Novel avatrombopag maleate trihydrate and preparation method therefor

Abstract

The present disclosure relates to a compound of formula (I), i.e., an avatrombopag maleate trihydrate crystal (AVAT-3H), and a preparation method therefor. The compound crystal of formula (I) of the present invention has the characteristics of simple preparation, strong operability, stable properties, low electrostatic properties, low bulk density, high compressibility, excellent hygroscopicity and the like, and is more suitable for industrial production.

Description

A new avatrombopag maleate trihydrate and its preparation method Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry. Specifically, the present invention relates to avatrombopag maleate trihydrate crystals, a preparation method thereof, and use thereof in pharmaceutical compositions. Technical Background

[0002] Immune thrombocytopenia (ITP), also known as idiopathic thrombocytopenic purpura, is a rare acquired autoimmune disease characterized by a decrease in platelet count (<100×10^9 / L). This immune platelet destruction can increase the risk of bleeding in patients, leading to a variety of serious complications.

[0003] Thrombocytopenia is a common complication of chronic liver disease (CLD). Approximately 6% of patients with chronic hepatitis and 78% of patients with cirrhosis experience thrombocytopenia. It is a hallmark of advanced liver disease. There are currently no approved treatments for thrombocytopenia in patients with CLD who are undergoing elective diagnostic testing or surgery and are at risk of bleeding.

[0004] As the world's first thrombopoietin receptor agonist (TPO-RA) approved by the FDA and EMA with dual indications for CLD and ITP, avatrombopag maleate promotes platelet production by stimulating the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. It can quickly increase platelet counts in a short period of time (3-5 days after treatment) and is suitable for adult patients with chronic liver disease-related thrombocytopenia who are scheduled to undergo diagnostic procedures or surgery.

[0005] Patent WO2013018362 discloses three crystalline forms of avatrombopag maleate: Form A, Form B, and Form C, and their preparation methods. Form A contains some solvent in its molecular structure, such as half an ethanol molecule and half water. Form A is difficult to separate and easily converts during large-scale production, resulting in poor stability. Form B exhibits poor oral absorption compared to Forms A and C, and has low bioavailability. The preparation of Form C requires the use of large doses of solvents, such as dimethyl sulfoxide or diformimide, water, and acetone, which are dissolved at high temperature and then crystallized by cooling to obtain Form C.

[0006] Patent CN106749226A discloses a method for obtaining avatrombopag maleate Form C through recrystallization. This method uses avatrombopag maleate as the raw material, DMF as the good solvent, and one or more of ethanol, ethyl acetate, dichloromethane, and acetonitrile as the antisolvent, with stirring at approximately 40°C for crystallization. However, due to the poor solubility of avatrombopag maleate, a large amount of the good solvent DMF is required for dissolution, resulting in high production costs, low yield and production capacity, and is not conducive to commercial production.

[0007] Patent CN112409350A discloses a method for preparing avatrombopag maleate crystal form C, which uses crystal form D as a raw material and then obtains crystal form C after drying.

[0008] Patent WO2020044364A1 only discloses avatrombopag maleate crystalline form M1, crystalline form M2 and crystalline form M3, but does not explain its advantages compared with other crystalline forms and has no production value.

[0009] Avatrombopag maleate crystal form C was selected by the original research company as the marketed pharmaceutical crystal form due to its advantages in bioavailability and stability. However, the crystal structure of crystal form C shows that it belongs to the monoclinic system, P21 / n space group, and the crystallographic parameters are: β=99.408(7)°, Z=4,Molecular formula:C 29 H 35 Cl2N6O3S2·C4H3O4 has a long crystal axis b, approximately 6 to 10 times longer than the a or c axis. This crystal structure results in a hair-like appearance and a high tendency to form flocculent crystal habits. This leads to high static charges and poor tableting properties, hindering the production and processing of raw materials and the formation of pharmaceutical preparations. Therefore, further research on the crystal forms of avatrombopag maleate is necessary to develop more soluble and stable crystal forms, providing more options for the development of pharmaceutical preparations. Summary of the Invention

[0010] In a first aspect, the present invention provides an avatrombopag maleate trihydrate as shown in formula I, represented by AVAT-3H.

[0011] In one embodiment, the compound of formula I is in crystalline form, characterized in that when Cu-Kα When the θ-2θ one-dimensional continuous scanning is performed with radiation, tube voltage of 40 kV, tube current of 180 mA, scanning speed of 10° / min, step width of 0.02°, and scanning range of 3-50° (2θ), its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.28±0.2°, 14.96±0.2°, 15.28±0.2°, 18.46±0.2° and 25.64±0.2° expressed as 2θ diffraction angles.

[0012] In another embodiment, the compound of formula I is in crystalline form, characterized in that when Cu-Kα When the θ-2θ one-dimensional continuous scanning is performed with radiation, tube voltage of 40 kV, tube current of 180 mA, scanning speed of 10° / min, step width of 0.02°, and scanning range of 3-50° (2θ), its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.28±0.2°, 14.96±0.2°, 15.28±0.2°, 18.46±0.2°, 18.84±0.2°, 21.22±0.2°, 21.56±0.2°, 24.10±0.2°, 25.64±0.2° and 26.22±0.2° expressed by 2θ diffraction angles.

[0013] In another embodiment, the compound of formula I is in crystalline form, characterized in that when Cu-Kα When the θ-2θ one-dimensional continuous scanning is performed with radiation, tube voltage of 40 kV, tube current of 180 mA, scanning speed of 10° / min, step width of 0.02° and scanning range of 3-50° (2θ), its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.06±0.2°, 6.28±0.2°, 12.60±0.2°, 14.96±0.2°, 15.28±0.2°, 17.64±0.2°, 17.84±0.2°, 18.46±0.2°, 18.84±0.2°, 21.22±0.2°, 21.56±0.2°, 24.10±0.2°, 25.64±0.2° and 26.22±0.2° expressed as 2θ diffraction angles.

[0014] In another embodiment, the compound of formula I is in crystalline form, characterized in that when Cu-Kα When the θ-2θ one-dimensional continuous scanning is performed with radiation, a tube voltage of 40 kV, a tube current of 180 mA, a scanning speed of 10° / min, a step width of 0.02°, and a scanning range of 3-50° (2θ), the X-ray powder diffraction pattern is as shown in Figure 1. Among them, the main characteristic diffraction lines expressed in 2θ diffraction angles are shown in Table 1.

[0015] Table 1 Main characteristic diffraction lines of AVAT-3H

[0016] The single crystal structure data of the compound of formula I of the present invention are shown in Table 2.

[0017] The crystal structure analysis results show that the crystal of the compound of formula I of the present invention belongs to the triclinic system, P-1 space group, and the unit cell parameters are α=73.319(2)°, β=73.513(2)°, γ=77.008(2)°, Z=2,the molecular formula is C 29 H35 Cl2N6O3S2·C4H3O4·3H2O, with the structural formula shown in Figure 2. Its smallest asymmetric unit contains an avatrombopag cation, a maleic acid anion and three water molecules. The hydrogen atom on the maleic acid carboxyl group is transferred to the nitrogen atom of the piperazine ring in the avatrombopag molecule to form avatrombopag maleate. The hydroxyl group on the carboxyl group and the amino group on the amide group in the avatrombopag molecule act as hydrogen bond donors to form O3-H3···O4 and N4-H4···O5 hydrogen bonds with the deprotonated carboxyl oxygen in the maleic acid molecule, respectively. These two hydrogen bonds connect the avatrombopag maleate molecules to form The hydrogen bond ring is shown in Figure 3. Water molecules act as hydrogen bond "bridge" atoms to connect this hydrogen bond ring into a two-dimensional layered structure, as shown in Figure 4. The water molecules are located in the cavity formed by the stacking of avatrombopag molecules (see Figure 5), so the water in the structure has good stability.

[0018] Table 2. Single crystal structure data of compound of formula I

[0019] The DSC results of the crystals of the compound of formula I show that it has an endothermic peak at 103.2°C (peak value), which is the phase change endothermic peak caused by the removal of crystal water, and the melting decomposition temperature (peak value) is 289.3°C, as shown in Figure 6.

[0020] The TG results of the crystals of the compound of formula I show that its structure contains approximately 7.0% crystalline water, which is equivalent to the 6.6% water molecule content in the structure of formula I, that is, there are three crystalline waters in the structure, see Figure 7.

[0021] In a second aspect, the present invention provides a method for preparing crystals of the compound of formula I.

[0022] In one embodiment, the present invention provides a method for preparing a crystal of a compound of formula I, comprising the steps of:

[0023] a) dissolving avatrombopag maleate in a solvent containing water,

[0024] b) precipitating a solid from the solution obtained in step a),

[0025] c) isolating the solid and drying it to obtain crystals of the compound of formula I.

[0026] The crystalline form of avatrombopag maleate used in step a) of the method is not limited and can be one of amorphous form, crystalline form A, crystalline form B or crystalline form C, or a mixed crystalline form thereof.

[0027] In one embodiment, the aqueous solvent used in step a) of the method comprises a mixed solvent of one or two or more solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, acetone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and dichloromethane and water.

[0028] In one embodiment, the aqueous solvent used is a mixed solvent of one or two or more solvents selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile and water.

[0029] In one embodiment, the aqueous solvent used is a mixed solvent of water and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or acetonitrile.

[0030] In one embodiment, the volume ratio between the solvent and water is 1:1-15:1, preferably 7:3-9:1, such as 4:1, 5:1, 6:1, 7:1 or 8:1, and more preferably 8: 1. In one embodiment, in step a), avatrombopag maleate is dissolved in an aqueous solvent at room temperature.

[0031] In one embodiment, in step a), avatrombopag maleate is dissolved in an aqueous solvent under heating, and the heating temperature is 30-70°C, such as 40-70°C, such as 50-60°C, 60-70°C, 65-70°C.

[0032] In one embodiment, in step b), the solid is precipitated by cooling the solution obtained in step a) to -10-10°C, for example, cooling the solution obtained in step a) to -5-5°C, such as 0-5°C.

[0033] In one embodiment, in step c), the precipitated solid is isolated by centrifugation or filtration.

[0034] In one embodiment, in step c), the drying is normal pressure drying or reduced pressure drying, and the drying temperature is 30-60°C, such as 30-50°C, 30-45°C, 30-40°C, 35-40°C, such as about 45°C, about 50°C.

[0035] In another embodiment, the present invention provides a method for preparing a crystal of a compound of formula I, comprising the steps of:

[0036] a') adding avatrombopag free base and maleic acid to an aqueous solvent and stirring for several hours,

[0037] b') cooling,

[0038] c') isolating the solid and drying it to obtain crystals of the compound of formula I.

[0039] In one embodiment, the aqueous solvent in step a') of the method comprises a mixed solvent of one or two or more solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, acetone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and dichloromethane and water.

[0040] In one embodiment, the aqueous solvent used in step a') is a mixed solvent of one or two or more solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and isopentanol and water.

[0041] In one embodiment, the aqueous solvent used in step a') is a mixed solvent of a solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or isopentanol and water, for example a mixed solvent of a solvent selected from methanol, ethanol or isopropanol and water.

[0042] In one embodiment, the volume ratio between the solvent and water in the aqueous solvent used in step a') is 8:2 to 6:1, such as 8:2, 5:1 or 6:1; more preferably 8:2.

[0043] In one embodiment, the molar ratio of avatrombopag free base to maleic acid in step a′) is 1:0.6 to 5.0, for example, about 1:1 to 1:2.

[0044] In one embodiment, in step a'), avatrombopag free base and maleic acid are added to an aqueous solvent and stirred at -15-45°C, e.g. 20-40°C, 20-30°C, 25-40°C, 30-40°C, preferably 20-30°C, e.g. room temperature, e.g. 25°C, for 1 to 3 hours, e.g. 1 to 2 hours.

[0045] In one embodiment, in step b') the temperature is lowered to 0-5°C.

[0046] In one embodiment, in step c'), the precipitated solid is isolated by centrifugation or filtration.

[0047] In one embodiment, in step c'), the drying is normal pressure drying or reduced pressure drying, and the drying temperature is 30-60°C, such as 30-50°C, 30-45°C, 30-40°C, 35-40°C, such as about 45°C, about 50°C.

[0048] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I and optionally a pharmaceutically acceptable excipient and carrier.

[0049] In a fourth aspect, the present invention provides use of a compound of formula I in the preparation of a medicament for treating thrombocytopenia. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG1 is a PXRD spectrum of crystals of the compound of formula I prepared according to the method of the present invention.

[0051] FIG2 is a crystal structure diagram (ORTEP diagram) of the compound of formula I prepared according to the method of the present invention.

[0052] FIG3 is a structural diagram of a hydrogen-bonded dimer of a crystal of the compound of formula I prepared according to the method of the present invention.

[0053] FIG4 is a two-dimensional layered stacking diagram of crystals of the compound of formula I prepared according to the method of the present invention.

[0054] FIG5 is a stacking diagram of crystals of the compound of formula I prepared according to the method of the present invention.

[0055] FIG6 is a DSC chart of crystals of the compound of formula I prepared according to the method of the present invention.

[0056] FIG7 is a TG chart of crystals of the compound of formula I prepared according to the method of the present invention.

[0057] FIG8 is a PXRD comparison diagram of the crystals of the compound of formula I prepared according to the method of the present invention after being heated at 60° C. for 6 hours and the original crystals.

[0058] FIG9 is a PXRD comparison diagram of the crystals of the compound of formula I prepared according to the method of the present invention after being heated at 100° C. for 2 hours and the original crystals.

[0059] FIG10 is a diagram showing the equilibrium solubility of three crystalline forms of avatrombopag maleate.

[0060] Figure 11 shows the crystal form B of Avatrombopag maleate Hydrogen bond ring.

[0061] FIG12 is a hydrogen-bonded ring-penetrating structure of avatrombopag maleate crystal form B (hydrogen atoms are ignored).

[0062] FIG13 is a hydrogen bond stacking diagram of avatrombopag maleate crystal form B (hydrogen atoms are ignored).

[0063] FIG14 is a hydrogen bond molecular chain of avatrombopag maleate crystal form C. Specific implementation method:

[0064] The raw material of avatrombopag maleate used was prepared according to the method of WO2013018362. Solvent reagents used, such as methanol, ethanol, isopropanol, tetrahydrofuran, dimethyltetrahydrofuran, etc., can be purchased from commercial sources.

[0065] The single crystal X-ray diffractometer model is Bruker D8 Venture, and the parameters used are The structures were solved and modified using SHELXS97 and SHELXL97. The structures were obtained using Diamond and Mercury software.

[0066] The powder X-ray diffraction (XRD) characterization instrument was Rigaku SmartLab.

[0067] Thermogravimetric analysis (TG) was performed using a TA Instruments SDT Q600 instrument. Parameters included purge gas: nitrogen 120 ml / min, heating rate: 10°C / min, and temperature range: room temperature to 500°C.

[0068] The differential scanning calorimetry (DSC) instrument was a TA company DSC Q100. The parameters were as follows: purge gas: nitrogen 50 ml / min, heating rate: 10°C / min, temperature range: room temperature to 350°C.

[0069] The method of the present invention is further illustrated by the following examples. It should be understood that the purpose of providing the following examples is only to enable a better understanding of the present invention, and is not intended to limit the scope of the present invention in any way.

[0070] Example 1:

[0071] 3.7 g of Avatrombopag Maleate Form C was added to 40 mL of a mixture of tetrahydrofuran and water (THF:H₂O, volume ratio 8:1) and stirred at reflux at 65-70°C for 2 hours. The resulting solution was cooled to 0-5°C to allow crystallization. The wet product was filtered, and the drying weight loss was 7.0%. The product was then dried at 50°C at ambient pressure for 8 hours to obtain Avatrombopag Maleate Trihydrate as a crystalline solid with a yield of 96% and a purity of 99.9%.

[0072] Example 2:

[0073] 2 grams of avatrombopag maleate Form B was added to 40 mL of a mixed solvent of 2-methyltetrahydrofuran and water (volume ratio of 2-methyltetrahydrofuran to water: 8:2) and stirred at 50-60°C for 4 hours. The resulting solution was cooled to 0-5°C to allow crystallization. The wet product was filtered, and the drying weight loss was 7.5%. The product was then dried at 55°C at ambient pressure for 7 hours to obtain avatrombopag maleate trihydrate as a crystalline solid with a yield of 95% and a purity of 99.9%.

[0074] Example 3:

[0075] 2 grams of avatrombopag maleate Form C were added to 40 mL of a mixed solvent of 1,4-dioxane and water (volume ratio of 1,4-dioxane to water 7:1) and stirred at 50-60°C for 2 hours. The resulting solution was cooled to 0-5°C to allow crystallization. The wet product was filtered, and the drying weight loss was 7.5%. The product was then dried at 45°C at ambient pressure for 12 hours to obtain avatrombopag maleate trihydrate as a crystalline solid with a yield of 95.4% and a purity of 99.9%.

[0076] Example 4

[0077] 3.7 g of Avatrombopag Maleate Form C was added to 50 mL of a mixed solvent of acetonitrile and water (acetonitrile:water, volume ratio 8:1) and refluxed at 50-60°C with stirring for 2 hours. The resulting solution was cooled to 0-5°C to allow crystallization. The wet product was filtered, and the drying weight loss was 6.0%. The product was then dried under reduced pressure at 35-40°C for 9 hours to obtain Avatrombopag Maleate Trihydrate as a crystalline solid with a yield of 92% and a purity of 99.9%.

[0078] Example 5:

[0079] 2 grams of avatrombopag free base and 0.21 grams of maleic acid were added to 50 mL of ethanol / water (ethanol:water volume ratio 9:1), stirred at 25°C for 1-4 hours, then cooled to 0-5°C and filtered. The wet product had a drying weight loss of 8.0%. Avatrombopag maleate trihydrate was obtained as a crystalline solid by drying at 35-40°C under reduced pressure for 9 hours with a yield of 95.5% and a purity of 99.9%.

[0080] Example 6:

[0081] 2 grams of avatrombopag free base and 0.42 grams of maleic acid were added to 50 mL of ethanol / water (ethanol:water volume ratio = 8:2), stirred at 25°C for 1-2 hours, then cooled to 0-5°C and filtered. The wet product had a drying weight loss of 8.5%. Avatrombopag maleate trihydrate was obtained as a crystalline solid by drying at 45°C at ambient pressure for 12 hours with a yield of 96% and a purity of 99.9%.

[0082] Example 7:

[0083] 2 grams of avatrombopag free base and 0.42 grams of maleic acid were added to 50 mL of 80% isopropyl alcohol / water (8:2 isopropyl alcohol:water volume ratio). The mixture was stirred at 30-40°C for 1-2 hours, then cooled to 0-5°C and filtered. The wet product had a drying loss of 9.0%. Avatrombopag maleate trihydrate was obtained as a crystalline solid by drying at 45°C at ambient pressure for 11 hours with a yield of 96% and a purity of 99.9%.

[0084] Example 8:

[0085] 20 grams of avatrombopag free base and 4.2 grams of maleic acid were added to 300 mL of a mixed solvent of methanol and water (methanol:water volume ratio 8:2). The mixture was stirred at 25-40°C for 1-2 hours, then cooled to 0-5°C and filtered. The wet product had a drying weight loss of 7.5%. Avatrombopag maleate trihydrate was obtained as a crystalline solid by drying at 50°C at atmospheric pressure for 12 hours with a yield of 96.7% and a purity of 99.9%.

[0086] Comparative experimental group 1:

[0087] According to the method described in the literature, 1.9 g of maleic acid and 210 ml of 80% ethanol / water were added to 8.9 g of avatrombopag free base. The reaction solution was stirred at room temperature for 1 hour and then at 100°C for an additional hour. The mixture was cooled to 0°C, insulated, filtered, and dried to yield 8.78 g of crude product with a yield of 83.7%. 0.68 g of maleic acid and 23.1 g of the crude product were then added to 550 ml of 80% ethanol / water, insulated and stirred at room temperature, and filtered. The wet product lost 5.6% weight on drying and was dried under reduced pressure at 50°C for 12 hours to yield 20.3 g of avatrombopag maleate Form B with a moisture content of 0.1%, a yield of 87.8%, and a purity of 99.8%.

[0088] Comparative experimental group 2:

[0089] According to the method described in the literature, 8.0 g of avatrombopag free base and 1.7 g of maleic acid were added to a mixed solvent of 58 mL of dimethyl sulfoxide, 58 mL of acetone, and 29 mL of water, heated to 69°C, and stirred. The mixture was filtered and washed with a mixed solvent of 3.2 mL of dimethyl sulfoxide, 3.2 mL of acetone, and 1.6 mL of water. The filtrate was cooled to 25°C and stirred for 1-2 hours. The wet product was filtered, and the drying loss was 23.4%. The product was then dried under reduced pressure at 1°C for 24 hours to obtain 7.0 g of avatrombopag maleate Form C, with a moisture content of 0.3%, a yield of 74.3%, and a purity of 99.8%.

[0090] From the above comparative experiments, it can be seen that the preparation of Form B according to the method in the literature requires two salt formations, with a total yield of 73.5%. The preparation of Form C has a wet product drying loss of 23.4% and a yield of 74.3%. In comparison, the avatrombopag maleate trihydrate form (AVAT-3H) prepared by the method of the present invention has a wet product drying loss of less than 10% and a yield of greater than 95%. Therefore, the yield is high, the material is easy to dry, and it is suitable for industrial scale-up.

[0091] Study on thermal stability of crystals of compound I

[0092] The crystals of the compound of formula I prepared according to the method of Examples 1-8 were heated at 60°C for 6 hours, and their XRD patterns did not change, as shown in Figure 8 (Figure a before heating, Figure b after heating), indicating that no crystal transformation occurred when heated at 60°C for 6 hours, that is, they had good thermal stability.

[0093] It was then heated at 100°C for 2 hours. The XRD results showed that crystal transformation had occurred and it was transformed into a new anhydrous crystalline form of avatrombopag maleate salt, as shown in Figure 9 (Figure a before heating and Figure b after heating), indicating that it was unstable when heated at 100°C for 2 hours.

[0094] Solubility

[0095] The 24-hour equilibrium solubility results of the three crystalline forms B (AVAT-B) and C (AVAT-C) of avatrombopag maleate and the compound of formula I (AVAT-3H) prepared according to the method of Examples 1-8 in aqueous medium (37° C.) showed that the solubility of the crystals of the compound of formula I was significantly better than that of crystalline forms B and C of avatrombopag maleate, as shown in Figure 10.

[0096] Without wishing to be bound by any theory, it is believed that the difference in solubility of the three crystalline forms of avatrombopag maleate (B, C, AVAT-3H) is related to their crystal structures. The crystal structure of avatrombopag maleate crystalline form B shows that avatrombopag maleate crystalline form B belongs to the monoclinic system, P21 / n space group, and the crystallographic parameters are: β=96.789(2)°, Z=4Molecular formula:C 29 H 35 Cl2N6O3S2·C4H3O4. Its smallest asymmetric unit contains an avatrombopag cation and a maleic acid anion. The hydrogen atom on the maleic acid carboxyl group is transferred to the nitrogen atom of the piperazine ring in the avatrombopag molecule to form the maleate salt of avatrombopag. The maleic acid molecule and the avatrombopag molecule are connected by two sets of strong hydrogen bonds (NH···O and OH···O) to form avatrombopag maleate. As shown in Figure 11, the hydrogen bond ring between the amide group in the avatrombopag molecule and the carboxyl group at the end of the avatrombopag molecule forms an interlaced structure (see Figure 12), which in turn forms a two-dimensional close-packed structure, as shown in Figure 13. Crystal structure studies of Form C of avatrombopag maleate show that Form C, like Form B, belongs to the monoclinic system and the P21 / n space group, but has significant differences in crystallographic parameters. The crystallographic parameters are: β=99.408(7)°, Z=4, molecular formula: C 29 H 35Cl2N6O3S2·C4H3O4. Its smallest asymmetric unit contains an avatrombopag cation and a maleic acid anion. The hydrogen atom on the maleic acid carboxyl group is transferred to the nitrogen atom of the piperazine ring in the avatrombopag molecule to form the maleate salt of avatrombopag. Maleic acid and the avatrombopag molecule are connected by a set of hydrogen bonds (NH···O). At the same time, the carboxyl group at the end of the avatrombopag molecule acts as a hydrogen bond donor and acceptor, forming two sets of hydrogen bonds (NH···O, OH···N) with the amide group in another avatrombopag molecule and the amino group on the thiazole ring, respectively, connecting the avatrombopag molecules into a hydrogen bond dimer. This dimer connects the avatrombopag molecules through the aforementioned hydrogen bonding, forming a zigzag molecular chain that extends infinitely along the c-direction (see Figure 14). Compared to avatrombopag maleate form B, the hydrogen bonding stacking of form C is looser.

[0097] In the trihydrate crystal form of avatrombopag maleate (AVAT-3H), there are no hydrogen bonds between avatrombopag molecules. Instead, they are connected together by maleic acid or crystal water as a "bridge". Moreover, from its hydrogen bond stacking, it is found that although a hydrogen bond ring of avatrombopag maleate is also formed, the form of the ring is different. In the hydrogen bond ring of avatrombopag maleate crystal form B, except for the cyclohexane at the end of the avatrombopag molecule exposed outside the ring, the others all participate in the formation of the ring; while the hydrogen bond ring of the trihydrate crystal form of avatrombopag maleate shows that only some avatrombopag molecules participate in the formation of the hydrogen bond ring, and the thiazole ring, thiophene ring, piperazine ring, and cyclohexane ring are all exposed outside the ring. Moreover, the rings are connected to form a two-dimensional layered structure by crystal water as a "bridge", and their bonding is relatively loose.

[0098] In summary, the differences in hydrogen bonding interactions and hydrogen bond stacking structures between avatrombopag molecules in the three crystal forms lead to differences in their solubility.

[0099] Hygroscopicity

[0100] The hygroscopicity of the compound of Formula I (AVAT-3H) prepared by the present invention at 25°C and 80% relative humidity is compared with that of avatrombopag maleate crystalline Form B and Form C, as shown in Table 3. As can be seen from the data in Table 3, AVAT-3H is essentially non-hygroscopic.

[0101] Table 3: Comparison of hygroscopicity of the compound of formula I, crystalline form B and crystalline form C

[0102] Bulk density

[0103] Table 4 shows a comparison of the bulk density of the compound of Formula I (AVAT-3H) prepared by the present invention with Form B and Form C of avatrombopag maleate. As shown in Table 4, the bulk density of the compound of Formula I is lower than that of Form B of avatrombopag maleate, but higher than that of Form C. This indicates that the compressibility of the compound of Formula I is superior to that of the commercially available Form C, making it more suitable for tableting and scale-up of the preparation.

[0104] Table 4: Comparison of bulk density of the compound of formula I with those of Form B and Form C

[0105] In summary, the crystal of the compound of formula I (AVAT-3H) of the present invention has the following advantages compared with the crystal form of avatrombopag maleate known in the prior art:

[0106] ① The crystal preparation of the compound of formula I is simple and has strong operability. It can be prepared from avatrombopag maleate salt or avatrombopag free base by recrystallization or salt formation method, and is suitable for industrial production.

[0107] ② The crystals of the compound of formula I are stable, providing options for the development of dry granulation or tableting methods for pharmaceutical preparations.

[0108] ③ The crystals of the compound of formula I are easy to form flake to block crystal habits, have low electrostatic properties, and overcome the problem of poor tablet forming properties of avatrombopag maleate crystal form C.

[0109] ④ The solubility of the crystals of the compound of formula I is significantly better than that of crystal forms B and C, providing an option for the development of formulations.

[0110] ⑤ The crystals of the compound of formula I are substantially non-hygroscopic at 25° C. and a relative humidity of 80%.

Claims

1. A compound, which is avatrombopag maleate trihydrate as shown in formula I, 2. The compound according to claim 1, which is in crystalline form, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.28±0.2°, 14.96±0.2°, 15.28±0.2°, 18.46±0.2° and 25.64±0.2° expressed as 2θ diffraction angles.

3. The compound according to claim 1, which is in crystalline form, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.28±0.2°, 14.96±0.2°, 15.28±0.2°, 18.46±0.2°, 18.84±0.2°, 21.22±0.2°, 21.56±0.2°, 24.10±0.2°, 25.64±0.2° and 26.22±0.2°, expressed as 2θ diffraction angles.

4. The compound according to claim 1, which is in crystalline form, characterized in that Its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.06±0.2°, 6.28±0.2°, 12.60±0.2°, 14.96±0.2°, 15.28±0.2°, 17.64±0.2°, 17.84±0.2°, 18.46±0.2°, 18.84±0.2°, 21.22±0.2°, 21.56±0.2°, 24.10±0.2°, 25.64±0.2° and 26.22±0.2°, expressed as 2θ diffraction angles. The compound according to claim 1 , which has an X-ray powder diffraction pattern as shown in FIG1 .

6. A method for preparing the compound of formula I according to claim 1, comprising the steps of: a) dissolving avatrombopag maleate in a solvent containing water, b) precipitating a solid from the solution obtained in step a), c) isolating the solid and drying it to obtain crystals of the compound of formula I.

7. The method according to claim 6, wherein the aqueous solvent comprises one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, acetone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and dichloromethane, or a mixture of two or more thereof with water; preferably a mixture of one or two or more thereof selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and acetonitrile with water; more preferably a mixture of one selected from tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane or acetonitrile with water.

8. The method for preparing the compound of formula I according to claim 1, comprising the steps of: a') adding avatrombopag free base and maleic acid to an aqueous solvent and stirring for several hours, b') cooling, c') isolating the solid and drying it to obtain crystals of the compound of formula I.

9. The method according to claim 8, wherein the aqueous solvent in step a') comprises a mixed solvent of one or two or more solvents selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, isoamyl alcohol, ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, xylene, acetonitrile, acetone, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate and dichloromethane, and water; preferably, a mixed solvent of one or two or more solvents selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and isoamyl alcohol, and water; more preferably, a mixed solvent of one selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or isoamyl alcohol, and water, for example, a mixed solvent of one selected from the group consisting of methanol, ethanol or isopropanol and water.

10. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 5 and optionally pharmaceutically acceptable excipients and carriers.

11. Use of a compound of formula I as defined in any one of claims 1 to 5 in the preparation of a pharmaceutical composition for treating thrombocytopenia.

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