CN111377915B

CN111377915B - Pyrazolo-pyridone compound crystal form D

Info

Publication number: CN111377915B
Application number: CN201811644156.8A
Authority: CN
Inventors: 翟立海; 杨丹; 董怀民; 刘建设
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2018-12-30
Filing date: 2018-12-30
Publication date: 2023-10-24
Anticipated expiration: 2038-12-30
Also published as: CN111377915A

Abstract

The application belongs to the technical field of medicines, and particularly provides a pyrazolo-pyridone compound crystal form D. The pyrazolo-pyridone compound crystal form D prepared by the application uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.8+/-0.2 degrees, 15.1+/-0.2 degrees, 16.2+/-0.2 degrees, 20.2+/-0.2 degrees, 21.7+/-0.2 degrees, 22.8+/-0.2 degrees, 24.6+/-0.2 degrees and 25.2+/-0.2 degrees. The yield of the pyrazolo-pyridone compound crystal form D prepared by the application is more than 89%, and the purity is higher than 99.85%; and the pyrazolo-pyridone compound crystal form D prepared by the application has higher solubility which is 1.5 times of the solubility of the existing crystal form. The preparation method is simple in preparation process and has good industrial application prospect.

Description

Pyrazolo-pyridone compound crystal form D

Technical Field

The application belongs to the technical field of crystal form drug molecules, and particularly relates to a pyrazolo-pyridone compound crystal form D.

Background

Apixaban (Apixaban trade name Eliquis,) with chemical name 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxo-1-piperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, CAS:503612-47-3, the structure of which is shown in formula I. Apixaban is an oral selective activation factor Xa inhibitor which is developed by combining the pyroxene and the Baishi Meishibao, can directly inhibit the blood coagulation factor Xa, blocks the conversion of prothrombin into thrombin in the blood coagulation cascade process, and has high Xa selectivity and strong effect. In addition, apixaban can inhibit not only free Xa and Xa in prothrombin complex, but also Xa in blood clot, and there is no need for antithrombin III in the inhibition process, unlike heparin anticoagulants such as fondaparinux sodium. Apixaban was approved for sale in the european union for use in preventing Venous Thromboembolic (VTE) events in adult patients undergoing a selective hip or knee replacement procedure 5 months 2011; the FDA in the united states approved the drug for reducing the risk of stroke and systemic embolism in non-valvular atrial fibrillation patients in month 12 2012. The chemical structural formula is shown as follows:

different crystal forms of the same drug have different characteristics in terms of solubility, melting point, density, thermal stability, chemical reactivity, optical and mechanical properties, etc., which can directly affect the stability, uniformity, bioavailability, therapeutic effect and safety of the drug. Therefore, comprehensive and systematic polymorphic screening is performed in drug development, and the selection of the most suitable crystal form for development is one of important research contents which cannot be ignored.

US20060160841 first discloses non-solvent crystalline form N-1 and dihydrate crystalline form H2-2 of apixaban, and in patent document WO2007001385 and CN101065379a specific unit cell parameters, position coordinate parameters, X-ray diffraction characteristic peak positions, SSNMR (solid state nuclear magnetic resonance) shift and other crystal characterization parameters of crystalline form N-1 and crystalline form H2-2 are disclosed.

US20070203178 discloses apixaban N, N-dimethylformamide solvate form DMF-5 and formamide solvate form FA-2.

WO2012168364 discloses in detail the crystalline form α of apixaban and its characterization.

Patent CN102770126 and patent CN103830199 disclose various crystal forms of apixaban, but these invented processes have low production efficiency and low product yield, and are not suitable for industrial production.

The currently disclosed apixaban crystal forms have poor solubility and influence the curative effect and clinical effect of the medicine, so that more crystal forms need to be developed, on one hand, more apixaban crystal forms are provided for medicine application, and on the other hand, the apixaban crystal forms which are more suitable for industrial production and have high economic benefit are also developed.

Disclosure of Invention

In view of the deficiencies of the prior art, one aspect of the present application is to provide a pyrazolo-pyridone compound form D.

The pyrazolo-pyridone compound of the present application is defined as form D, and the pyrazolo-pyridone compound of the present application is defined as apixaban.

According to a first aspect of the present application there is provided a pyrazolo-pyridone compound form D. The pyrazolo-pyridone compound crystal form uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 5.8+/-0.2 degrees, 15.1+/-0.2 degrees, 16.2+/-0.2 degrees, 20.2+/-0.2 degrees, 21.7+/-0.2 degrees, 22.8+/-0.2 degrees, 24.6+/-0.2 degrees and 25.2+/-0.2 degrees.

Preferably, the pyrazolo-pyridone compound of form D has an X-ray diffraction pattern expressed in 2θ having characteristic peaks at 5.8±0.2°,7.1±0.2°,7.4±0.2°,11.6±0.2°,12.8±0.2°,15.1±0.2°,16.2±0.2°,18.5±0.2°,20.2±0.2°,21.7±0.2°,22.8±0.2°,23.5±0.2°,24.6±0.2°,25.2±0.2° using Cu-ka radiation.

Preferably, the pyrazolo-pyridone compound crystalline form D has an X-ray diffraction pattern expressed in 2θ of characteristic peaks at 5.8±0.2°,7.1±0.2°,7.4±0.2°,11.6±0.2°,12.8±0.2°,15.1±0.2°,16.2±0.2°,16.8±0.2°,17.6±0.2°,17.9±0.2°,18.5±0.2°,20.2±0.2°,20.5±0.2°,21.7±0.2°,22.2±0.2°,22.8±0.2°,23.5±0.2°,24.4±0.2°,24.6±0.2°,25.2±0.2°,26.1±0.2°,30.1±0.2°,31.3±0.2°, using Cu-ka radiation

Preferably, the pyrazolo-pyridone compound of form D has a characteristic peak conforming to the X-ray powder diffraction pattern shown in fig. 1 using Cu-ka radiation.

Preferably, the pyrazolo-pyridone compound form D has an exothermic peak at 176±2 ℃ and an endothermic peak at 239±2 ℃ as detected by differential scanning calorimetric analysis.

The second aspect of the application provides a preparation method of pyrazolo-pyridone compound crystal form D, which comprises the following specific preparation steps:

(1) Adding pyrazolo-pyridone compound into N-methyl pyrrolidone solution, and heating to dissolve completely;

(2) Cooling the solution in the step (1), adding a mixed solution of an organic solvent A and water, and stirring at a constant temperature;

(3) And (3) cooling and crystallizing the solution in the step (2), filtering and drying to obtain the pyrazolo-pyridone compound crystal form D.

According to the preparation method, in the step (1), the mass ratio of the pyrazolo-pyridone compound to the N-methylpyrrolidone is 1:5 to 20.

In the preparation method, the dosage of the organic solvent A in the step (2) is 2.5-45 times of the mass of the pyrazolo-pyridone compound.

According to the preparation method, in the step (2), the mass ratio of the pyrazolo-pyridone compound to water is 1:0.1-5.

In the preparation method, the organic solvent A in the step (2) is selected from one or more of ethylene glycol, propylene glycol, benzyl alcohol, isopropyl ether, ethylene glycol dimethyl ether, acetone, formamide, acetonitrile, tetrahydrofuran, dichloromethane and acetic acid.

Preferably, the organic solvent A in the step (2) is selected from one or more of benzyl alcohol, isopropyl ether, ethylene glycol dimethyl ether, acetone, acetonitrile and dichloromethane.

In the preparation method, the temperature of the cooling in the step (2) is 30-45 ℃.

In the preparation method, the temperature of the cooling crystallization in the step (3) is-15-10 ℃.

The following further details the preparation of pyrazolo-pyridone compound form D:

(2) Cooling the solution in the step (1) to 30-45 ℃, then adding the cooled solution into a mixed solution of an organic solvent A and water, and carrying out heat preservation and stirring for 2-6 h;

(3) Cooling the solution in the step (2) to-15-10 ℃, crystallizing for 1-5 h, filtering, and drying to obtain pyrazolo-pyridone compound crystal form D.

Preferably, the amount of the organic solvent A is 10 to 30 times the mass of the pyrazolo-pyridone compound.

Preferably, the temperature of the cooling crystallization in the step (3) is-8-6 ℃.

Further preferably, the temperature of the cooling crystallization in the step (3) is-2 to 3 ℃.

In a third aspect, the application provides a pharmaceutical composition comprising a pyrazolo-pyridone compound of form D according to the application, together with other pharmaceutically acceptable adjuvant components.

Preferably, the pharmaceutical composition of the present application is prepared as follows: the compounds of the present application are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.

Preferably, the additional components include additional active ingredients, excipients, fillers, and the like, which may be used in combination.

Preferably, the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.

In the application, an X-ray powder diffraction test instrument and test conditions are as follows: an X-ray powder diffractometer, PANalytical E; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg. The corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 1 in detail.

TABLE 1 PXRD peak of pyrazolo-pyridone compound form D

DSC thermal analysis tester and test conditions in the application: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3+; dynamic temperature section: 30-350 ℃; heating rate: 10 ℃/min; procedure section gas N ₂ The method comprises the steps of carrying out a first treatment on the surface of the Gas flow rate: 50mL/min; crucible: 40 μl of aluminum crucible.

The TGA/DSC test results of the pyrazolo-pyridone compound crystal form prepared by the method of the present application are shown in FIG. 2. DSC results show that the pyrazolo-pyridone compound crystal form prepared by the application does not contain solvent and water.

The combination of TGA/DSC detection results and X-ray powder diffraction results show that the crystal form prepared by the method is a novel pyrazolo-pyridone compound crystal form.

The pyrazolo-pyridone compound crystal form D prepared by the method has the following advantages compared with the pyrazolo-pyridone compound crystal form reported at present:

(1) High yield and purity. The yield is more than 89%, and the purity is more than 99.89%.

(2) The solubility is good. Compared with the existing crystal form, the pyrazolo-pyridone compound crystal form D prepared by the application has higher solubility in different dissolution media, which is more than 1.5 times of the solubility of the existing pyrazolo-pyridone compound crystal form.

(3) The dissolution rate is high. Compared with the tablets prepared by the existing crystal forms, the tablets prepared by the pyrazolo-pyridone compound crystal form D have the advantages of quick dissolution and high dissolution proportion of the active ingredient of the pyrazolo-pyridone compound.

(4) The preparation method is simple and convenient, has lower requirements on equipment, has low cost, is suitable for industrial production of pyrazolo-pyridone compounds with high purity and high yield, and has high economic benefit.

Drawings

Fig. 1: x-ray powder diffraction pattern of pyrazolo-pyridone compound form D.

Fig. 2: differential Scanning Calorimetry (DSC) profile of crystalline pyrazolo-pyridone compound form D.

Detailed Description

The beneficial effects of the present application will now be further described by the following examples, which are given for illustration purposes only and do not limit the scope of the present application, while obvious changes and modifications made by those skilled in the art in light of the present application are also included within the scope of the present application, and the pyrazolo-pyridone compound is apixal.

Example 1:

(1) 10.0g of pyrazolo-pyridone compound is added to a 120g N-methylpyrrolidone solution and heated to 100℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 45 ℃, adding 110g of mixed solvent (100 g of acetone+10 g of purified water), and stirring for 4 hours at a constant temperature;

(3) And (3) cooling the solution in the step (2) to 0 ℃, stirring and crystallizing for 5 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.6g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 96.0% and the HPLC purity is 99.98%.

Example 2:

(1) 10.0g of pyrazolo-pyridone compound is added to a 50g N-methylpyrrolidone solution and heated to 110℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 40 ℃, adding 210g of mixed solvent (180 g of acetonitrile+30 g of purified water), and stirring for 2h at a constant temperature;

(3) And (3) cooling the solution in the step (2) to 3 ℃, stirring and crystallizing for 4 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.57g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 95.7%, and the HPLC purity is 99.96%.

Example 3:

(1) 10.0g of pyrazolo-pyridone compound is added to a 200g N-methylpyrrolidone solution and heated to 95℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 30 ℃, adding 305g of mixed solvent (300 g of ethylene glycol dimethyl ether plus 5g of purified water), and stirring for 6h at a constant temperature;

(3) Cooling the solution in the step (2) to-2 ℃, stirring and crystallizing for 1h, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.45g pyrazolo-pyridone compound crystal form D compound with the yield of 94.5% and the HPLC purity of 99.95%.

Example 4:

(1) 10.0g of pyrazolo-pyridone compound is added to a 150g N-methylpyrrolidone solution and heated to 120℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 45 ℃, adding 26g of mixed solvent (25 g of isopropyl ether plus 1g of purified water), and stirring for 5h at a constant temperature;

(3) And (3) cooling the solution in the step (2) to 6 ℃, stirring and crystallizing for 1h, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.41g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 94.1%, and the HPLC purity is 99.94%.

Example 5:

(1) 10.0g of pyrazolo-pyridone compound is added to a 90g N-methylpyrrolidone solution and heated to 85 ℃ to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 40 ℃, adding 500g of mixed solvent (450 g of benzyl alcohol and 50g of purified water), and stirring for 3h at a constant temperature;

(3) Cooling the solution in the step (2) to-8 ℃, stirring and crystallizing for 2 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.35g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 93.5%, and the HPLC purity is 99.93%.

Example 6:

(1) 10.0g of pyrazolo-pyridone compound is added to a 70g N-methylpyrrolidone solution and heated to 70 ℃ to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 30 ℃, adding 180g of mixed solvent (140 g of acetone+40 g of purified water), and stirring for 5h at a constant temperature;

(3) Cooling the solution in the step (2) to-15 ℃, stirring and crystallizing for 4 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.26g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 92.6%, and the HPLC purity is 99.92%.

Example 7:

(1) 10.0g of pyrazolo-pyridone compound is added to a 250g N-methylpyrrolidone solution and heated to 90℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 20 ℃, adding 180g of mixed solvent (90 g of benzyl alcohol and 90g of dichloromethane), and stirring for 8 hours at a constant temperature;

(3) Cooling the solution in the step (2) to-5 ℃, stirring and crystallizing for 5 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.14g pyrazolo-pyridone compound crystal form D compound with the yield of 91.4% and the HPLC purity of 99.91%.

Example 8:

(1) 10.0g of pyrazolo-pyridone compound is added to 80g N-methylpyrrolidone solution and heated to 130 ℃ to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 60 ℃, adding 860g of mixed solvent (800 g of ethylene glycol plus 60g of purified water), and stirring for 1h at a constant temperature;

(3) Cooling the solution in the step (2) to 10 ℃, stirring and crystallizing for 0.5h, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.04g pyrazolo-pyridone compound crystal form D compound with a yield of 90.40% and an HPLC purity of 99.90%.

Example 9:

(1) 10.0g of pyrazolo-pyridone compound is added to a 100g N-methylpyrrolidone solution and heated to 130℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 50 ℃, adding 420g of mixed solvent (300 g of propylene glycol plus 120g of purified water), and stirring for 3h at a constant temperature;

(3) Cooling the solution in the step (2) to-10 ℃, stirring and crystallizing for 0.5h, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 8.9g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 89.0%, and the HPLC purity is 99.89%.

Example 10:

(1) 10.0g of pyrazolo-pyridone compound is added to 40g N-methylpyrrolidone solution and heated to 130 ℃ to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 70 ℃, adding 500g of mixed solvent (400 g of tetrahydrofuran+100 g of purified water), and stirring for 2h at a constant temperature;

(3) Cooling the solution in the step (2) to 5 ℃, stirring and crystallizing for 1.5 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 9.06g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 90.6%, and the HPLC purity is 99.90%.

Example 11:

(1) 10.0g of pyrazolo-pyridone compound is added to a 250g N-methylpyrrolidone solution and heated to 110℃to dissolve it completely;

(2) Slowly cooling the solution in the step (1) to 70 ℃, adding 350g of mixed solvent (200 g of formamide+150 g of purified water), and stirring for 2h at a constant temperature;

(3) Cooling the solution in the step (2) to 5 ℃, stirring and crystallizing for 1.5 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 8.91g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 89.1%, and the HPLC purity is 99.85%.

Example 12:

(2) Slowly cooling the solution in the step (1) to 70 ℃, adding 300g of mixed solvent (100 g of tetrahydrofuran+200 g of purified water), and stirring for 2h at a constant temperature;

(3) Cooling the solution in the step (2) to 10 ℃, stirring and crystallizing for 1.5 hours, filtering, collecting precipitated crystals, and vacuum drying at 55 ℃ to obtain 8.93g pyrazolo-pyridone compound crystal form D compound, wherein the yield is 89.3%, and the HPLC purity is 99.87%.

Comparative example 1:

at room temperature, adding 10g of apixaban and 50g of N, N-dimethylformamide, stirring, heating to 80-90 ℃ for dissolution and clarification, adding 1% active carbon for decoloration for 30 minutes, and carrying out hot filtration to obtain a clarified solution; and (3) dropwise adding 20g of isopropanol into the apixaban clarified solution at 80 ℃ at the temperature of 30 revolutions per minute, stirring and growing the crystal for 20 minutes, continuously dropwise adding 80g of isopropanol at the temperature of 90 minutes, stirring for 1 hour, naturally cooling to room temperature, filtering, washing the solid with 10g of isopropanol, and vacuum drying the solid at 70 ℃ to obtain apixaban white glossy solid with the yield of 80.1% and the HPLC purity of 90.0%.

Comparative example 2:

apixaban 3.5g is taken in a round bottom flask with proper volume, 1000ml of acetonitrile is added, stirred and dissolved at reflux temperature,

filtering to remove impurities, and freeze-drying the filtrate at-80deg.C to obtain 3.0g apixaban crystal I with yield of 85.7% and HPLC purity of 97.2%.

Comparative example 3:

2g of apixaban is taken in a round-bottom flask with proper volume, 500ml of acetonitrile is added, stirring and dissolution are carried out at reflux temperature, impurities are removed by filtration, the solvent is rapidly removed from the filtrate by a rotary evaporator, and the filtrate is dried at room temperature, thus obtaining 1.72g of apixaban crystal II, the yield is 86.2%, and the HPLC purity is 97.7%.

Comparative example 4:

into a 500ml reaction flask, apixaban (2 g) in non-B crystal form was put, tetrahydrofuran (350 ml) was added, and the mixture was stirred and heated to a solid state

Dissolving the whole body, cooling to below 40deg.C, adding apixaban B crystal form seed crystal, slowly cooling to room temperature, adding 100ml water,

cooling to 0 ℃ for crystallization, suction filtration and drying to obtain 1.63g apixaban B crystal form product with the yield of 81.5% and the HPLC purity: 95.6%.

Comparative example 5:

5.0g of apixaban crude product is added into a mixed solvent of 50ml of acetonitrile and 50ml of ethanol, heated to be dissolved, cooled to 0-5 ℃ for crystallization for 2 hours, filtered by suction, dried in vacuum at 50 ℃ to obtain 4.0g of apixaban in white gamma crystal form, the yield is about 80.1%, and the purity of HLPC is 97.4%.

Comparative example 6:

adding 1.00g of apixaban crude product into a reaction bottle, adding 8.0ml of 1, 3-propanediol, stirring and heating to 120 ℃, continuously heating and stirring for 0.5h after complete dissolution, stopping heating, naturally cooling and precipitating crystals. When the temperature in the reaction bottle is 55 ℃, 10ml of water is added, stirring is continued, when the temperature is reduced to room temperature, the ice water bath is cooled to 10 ℃, and stirring crystallization is carried out for 2 hours. Suction filtration, water washing (3X 5 ml), vacuum drying at 65 ℃ for 30 hours, obtaining 0.86g of the crystal form product of the apigenin Sha Ban, the yield is 86.0%, and the HPLC purity is 96.8%.

Comparative example 7:

17g of apixaban crude product is added into a three-neck flask filled with 120ml of ethyl acetate, the mixture is heated to 70 ℃, stirred for 2 hours, the suspension is cooled to 40 ℃, and then sheared for 10 minutes by a high-speed shearing machine at a rotating speed of 10000 revolutions per minute. Filtration and vacuum drying of the resulting filter cake at 50 ℃ for 3 hours gave 12.3g of white apixaban form I in 72.4% yield. HPLC purity: 95.1%.

Comparative example 8:

adding 130ml of 6% acetic acid methanol solution into 4.35g of apixaban crude product with purity of 98.2%,

heating to reflux and dissolve, stirring and naturally cooling to 0-5 ℃ for crystallization, filtering, and vacuum drying to obtain 3.4g of white apixaban crystals. Crystallization yield: 78.1%, HPLC purity: 98.8%.

Comparative example 9:

adding apixaban into glacial acetic acid under the environment with humidity of more than 75%, and heating to dissolve or stirring to suspend; slowly cooling to room temperature, and separating out solid; filtering, washing, vacuum drying at 40 ℃, and vacuum drying until the difference between the two times of weighing (about 1 hour interval) is less than 0.5% and the constant weight is obtained, thus obtaining the product apixaban monohydrate, the yield is 81.6%, and the HPLC purity is as follows: 93.7%.

Comparative example 10:

apixaban (0.5 g) was added to acetic acid (2 ml), heated to 80 ℃, and stirred to form a solution. Ethyl acetate (10 ml) was slowly added to the solution, and after a large amount of solids had precipitated, the temperature was slowly lowered to 30℃and stirred for 3 hours. The solid collected was filtered and dried in vacuo at 80℃to give apixaban (0.35 g) in 70% yield and 97.8% HPLC purity.

Solubility experiment

Specific solubility tests refer to the chinese pharmacopoeia 2015. The apixaban excess of examples 1 to 12 and comparative examples 1 to 10 was precisely weighed, placed in a small penicillin bottle, respectively, water, 0.1mol/L hydrochloric acid, phosphate buffer solution of pH6.8 was added to prepare apixaban saturated solution, shaking and dissolving, filtration, and absorbance was measured at a wavelength of 280nm to calculate the solubility according to ultraviolet-visible spectrophotometry (general rule 0401), and the results are shown in Table 2.

TABLE 2 solubility of different apixaban crystal forms in different media

Through experiments, all apixaban forms D prepared by the scheme of the application have similar solubility effects. As can be seen from Table 2, the solubility of apixaban prepared by the scheme of the application in solutions with different pH values is higher than that of the crystal forms of comparative examples 1 to 10, and the apixaban crystal form prepared by the scheme of the application has higher solubility than the existing crystal forms.

Dissolution test

Using the apixaban crystals prepared in examples 1 to 12 and comparative examples 1 to 10, respectively, 1000 apixaban (specification: 5 mg/tablet) tablets were prepared in accordance with the formulation ratio of Table 3 by a dry granulation method, respectively.

Table 3 formulation of the pharmaceutical formulations containing apixaban crystalline form

Referring to the FDA dissolution test method and sampling time, dissolution test was performed at 37℃in 0.1mol/L hydrochloric acid dissolution medium using the USP apparatus 2 (paddle) method at a rotation speed of 75 rpm. Samples were removed 10, 20, 30, 45 and 60 minutes after the start of the test and analyzed by HPLC at wavelength 280nm for apixaban. The results are shown in Table 4.

TABLE 4 dissolution of tablets prepared from different apixaban crystal forms in 0.1mol/L hydrochloric acid

Through experiments, all the tablets prepared by the apixaban crystal form D prepared by the scheme have similar dissolution effect. As can be seen from Table 4, the tablet prepared from the apixaban crystal form prepared by the technique of the present application has a higher dissolution rate in a 0.1mol/L hydrochloric acid solution than the tablet prepared from the existing apixaban crystal form.

Claims

1. Form D of apixaban, characterized in that said compound crystallization uses Cu-ka radiation, having an X-ray diffraction pattern expressed in 2Θ with characteristic peaks at 5.8±0.2°,15.1±0.2°,16.2±0.2°,20.2±0.2°,21.7±0.2°,22.8±0.2°,24.6±0.2°,25.2±0.2°.

2. Form D according to claim 1, wherein the compound crystals use Cu-ka radiation and the X-ray diffraction pattern expressed in 2Θ has a characteristic peak at 5.8±0.2°,7.1±0.2°,7.4±0.2°,11.6±0.2°,12.8±0.2°,15.1±0.2°,16.2±0.2°,18.5±0.2°,20.2±0.2°,21.7±0.2°,22.8±0.2°,23.5±0.2°,24.6±0.2°,25.2±0.2°.

3. Form D according to claim 2, wherein the compound crystals use Cu-ka radiation and have characteristic peaks at 5.8±0.2°,7.1±0.2°,7.4±0.2°,11.6±0.2°,12.8±0.2°,15.1±0.2°,16.2±0.2°,16.8±0.2°,17.6±0.2°,17.9±0.2°,18.5±0.2°,20.2±0.2°,20.5±0.2°,21.7±0.2°,22.2±0.2°,22.8±0.2°,23.5±0.2°,24.4±0.2°,24.6±0.2°,25.2±0.2°,26.1±0.2°,31.3±0.2°.

4. Form D according to claim 1, wherein the compound is crystallized using Cu-ka radiation, the X-ray diffraction pattern of which in terms of 2Θ has the characteristic peaks shown in table 1.

5. Form D of claim 1, characterized by its differential scanning calorimetric assay detection occurring at 176±2℃

Exothermic peaks, and endothermic peaks appear at 239±2 ℃.

6. A process for the preparation of form D according to any one of claims 1 to 5, characterized in that the specific preparation steps comprise:

(1) Adding apixaban into N-methyl pyrrolidone solution, and heating to dissolve completely;

(3) And (3) cooling and crystallizing the solution in the step (2), filtering and drying to obtain the apixaban crystal form D.

7. The process for preparing form D according to claim 6, wherein pyrazolo-pyridone compound in step (1)

The mass ratio of the compound to N-methylpyrrolidone is 1:5 to 20.

8. The process for preparing form D according to claim 6, wherein the amount of the organic solvent a used in step (2) is 2.5 to 45 times the mass of the pyrazolo-pyridone compound; the mass ratio of apixaban to water in the step (2) is 1:0.1-5; the temperature of the cooling in the step (2) is 30-45 ℃; the temperature of the cooling crystallization in the step (3) is-15-10 ℃.

9. The process for preparing form D according to claim 6, wherein the organic solvent a in step (2) is selected from one or more of ethylene glycol, propylene glycol, benzyl alcohol, isopropyl ether, ethylene glycol dimethyl ether, acetone, formamide, acetonitrile, tetrahydrofuran, methylene chloride, and acetic acid.

10. The process for preparing form D according to claim 6, wherein the organic solvent a in step (2) is one or more selected from benzyl alcohol, isopropyl ether, ethylene glycol dimethyl ether, acetone, acetonitrile, and methylene chloride.

11. The process for preparing form D according to claim 6, wherein the organic solvent a in step (2) is one or more selected from benzyl alcohol, isopropyl ether, acetone, ethylene glycol dimethyl ether, acetonitrile.

12. A pharmaceutical composition comprising apixaban form D of any one of claims 1 to 5, and comprising other pharmaceutically acceptable adjuvant components.