Crystal forms of ostarol and methods of making the same

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to the crystal forms of omaglineline and their preparation methods. This invention provides crystal forms A and C of the hemicalcium hydrate of omaglineline (compound of formula I), and crystal form A of the anhydrous omaglineline (compound of formula II). Compared with the amorphous form, the omaglineline crystal forms of this invention possess superior stability, solubility, hygroscopicity, powder properties, and mechanical properties, and have potential value for industrial pharmaceutical applications. Furthermore, the purification steps in the crystal form preparation method of this invention are simple, adaptable to commercial production routes, and practical.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the crystal form of oxaliplatin and its preparation method. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin consisting of 30 or 31 amino acids, secreted by L cells in the small intestine. GLP-1 exerts a wide range of effects through its receptor, including promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing appetite. Therefore, GLP-1 analogs have shown efficacy in reducing glycated hemoglobin (HbA1c) and promoting weight loss, and have been developed as effective therapeutic agents for the treatment of diabetes and obesity. GLP-1 analogs have also demonstrated efficacy in improving cardiovascular outcomes and preserving renal function in patients with diabetes, thus providing therapeutic opportunities for a variety of metabolic disorders and related comorbidities. Orforglipron (3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazole-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one) hemicalcium hydrate is a glucagon-like peptide-1 receptor agonist (GLP-1RA) indicated for adult obesity and type 2 diabetes (T2D).

[0003] The calcium salt structure of oxaliplatin (compound I) is as follows:

[0004]

[0005] The structural formula of the free form of oxalidomide (compound II) is as follows:

[0006]

[0007] Currently, the oligoferone used in the market is in an amorphous form, which has drawbacks such as poor physical stability, high solubility and dissolution rate, and relatively high hygroscopicity. Therefore, it is necessary to develop other crystalline forms of oligoferone. The original manufacturer of oligoferone is Chugai Pharmaceutical Co., Ltd. of Japan, and its compound patent (CN109790161B) describes a method for preparing oligoferone. This patent mentions the crystalline form of oligoferone compound I, but it does not specify the diffraction angle, perform quantitative characterization, or examine its scalability, stability, and other properties. Repeating experiments according to this method fails to obtain the crystalline form of compound I, yielding only an amorphous solid.

[0008] Different crystal forms of the same drug can result in variations in bioavailability, stability, solubility, hygroscopicity, powder properties, and mechanical properties. These physicochemical properties can also influence the application of the drug. Therefore, providing oligomeryne crystal forms with good crystal stability, low hygroscopicity, high solubility, good mechanical stability, and good flowability has significant practical application value. Summary of the Invention

[0009] Technical issues

[0010] The present invention aims to provide an Olegron crystal form with good crystal form stability, low hygroscopicity, high solubility, good mechanical stability and flowability.

[0011] Technical solution

[0012] The first aspect of this application provides a crystal form A of oxaliplatin hemicalcium hydrate, having the structure shown in Formula I.

[0013]

[0014] Wherein, n is selected from 0.25 to 3; and its X-ray powder diffraction (XRPD) pattern has diffraction peaks at 2θ of 3.4°, 6.8°, 10.3°, 10.9°, 12.0°, 13.6°, 15.0°, 17.8°, 19.3° and 20.6°, where the error range of 2θ value is ±0.2°.

[0015] In some embodiments, n = 1; using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form A of the auglelon hemicalcium hydrate is as follows: Figure 1 As shown.

[0016] In some embodiments, n = 1; the differential scanning calorimetry (DSC) curve of crystal form A of the octanelong hemicalcium hydrate is as follows: Figure 2 As shown.

[0017] In some embodiments, n = 1; the thermogravimetric analysis curve of crystal form A of the oxaliplatin hemicalcium hydrate is as follows: Figure 3 As shown.

[0018] In some embodiments, the thermogravimetric (TGA) analysis of crystal form A of the oxaliplatin hemicalcium hydrate shows a total weight loss of less than 2% during heating to 170±2℃.

[0019] A second aspect of the present invention provides a method for preparing crystal form A of the oxaliplatin hemicalcium hydrate according to any one of the above claims, comprising the following steps: (a) adding the amorphous solid of the compound of formula I to a mixed solvent of water and an organic solvent; (b) heating to 40-45°C and stirring, then cooling to 25-30°C and stirring to precipitate crystals; (c) post-treatment to obtain crystal form A of the compound of formula I; wherein the organic solvent is selected from one or more of anhydrous ethanol, acetonitrile or n-heptane; the mass ratio of water to organic solvent in step (a) is 1:4-100.

[0020] A third aspect of the present invention provides a method for preparing crystal form A of the oxaliplatin hemicalcium hydrate according to any one of the above claims, comprising the steps of: (a) adding the amorphous solid of the compound of formula II to an organic solvent,

[0021]

[0022] (a) Add calcium acetate; (b) Heat to 40-45°C to react and crystallize while stirring, then cool to 25-30°C and stir to precipitate crystals; (c) Post-treatment to obtain crystal form A of compound I; wherein the organic solvent is selected from one or more of methanol, anhydrous ethanol, acetonitrile or n-heptane.

[0023] In some embodiments, when the organic solvent is methanol, step (b) further includes the following step: seeding the crystal form A of compound I before cooling.

[0024] A fourth aspect of the present invention provides a crystal form B of oxaliplatin hemicalcium hydrate having the structure shown in Formula I.

[0025]

[0026] , where n is selected from 0.25 to 3; and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 6.0°, 6.9°, 8.3°, 9.0°, 11.7°, 12.3°, 13.6°, 17.6°, 20.3° and 20.9°, where the error range of 2θ value is ±0.2°.

[0027] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form B of the hemicalcium hydrate of compound I is as follows: Figure 4 As shown.

[0028] The fifth aspect of this invention provides a crystal form C of oxaliplatin hemicalcium hydrate, having the structure shown in Formula I.

[0029]

[0030] , where n is selected from 0.25 to 3, and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 4.0°, 5.9°, 6.4°, 7.0°, 8.0°, 9.3°, 10.1°, 10.4°, 10.8° and 11.8°, with the error range of 2θ value being ±0.2°.

[0031] In some embodiments, n = 1.5; using Cu-Kα radiation, the X-ray powder diffraction pattern of crystal form C of the auglelon hemicalcium hydrate is as follows: Figure 5 As shown.

[0032] The sixth aspect of the present invention provides a method for preparing crystal form C of the oxaliplatin hemicalcium hydrate, comprising the following steps: (a) adding the amorphous solid of the compound of formula I to a mixed solvent of water and an organic solvent; (b) stirring at room temperature, then cooling to 3-5°C, stirring to dissolve and crystallize; (c) post-treatment to obtain crystal form C of the compound I; wherein the organic solvent is selected from one or more of acetonitrile, acetone, methyl tert-butyl ether or n-heptane; the mass ratio of water to organic solvent in step (a) is 1:3-450.

[0033] The seventh aspect of the present invention provides an anhydrous crystal form A of oxaliplatin, having the structure shown in Formula II.

[0034]

[0035] The X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 7.1°, 10.4°, 13.4°, 14.2°, 14.5°, 17.3°, 17.7°, 20.3°, 20.8°, and 23.3°, with an error range of ±0.2° for the 2θ values.

[0036] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern of the anhydrous crystal form A of the oglelon is as follows: Figure 7 As shown.

[0037] In some embodiments, the differential scanning calorimetry (DSC) curve of the anhydrous form A of the oxaliplatin is as follows: Figure 8 As shown.

[0038] In some embodiments, the thermogravimetric analysis curve of the anhydrous crystal form A of the oxaliplatin is as follows: Figure 9 As shown.

[0039] The present invention provides a method for preparing an anhydrous crystal form A of the compound of formula II as described in any one of the above claims, comprising the following steps: (a) adding an amorphous solid of the compound of formula II to an organic solvent; (b) heating to 40-45°C and stirring, then cooling to 25-30°C and stirring to precipitate crystals; (c) post-treatment to obtain crystal form A of the compound of formula II; wherein the organic solvent is selected from anhydrous acetonitrile or acetonitrile alcohol.

[0040] Technical effect

[0041] This invention provides the crystal forms of oxaliplatin (compound of formula I) and their preparation methods. Studies have revealed that compound of formula I has multiple crystal forms, including but not limited to crystal form A, crystal form B, and crystal form C. Comparison of various indicators such as stability, solubility, hygroscopicity, powder properties, and mechanical properties shows that, compared to the amorphous form, crystal forms A and C exhibit better crystal stability, lower hygroscopicity, higher solubility, better mechanical stability, and better flowability. Crystal form B also demonstrates better physicochemical stability compared to the amorphous form. Therefore, crystal forms A, B, and C of compound of formula I have pharmaceutical industrial application value.

[0042] This invention provides the crystal form of oligolide in its free form (compound of formula II) and its preparation method. Research revealed that compound II has two crystal forms: crystal form A with high crystallinity and an amorphous form. The inventors unexpectedly discovered that preparing crude compound II of relatively low purity into crystal form A can increase the product purity to over 99.6%, thus solving the problem of difficult purification of crude oligolide and meeting the pharmaceutical purity (>99.5%) and impurity (known impurities <0.15%, unknown impurities <0.10%) requirements. Furthermore, crystal form A is anhydrous, possessing value for pharmaceutical industrial applications. Comparison of various indicators, including stability, hygroscopicity, purification characteristics, and powder properties, showed that compared to the amorphous form, crystal form A of compound II exhibits better stability, lower hygroscopicity, stronger purification characteristics, and better flowability. Attached Figure Description

[0043] Figure 1 XRPD spectrum of the amorphous compound of formula I;

[0044] Figure 2 XRPD spectra of the amorphous form of compound II;

[0045] Figure 3 XRPD spectrum of crystal form A of compound I;

[0046] Figure 4 DSC diagram of crystal form A of compound I;

[0047] Figure 5TGA image of crystal form A of compound I;

[0048] Figure 6 XRPD spectrum of compound B of formula I;

[0049] Figure 7 XRPD spectrum of crystal form C of compound I;

[0050] Figure 8 XRPD spectrum of crystal form A of compound II;

[0051] Figure 9 DSC diagram of crystal form A of compound II;

[0052] Figure 10 TGA diagram of crystal form A of compound II. Detailed Implementation

[0053] To facilitate the explanation of the technical solution of this application, the following is a general explanation and definition of the terms and expressions used in this application.

[0054] The terms “comprising,” “including,” or any other variations thereof are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase “comprising one…” does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0055] The term XRPD refers to X-ray powder diffraction. In this invention, the powder X-ray diffraction testing instrument involved is a Bruker D2 Phaser. 2nd Powder diffractometer; Test conditions: CuKα radiation, 30kV, 10mA, 3-40°.

[0056] The term DSC refers to Differential Scanning Calorimeter. In this invention, the differential scanning calorimeter involved is the American TADSC25; test conditions: 20-300℃, 10℃ / min; N2 (60mL / min).

[0057] The term TGA refers to thermogravimetric analyzer. In this invention, the thermogravimetric analyzer involved is the American TATGA55; the test conditions are: room temperature - 300℃, 10℃ / min; N2 (50mL / min).

[0058] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be ±0.2 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0059] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0060] The thermogravimetric analysis (TGA) curves of the crystals are subject to experimental error. The endothermic curves or weight loss rates may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 0.4%, 0.3%, 0.2%, or 0.1%. Therefore, the thermogravimetric analysis curves or their weight loss rates cannot be considered absolute.

[0061] In the comparative experiments provided in this application, unless otherwise specified, all experimental conditions and materials are kept consistent to ensure comparability.

[0062] Unless otherwise specified, all reagents and instruments used in the embodiments of this invention can be purchased from the market.

[0063] The following provides further details regarding the crystal form of oxaliron and its preparation method provided in this application.

[0064] Example 1: Preparation of the amorphous form of compound I

[0065] 20 g of the amorphous solid of compound II was added to a 250 mL double-glass jacketed reactor, followed by 100 mL of anhydrous ethanol and 17.9 g wt% 20% calcium acetate aqueous solution. The mixture was stirred at room temperature to induce crystallization. The crystals were filtered, and the wet product was dried under reduced pressure at 40±5 °C for 8 hours. 20.1 g of the product was collected and characterized by XRPD. Figure 1 The results indicate that the substance is an amorphous form of compound I, with a purity of 99.01%.

[0066] Example 2: Preparation of crystal seed A of compound I

[0067] Add 700 mg of the amorphous solid of compound II, 62 mg of sodium hydroxide and 14 mL of water to a 20 mL glass vial. Stir magnetically at 30 ± 5 °C until dissolved. Set aside for later use.

[0068] Add 2.5 mL of calcium chloride aqueous solution (10% wt) to the above vial, heat to 45 ± 5 °C and stir magnetically. Filter by suction and blow under nitrogen until nearly dry. Pulverize the wet filter cake with 5 mL of acetonitrile for 1 hour. Filter by suction and dry the filter cake under reduced pressure at 50 ± 5 °C for 12 hours. Collect the material and characterize it by XRPD to be the calcium salt crystal form A of formula I, which is used as the seed crystal of crystal form A.

[0069] Example 3: Preparation of amorphous hemicalcium salt hydrate of Formula II compound

[0070] The amorphous solid (1120 mg) of compound II was added to ethanol (5.60 mL) and 2 M sodium hydroxide aqueous solution (0.75 mL), and the compound was dissolved at room temperature. 1.26 M calcium acetate aqueous solution (0.68 mL) was added to the solution, and the mixture was stirred at room temperature for 3 hours. Then, water (1.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, water (2.3 mL) was added, and the mixture was stirred at room temperature for 1 hour to obtain 900 mg of powdered crystals, which were characterized by XRPD. Figure 2 The results indicate that the substance is an amorphous hemicalcium salt with a purity of 95.0%.

[0071] Example 4: Preparation of hemicalcium salt hydrate seed crystals of compound II

[0072] The amorphous solid of compound II (69.0 mg) was dissolved in DMSO (0.229 mL), and 1.06 M calcium methoxyethoxide (0.147 mL) was added. The solution (0.015 mL) was lyophilized at -20 °C for 2 days. A water-acetonitrile mixture (3:1, 0.015 mL) was added to obtain the lyophilized product, and the mixture was shaken and stirred at room temperature for 7 days to obtain a hemicalcium salt powder crystal. XRPD characterization showed that the substance was an amorphous hemicalcium salt with a purity of 95.1%.

[0073] Example 5: Preparation of Crystal Form A of Compound I

[0074] 10 g of the amorphous solid of compound I was added to a 250 mL double-glass jacketed reactor, along with 80 mL of anhydrous ethanol and 20 mL of water. The mixture was heated to 40 °C and stirred for 0.5 hours. The mixture was then cooled to room temperature (25–30 °C) and stirred for another 0.5 hours. The wet product was dried under reduced pressure at 40 ± 5 °C for 12 hours. 8.1 g of the product was collected and characterized by X-ray powder diffraction (XRPD). Figure 3The result shows that the substance is crystal form A of compound I, with a purity of 99.87%; the differential scanning calorimetry (DSC) chromatogram is shown below. Figure 4 Thermogravimetric analysis (TGA) chart is shown below. Figure 5 .

[0075] Table 1 below shows the characteristic XRPD diffraction peaks of isolated crystal form A of compound of formula I.

[0076] Table 1. XRPD parameters of crystal form A of compound I.

[0077]

[0078]

[0079] Example 6: Preparation of Crystal Form A of Compound I

[0080] 10 g of the amorphous solid of compound I was added to a 250 mL double-glass jacketed reactor, along with 80 mL of acetonitrile and 20 mL of water. The mixture was heated to 40 °C and stirred for 0.5 hours. The mixture was then cooled to room temperature (25–30 °C) and stirred for another 0.5 hours. The wet product was dried under reduced pressure at 40 ± 5 °C for 10 hours. 7.9 g of the product was collected. XRPD characterization showed that the substance was crystal form A of compound I, with a purity of 99.56%.

[0081] Example 7 Preparation of Crystal Form A of Compound I

[0082] Add 5g of the amorphous solid of compound I to a 100-mL double-glass jacketed reactor, along with 10mL of anhydrous ethanol, 0.5mL of water, and 40mL of n-heptane. Stir at 40°C for 2 hours, then cool to room temperature (25-30°C) and stir for 0.5 hours. Dry the wet product under reduced pressure at 40±5°C for 9 hours. Collect the product; XRPD characterization shows that the substance is crystal form A of compound I with a purity of 99.11%.

[0083] Example 8: Preparation of Crystal Form A of Compound I

[0084] 10 g of the amorphous solid of compound II was added to a 50 mL double-glass jacketed reactor, and suspended in 20 mL of methanol at 20 °C. 8.95 g of a 20% wt% calcium acetate aqueous solution was added, and the mixture was heated to 40 °C for crystallization. Crystallization seed A of compound I was then introduced, and the mixture was stirred for 2 hours. The mixture was cooled to room temperature (25–30 °C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40 ± 5 °C for 12 hours. 9.4 g of the product was collected, and XRPD characterization showed that the substance was crystallization A of compound I, with a purity of 99.90%.

[0085] Example 9: Preparation of Crystal Form A of Compound I

[0086] 10 g of the amorphous solid of compound II was added to a 50 mL double-glass jacketed reactor and suspended in 30 mL of anhydrous ethanol at 20 °C. 8.95 g of a 20% wt% aqueous solution of calcium acetate was added, and the mixture was heated to 45 °C and stirred for 2 hours to crystallize. The mixture was then cooled to room temperature (25–30 °C) and stirred for 0.5 hours. The wet product was dried under reduced pressure at 40 ± 5 °C for 8 hours. 9.8 g of the product was collected, and XRPD characterization showed that the substance was crystal form A of compound I, with a purity of 99.77%.

[0087] Example 10: Preparation of Crystal Form B of Compound I

[0088] Add 3g of the amorphous form of compound I to a 50-mL double-glass jacketed reactor, along with 8mL of acetonitrile and 4mL of water. Stir at 40°C for 0.5 hours, then cool to 4°C and stir for another 0.5 hours. Filter under nitrogen protection and dry. Collect 2.7g of the material, and characterize by XRPD. Figure 6 The results show that the substance is crystal form B of compound I, with a purity of 99.23%.

[0089] Table 2 below shows the characteristic XRPD diffraction peaks of isolated crystal form B of compound I.

[0090] Table 2 shows the XRPD parameters of crystal form B of compound I.

[0091]

[0092]

[0093] Example 11 Preparation of crystal form C of compound I

[0094] 9 g of the amorphous form of compound I was added to a 100-mL double-glass jacketed reactor, followed by 60 mL of acetonitrile and 20 mL of water. The mixture was stirred at room temperature until dissolved and crystallized. The mixture was then cooled to 4°C and stirred for 0.5 hours. The mixture was filtered under nitrogen protection and dried. 8.5 g of the material was collected and characterized by XRPD. Figure 7 The results show that the substance is crystal form C of compound I, with a purity of 99.24%.

[0095] Table 3 below shows the characteristic XRPD diffraction peaks of the isolated crystal form C of compound I.

[0096] Table 3 shows the XRPD parameters of crystal form C of compound I.

[0097]

[0098] Example 12 Preparation of crystal form C of compound I

[0099] 6 g of the amorphous form of compound I was added to a 100-mL double-glass jacketed reactor, followed by 60 mL of acetone and 0.2 mL of water. The mixture was stirred at room temperature until dissolved and crystallized. The temperature was then lowered to 4°C and stirred for 0.5 hours. The mixture was filtered under nitrogen protection and dried. 4.0 g of the sample was collected. XRPD characterization showed that the substance was crystal form C of compound I, with a purity of 99.17%.

[0100] Example 13 Preparation of crystal form C of compound I

[0101] 6 g of the amorphous form of compound I was added to a 100-mL double-glass jacketed reactor, along with 30 mL of acetone, 0.2 mL of water, and 60 mL of methyl tert-butyl ether. The mixture was stirred at room temperature until dissolved and crystallized. The temperature was then lowered to 4°C and stirred for 0.5 hours. The mixture was filtered under nitrogen protection and dried. 5.2 g of the sample was collected. XRPD characterization showed that the substance was crystalline form C of compound I, with a purity of 99.35%.

[0102] Example 14 Preparation of crystal form C of compound I

[0103] 10 g of the amorphous form of compound I was added to a 100-mL double-glass jacketed reactor, along with 30 mL of acetone, 0.2 mL of water, and 60 mL of n-heptane. The mixture was stirred at room temperature until dissolved and crystallized. The temperature was then lowered to 4°C and stirred for 0.5 hours. The mixture was filtered under nitrogen protection and dried. 8.7 g of the material was collected. XRPD characterization showed that the substance was crystal form C of compound I, with a purity of 99.27%.

[0104] Example 15 Preparation of Crystal Form A of Compound II

[0105] 10 g of the amorphous form of compound II was added to a 100-mL double-glass jacketed reactor, followed by 100 mL of anhydrous ethanol. The mixture was stirred at 40°C for 0.5 hours, then cooled to room temperature (25–30°C) and stirred for another 0.5 hours. The mixture was filtered, and the wet product was dried under reduced pressure at 40±5°C for 15 hours. 9.6 g of the product was collected and characterized by XRPD. Figure 8 The results show that the substance is crystal form A of compound II, with a purity of 99.89%; the differential scanning calorimetry (DSC) chromatogram is shown below. Figure 9 Thermogravimetric analysis (TGA) chart is shown below. Figure 10 .

[0106] Table 4 below shows the characteristic XRPD diffraction peaks of isolated crystal form A of compound II.

[0107] Table 4. XRPD parameters of crystal form A of compound II.

[0108]

[0109] Example 16 Preparation of Crystal Form A of Compound II

[0110] 8 g of the amorphous form of compound II was added to a 100-mL double-glass jacketed reactor, followed by 80 mL of acetonitrile. The mixture was stirred at 40°C for 0.5 hours, then cooled to room temperature (25–30°C) and stirred for another 0.5 hours. The mixture was filtered, and the wet product was dried under reduced pressure at 40±5°C for 15 hours. 9.1 g of the product was collected. XRPD characterization showed that the substance was crystal form A of compound II, with a purity of 99.51%. Example 1: Comparison of the physicochemical stability of crystal forms A, B, C, and amorphous forms of compound I, and the amorphous form of compound II.

[0111] Samples of compound I of the present invention in crystal form A, crystal form B, crystal form C, and amorphous form were placed at 60°C, 92.5% RH, under light, and at 45°C / 75% RH, respectively. Samples were taken before and after placement and XRPD was used to determine the composition of compound I. The results are shown in Table 5.

[0112] Table 5 shows the stability studies of crystal forms A, B, C, and amorphous forms of compound I, and the amorphous form of compound II.

[0113]

[0114]

[0115] The results showed that crystal form A and crystal form C had good physicochemical stability under light, 60℃, 92.5%RH and 45℃ / 75%RH conditions; the amorphous form showed a significant decrease in purity after 30 days under light, 60℃ and 45℃ / 75%RH conditions; the crystal form B showed a slight decrease in purity after 30 days under light, 60℃ and 45℃ / 75%RH conditions, and crystal form B would dehydrate and transform into crystal form C.

[0116] Experimental Example 2: Investigation of the dynamic solubility of compound I in crystal form A and crystal form B

[0117] Samples of crystal form A, crystal form C, and amorphous were prepared into suspensions in water and stirred at 37°C for 24 hours. The resulting saturated solutions were then filtered. Crystal form changes were monitored by X-ray powder diffraction. Additionally, the actual concentration of the sample in the saturated solution was determined by high-performance liquid chromatography (HPLC) (the filtrate was diluted as needed). The crystal forms of the solids before and after the experiment were characterized by XRPD to check for phase transitions. The experimental results are shown in Table 6.

[0118] Table 6 shows the solubility of compounds of formula I in crystal form A, crystal form C, and amorphous form.

[0119] Example Crystal form Solubility (mg / mL) Does the crystal form change? Example 1 amorphous 0.5 yes Example 5 Crystal form A 3.6 no Example 11 Crystal form C 0.6 no

[0120] The results showed that crystal form A was more soluble in water than crystal form C and amorphous form. The difference in solubility between crystal form C and amorphous form in water was small, but amorphous form had poor physical stability.

[0121] Experimental Example 3: Mechanical stability of crystal forms A and C of compound I

[0122] 100 mg of crystal form A and crystal form C of this invention were weighed and ground clockwise for 5 minutes using an agate mortar. XRPD tests were performed on the samples before and after grinding. The XRPD results showed that the crystal form of crystal form A remained unchanged after grinding, while crystal form C partially transformed into an amorphous state after grinding. The mechanical stability of crystal form A was better than that of crystal form C.

[0123] Experimental Example 4: Hygroscopicity of amorphous compounds A and C of Formula I

[0124] Dynamic moisture adsorption tests were conducted on crystal form A, crystal form C, and amorphous samples of the present invention. The results are shown in Table 7. The test results show that crystal form A has no or almost no hygroscopicity; crystal form C has slight hygroscopicity; and amorphous sample has hygroscopicity.

[0125] Table 7 Hygroscopicity of Formula I Compounds in Crystal Forms A, C, and Amorphous Forms

[0126] Example Crystal form Percentage of weight gain due to moisture absorption (%) Hygroscopicity assessment Example 1 amorphous 5.2 Hygroscopic Example 5 Crystal form A 0.02 None or almost none hygroscopic Example 11 Crystal form C 1.5 Slightly hygroscopic

[0127] Experimental Example 5: Flowability of Compound I in crystal form A, crystal form C, and amorphous form

[0128] The powder properties of the active pharmaceutical ingredient (API) affect its flowability. The angle of repose and Hauss-Nabi tests were performed on the crystal forms A, B, and amorphous forms of Formula I to compare their flowability. The flowability evaluation results are shown in Table 8. The adsorption rates of the three crystal forms differed significantly, with crystal form A exhibiting better flowability than crystal form C, and even better flowability than the amorphous form.

[0129] Methods for testing loose density and tapped density:

[0130] This experiment used a vibratory compactor and determined the density using the fixed volume method. The specific procedure was as follows: the weighed powder was placed into a 50-mL graduated cylinder, which was then fixed to a support. The cylinder was vibrated at 55±5 times per minute for 6-8 minutes. The volume change of the powder in the graduated cylinder was measured. The ratio of the powder mass to the volume of the material before compaction (50mL) is the loose density of the powder, and the ratio of the powder mass to the volume of the material after compaction is the tapped density of the powder.

[0131] Table 8 shows the flow parameters of crystal form A, crystal form C, and amorphous form of compound I.

[0132]

[0133] Note: Material Hausner ratio = tapped density / loose density; Material compressibility = (tapped density - loose density) / tapped density.

[0134] The descriptions of Hausnerby and liquidity are shown in Table 9:

[0135] Table 9. Relationship between Hausner Ratio and Liquidity

[0136] Hausner ratio Liquidity Description 1.00-1.11 The liquidity is very good. 1.12-1.18 Good liquidity 1.19-1.25 Good or moderate liquidity 1.26-1.34 Liquidity is acceptable 1.35-1.45 Poor liquidity 1.46-1.59 Very poor liquidity >1.60 Liquidity is extremely poor.

[0137] Purification of Compound II in Experimental Example 6

[0138] Conventional purification solvents were screened for the crude compound of Formula II (main compound purity 88.5%, maximum single impurity 5.8%), and the results are shown in Table 10. According to Table 10, anhydrous ethanol and acetonitrile showed excellent purification effects, achieving the required pharmaceutical purity (>99.5%) and impurity levels (known impurities <0.15%, unknown impurities <0.10%). Other solvent systems showed almost no purification effect on the crude compound of Formula II, and the differences between them were minimal (even in the presence of unknown crystal forms). Therefore, crystal form A exhibits high selectivity for the purification of Formula II compounds.

[0139] Table 10. Solvent Screening for Crude Purification of Compounds of Formula II (Table 10)

[0140]

[0141] Experimental Example 7: Hygroscopicity of Compound II (Crystal Form A and Amorphous Form)

[0142] Dynamic moisture adsorption tests were conducted on crystal form A and amorphous samples of the present invention. The results are shown in Table 11. The test results show that crystal form A has no or almost no hygroscopicity, while amorphous sample has hygroscopicity.

[0143] Table 11 Hygroscopicity of Compound II Crystal Form A and Amorphous Form

[0144] Crystal form Percentage of weight gain due to moisture absorption (%) Hygroscopicity assessment 1 Crystal form A 0.06 None or almost none hygroscopic 2 amorphous 4.3 Hygroscopic

[0145] The above specific embodiments further illustrate the purpose, technical solution and beneficial effects of this application. It should be understood that the above are only specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made on the basis of the technical solution of this application should be included within the scope of protection of this application.

Claims

1. A crystalline Form A of semicalcium hydrate of ostarolone characterized by It has the structure shown in Equation I. ， Wherein, n is selected from 0.25 to 3; and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 3.4°, 6.8°, 10.3°, 10.9°, 12.0°, 13.6°, 15.0°, 17.8°, 19.3° and 20.6°, where the error range of 2θ value is ±0.2°.

2. The crystalline Form A of augluron hemi-calcium hydrate according to claim 1, characterized in that, n=1; using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 1.

3. The crystalline Form A of augluron hemi-calcium hydrate according to claim 1, characterized in that, n=1; its differential scanning calorimetry curve is shown in Figure 2; its thermogravimetric analysis curve is shown in Figure 3.

4. A process for preparing crystalline Form A of the sem calcium hydrate of olgride according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: (a) adding the amorphous solid of the compound of formula I to a mixed solvent of water and an organic solvent; (b) heating to 40–45°C and stirring, then cooling to 25–30°C and stirring to induce crystallization; (c) post-treatment to obtain crystal form A of the compound of formula I; wherein the organic solvent is selected from one or more of anhydrous ethanol, acetonitrile or n-heptane; the mass ratio of water to organic solvent in step (a) is 1:4–100.

5. A process for preparing crystalline Form A of the sem calcium hydrate of olgride, according to any one of claims 1-3, characterized in that, The steps include: (a) adding the amorphous solid of the compound of formula II to an organic solvent, ， (a) Add calcium acetate; (b) Heat to 40-45°C to react and crystallize while stirring, then cool to 25-30°C and stir to precipitate crystals; (c) Post-treatment to obtain crystal form A of compound I; wherein the organic solvent is selected from one or more of methanol, anhydrous ethanol, acetonitrile or n-heptane.

6. A crystalline form C of semicalcium hydrate of ostarolone characterized by It has the structure shown in Equation I. ， Wherein, n is selected from 0.25 to 3; and its X-ray powder diffraction pattern has diffraction peaks at 2θ of 5.9°, 6.4°, 7.0°, 8.0°, 9.3°, 10.1°, 10.4°, 10.8° and 11.8°, where the error range of 2θ value is ±0.2°.

7. The crystalline Form C of augluron hemi-calcium hydrate according to claim 6, characterized in that, n = 1.5; using Cu-Kα radiation, its X-ray powder diffraction pattern is shown in Figure 5.

8. A method for preparing crystal form C of the oxaliplatin hemicalcium hydrate according to claim 6 or 7, characterized in that, The method comprises the following steps: (a) adding the amorphous solid of compound I to a mixed solvent of water and an organic solvent; (b) stirring at room temperature, then cooling to 3-5°C, stirring until dissolved and crystallized; (c) post-treatment to obtain crystal form C of compound I; wherein the organic solvent is selected from one or more of acetonitrile, acetone, methyl tert-butyl ether or n-heptane; the mass ratio of water to organic solvent in step (a) is 1:3-450.

9. Anhydrous crystal form A of Ogliotenone, characterized in that... It has the structure shown in Equation II. Its X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 7.1°, 10.4°, 13.4°, 14.5°, 17.3°, 17.7°, 20.3°, and 23.3°, with an error range of ±0.2° for the 2θ values.

10. The anhydrous crystal form A of oxaliplatin according to claim 9, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown in Figure 7.

11. The anhydrous crystal form A of oxaliplatin according to claim 9, characterized in that, Its differential scanning calorimetry curve is shown in Figure 8; its thermogravimetric analysis curve is shown in Figure 9.

12. A method for preparing anhydrous crystal form A of oxaliplatin according to any one of claims 9-11, characterized in that, The method comprises the following steps: (a) adding the amorphous solid of the compound of formula II to an organic solvent; (b) heating to 40–45°C and stirring, then cooling to 25–30°C and stirring to crystallize; (c) post-treatment to obtain crystal form A of the compound of formula II; wherein the organic solvent is selected from anhydrous acetonitrile or acetonitrile alcohol.

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