130 mL of methyl tert-butyl ether and stirred until dissolved. The resulting solution was added dropwise to 650 mL of n-heptane until a solid precipitated. After stirring for crystallization for 48 h, the mixture was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (1.05 g, yield 52%). Detection by X-ray powder diffraction showed that the product was polymorph H.

[0152] Example 25: Preparation of telithromycin polymorph I

[0153] Telithromycin (2.01 g, 3.23 mmol) was added to a mixed solvent of 100 mL of dimethyl sulfoxide and water (v / v, 1:4), and the mixture was suspended at room temperature for 7 days. The mixture was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (1.36 g, yield 75%). This product was defined as polymorph I, and the characteristic peaks are shown in the following table.

[0154] Characteristic peaks of telithromycin polymorph H

[0155]

[0156] Example 26: Preparation of telithromycin polymorph I

[0157] Telithromycin (2.03 g, 3.26 mmol) was added to 10 mL of dimethyl sulfoxide and stirred until dissolved. The resulting solution was added dropwise to 100 mL of water until a solid precipitated. After stirring for crystallization for 48 h, the mixture was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (1.13 g, yield 56%). Detection by X-ray powder diffraction showed that the product was polymorph I.

[0158] Example 27: Preparation of telithromycin polymorph J

[0159] Telithromycin (1.99 g, 3.19 mmol) was added to a mixed solvent of 100 mL of dioxane and cyclohexane (v / v, 1:9), and the mixture was suspended at room temperature for 7 days. The mixture was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (1.36 g, yield 75%). This product was defined as polymorph J, and the characteristic peaks are shown in the following table.

[0160] Characteristic peaks of telithromycin polymorph J

[0161]

[0162]

[0163]

[0164] Example 28: Preparation of Tirzepatide Polymorph J

[0165] Tirzepatide (2.03 g, 3.26 mmol) was added to 10 mL of dioxane and stirred until clear. The resulting solution was added dropwise to 100 mL of toluene until a solid precipitated. After stirring for crystallization for 48 h, filtration was carried out, the filter cake was collected, and dried under vacuum to obtain the title product (1.05 g, yield 52%). Detection by X-ray powder diffraction showed that this product was polymorph J.

[0166] Example 29: Preparation of Tirzepatide Polymorph J

[0167] Tirzepatide (2.05 g, 3.29 mmol) was added to 10 mL of dioxane and stirred until clear. It was added dropwise to 100 mL of dichloromethane until a solid precipitated. After stirring for crystallization for 48 h, filtration was carried out, the filter cake was collected, and dried under vacuum to obtain the title product (1.18 g, yield 58%). Detection by X-ray powder diffraction showed that this product was polymorph J.

[0168] Example 30: Preparation of Tirzepatide Polymorph K

[0169] Tirzepatide (2.06 g, 3.31 mmol) was added to a mixed solvent of 100 mL of tetrahydrofuran and cyclohexane (v / v, 1:9), and suspended at room temperature for 7 days. Filtration was carried out, the filter cake was collected, and dried under vacuum to obtain the title product (1.33 g, yield 65%). This product was defined as polymorph K, and the characteristic peaks are shown in the following table.

[0170] Characteristic Peaks of Tirzepatide Polymorph K

[0171]

[0172]

[0173] Example 31: Preparation of Tirzepatide Polymorph N

[0174] Tirzepatide (1.96 g, 3.15 mmol) was added to a mixed solvent of 100 mL of ethylene glycol dimethyl ether and n-heptane (v / v, 1:9), and suspended at room temperature for 7 days. Filtration was carried out, the filter cake was collected, and dried under vacuum to obtain the title product (1.25 g, yield 64%). This product was defined as polymorph N, and the characteristic peaks are shown in the following table.

[0175] Characteristic Peaks of Tirzepatide Polymorph N

[0176]

[0177]

[0178] Example 32: Preparation of the O crystal form of telcagepant

[0179] Telcagepant (1.98 g, 3.18 mmol) was added to a mixed solvent of 100 mL of isopropanol and n - heptane (v / v, 1:9), suspended at room temperature for 7 days, filtered, the filter cake was collected and dried in vacuo to obtain the title product (1.30 g, yield 66%). This product was defined as crystal form O, and the characteristic peaks are shown in the following table.

[0180] Characteristic peaks of the O crystal form of telcagepant

[0181]

[0182]

[0183] Summary of crystal forms and crystal form transformation relationships

[0184] A total of 17 new crystal forms were obtained in the crystal form screening, including 3 anhydrous crystal forms (Type A, Form C, Form K) and 13 solvates. The solvation information of Type P was not determined because it is a metastable crystal form. The characterization results of the 17 crystal forms are summarized in the following table.

[0185] Summary of characterization results of different crystal forms

[0186]

[0187]

[0188] Based on the comprehensive experimental results, Form B, Form E, and Form F can be transformed into Type A and Form C by thermal transformation; Form D can be transformed into Form J by thermal transformation; Form D and Form J can be transformed into Form C by thermal transformation; Form C can be transformed into Form I, Form J, Form K, Form O, and Type P by suspension at room temperature in different solvent systems; and Type P can be transformed into Form K by thermal transformation.

[0189] All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. 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 appended claims of this application.

Claims

1. A crystalline form of a compound of formula 1, It is characterized in that The crystal form is crystal form C, which has the following X-ray powder diffraction characteristic peaks: 7.52°±0.2°, 9.33°±0.2°, 15.17°±0.2°, 21.32°±0.2°, 21.96°±0.2°, 22.87°±0.2°, and 24.01°±0.2°.

2. The crystal form C according to claim 1, characterized in that The crystal form has the following X-ray powder diffraction characteristic peaks: 7.52°±0.2°, 9.33°±0.2°, 15.17°±0.2°, 21.32°±0.2°, 21.67°±0.2°, 21.96°±0.2°, 22.87°±0.2°, 24.01°±0.2°, 25.65°±0.2°, 27.05°±0.2°, 29.38°±0.2°, 30.35°±0.2°, and 33.59°±0.2°.

3. The crystal form C according to claim 1, characterized in that The crystal form has the following X-ray powder diffraction characteristic peaks: 7.52°±0.2°, 9.33°±0.2°, 15.17°±0.2°, 15.83°±0.2°, 18.82°±0.2°, 19.19°±0.2°, 21.32°±0.2°, 21.67°±0.2°, 21.96°±0.2°, 22.24°±0.2°, 22.87°±0.2°, 23.37°±0.2° .2°, 24.01°±0.2°, 25.65°±0.2°, 27.05°±0.2°, 27.58°±0.2°, 27.96°±0.2°, 28.43°±0.2°, 28.81°±0.2°, 29.38°±0.2°, 30.35°±0.2°, 30.70°±0.2°, 33.59°±0.2°, 36.29°±0.2°, 36.86°±0.2°.

4. The crystal form C according to claim 1, characterized in that The DSC spectrum of the crystal form has an endothermic peak at 170°C to 180°C.

5. The crystal form C according to claim 1, characterized in that The TG spectrum of the crystal form has no weight loss at 0-160°C.

6. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 1) dissolving the compound of formula 1 in a solvent, and allowing the solution to stand at room temperature for evaporation until the solvent evaporates completely to obtain the target crystalline form C; preferably, in the step 1, the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, ethyl formate, butyl formate, ethylene glycol dimethyl ether, acetonitrile, chloroform, or a combination thereof.

7. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 2) adding a solution of the compound of formula 1 in a good solvent to a poor solvent, and crystallizing to obtain the target crystalline form C; preferably, in the step 2, the good solvent is selected from the group consisting of acetone, ethyl acetate, butyl formate, ethylene glycol dimethyl ether, ethyl formate, methanol, n-propanol, acetone, acetonitrile, isopropanol, 4-methyl-2-pentanone, isopropyl acetate, ethyl formate, or a combination thereof, and the poor solvent is selected from n-heptane, cyclohexane, water, toluene, or a combination thereof.

8. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 3) adding a poor solvent to a solution of the compound of formula 1 in a good solvent until solids are precipitated, and filtering to obtain the target crystalline form C; preferably, in method 3, the good solvent is selected from the group consisting of n-propanol, ethyl formate, acetone, butyl formate, ethanol, isopropanol, ethyl acetate; the poor solvent is selected from n-heptane, cyclohexane, water, dichloromethane, or a combination thereof.

9. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 4) adding the compound of formula 1 to a poor solvent, heating to 45-55° C., then adding a preheated good solvent dropwise until the solution becomes clear, cooling to room temperature naturally, and filtering to obtain the target crystalline form C; preferably, in method 4, the good solvent is selected from the group consisting of ethanol, isopropanol, or a combination thereof, and the poor solvent is water.

10. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 5) suspending the compound of formula 1 in a solvent, crystallizing, and filtering to obtain the target crystalline form C; preferably, in the step 5), the solvent is selected from the following group: a mixed solvent of isopropanol and n-heptane, a mixed solvent of 4-methyl-2-pentanone and n-heptane, a mixed solvent of isopropyl acetate and n-heptane, a mixed solvent of ethyl formate and n-heptane, a mixed solvent of chloroform and n-heptane, a mixed solvent of ethyl acetate and cyclohexane, a mixed solvent of acetone and cyclohexane, a mixed solvent of acetone and water, a mixed solvent of acetonitrile and water, a mixed solvent of methanol and water, a mixed solvent of ethylene glycol dimethyl ether and water, a mixed solvent of tetrahydrofuran and water, isopropyl ether, chloroform, n-heptane, cyclohexane, water, toluene, dichloromethane, or a combination thereof.

11. A method for preparing the crystal form according to claim 1, characterized in that: The preparation method comprises the steps of: 6) The compound of formula 1 is dissolved in a good solvent, placed in a poor solvent atmosphere at room temperature, crystallized, filtered, and dried to obtain the target crystal form C.

12. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) the crystal according to claim 1, and (b) a pharmaceutically acceptable carrier; Preferably, the pharmaceutical composition is used to treat or prevent thyroid hormone resistance syndrome or thalassemia.

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