CN111377915A

CN111377915A - Pyrazolo-pyridone compound crystal form D

Info

Publication number: CN111377915A
Application number: CN201811644156.8A
Authority: CN
Inventors: 翟立海; 杨丹; 董怀民; 刘建设
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2018-12-30
Filing date: 2018-12-30
Publication date: 2020-07-07
Anticipated expiration: 2038-12-30
Also published as: CN111377915B

Abstract

The invention belongs to the technical field of medicines, and particularly provides a pyrazolo-pyridone compound crystal form D which is radiated by Cu-K α, wherein an X-ray diffraction spectrogram 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.

Description

Pyrazolo-pyridone compound crystal form D

Technical Field

The invention 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, product name) with the 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 is shown in formula I. Apixaban is an oral selective factor Xa activating inhibitor developed by combining feverfew and Baishimeibap, can directly inhibit blood coagulation factor Xa, and can block the conversion of prothrombin into thrombin in the blood coagulation cascade process, and is high in Xa selectivity and strong in effect. In addition, apixaban not only inhibits free Xa and the Xa in the prothrombin complex, but also inhibits Xa in the blood clot, and does not require antithrombin iii during inhibition, unlike the effects of heparin anticoagulants such as fondaparinux sodium. Apixaban was approved for marketing in the european union in 5 months 2011 for the prevention of Venous Thromboembolic (VTE) events in adult patients undergoing elective hip or knee replacements; the FDA in us 12 months 2012 approved the drug for reducing stroke and systemic embolic risk in patients with non-valvular atrial fibrillation. The chemical structural formula is as follows:

different crystal forms of the same drug have different characteristics in the aspects of solubility, melting point, density, thermal stability, chemical reactivity, optical and mechanical properties and the like, and the characteristics can directly influence the stability, uniformity, bioavailability, curative effect and safety of the drug. Therefore, comprehensive and systematic polymorphic form screening is performed in drug development, and the most suitable crystal form is selected, which is one of important research contents.

US20060160841 first discloses the non-solvent crystal form N-1 and the dihydrate crystal form H2-2 of apixaban, and discloses specific unit cell parameters, position coordinate parameters, X-ray diffraction characteristic peak positions, SSNMR (solid nuclear magnetic resonance) displacement and other crystal characterization parameters of the crystal form N-1 and the crystal form H2-2 in patent documents WO2007001385 and CN101065379A thereof.

US20070203178 discloses crystalline form DMF-5 of N, N-dimethylformamide solvate and crystalline form FA-2 of piperazine xaban.

WO2012168364 in turn 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 inventions have low production efficiency and low product yield, and are not suitable for industrial production.

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

Disclosure of Invention

In view of the deficiencies of the prior art, the present application provides, in one aspect, a pyrazolo-pyridone compound as crystalline form D.

The pyrazolo-pyridinone compound of form D referred to herein is apixaban of form D and the pyrazolo-pyridinone compound referred to herein is apixaban.

According to a first aspect of the present invention, there is provided a crystalline form d of a pyrazolo-pyridinone compound having 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 ° in an X-ray diffraction spectrum expressed in terms of 2 θ, using Cu-K α radiation.

Preferably, the pyrazolo-pyridone compound in the form D has 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 ° and 25.2 +/-0.2 ° by using Cu-K α as an X-ray diffraction spectrum shown in 2 theta.

Preferably, the pyrazolo-pyridone compound crystal form D has characteristic peaks at 5.8 +/-0.2 degrees, 7.1 +/-0.2 degrees, 7.4 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.8 +/-0.2 degrees, 15.1 +/-0.2 degrees, 16.2 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.6 +/-0.2 degrees, 17.9 +/-0.2 degrees, 18.5 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.2 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.4 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.1 +/-0.2 degrees, 30.1 +/-0.2 degrees, 31.3 +/-0.2 degrees, 31.2 degrees by using Cu-K α radiation and an X-ray diffraction spectrum expressed by 2 theta

Preferably, the pyrazolo-pyridone compound in the form D is irradiated by Cu-K α, and the characteristic peak of the pyrazolo-pyridone compound in the form D accords with an X-ray powder diffraction pattern shown in figure 1.

Preferably, the pyrazolo-pyridone compound in the crystal form D has an exothermic peak at 176 +/-2 ℃ and an endothermic peak at 239 +/-2 ℃ by differential scanning calorimetry.

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

(1) adding the pyrazolo-pyridinone compound into the N-methylpyrrolidone solution, and heating to completely dissolve the pyrazolo-pyridinone compound;

(2) cooling the solution in the step (1), adding a mixed solution of an organic solvent A and water, and stirring while keeping the temperature;

(3) and (3) cooling the solution obtained in the step (2) for crystallization, filtering and drying to obtain the pyrazolo-pyridinone compound crystal form D.

In the preparation method, the mass ratio of the pyrazolo-pyridinone compound to the N-methylpyrrolidone in the step (1) 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-pyridinone compound.

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

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

The preparation method comprises the step (2) of cooling at the temperature of 30-45 ℃.

The preparation method comprises the step (3) of cooling and crystallizing at-15-10 ℃.

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

(2) cooling the solution in the step (1) to 30-45 ℃, adding the solution into a mixed solution of an organic solvent A and water, and stirring for 2-6 hours under heat preservation;

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

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

Preferably, the temperature for cooling and crystallizing in the step (3) is-8-6 ℃.

Further preferably, the temperature for cooling and crystallizing in the step (3) is-2 to 3 ℃.

In a third aspect, the invention provides a pharmaceutical composition comprising crystalline form D of a pyrazolo-pyridinone compound according to the invention, together with other pharmaceutically acceptable excipient components.

Preferably, the pharmaceutical composition of the present invention is prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.

Preferably, the other components include other active ingredients, excipients, fillers, etc. that may be used in combination.

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

The X-ray powder diffraction test instrument and test conditions comprise that the X-ray powder diffraction instrument comprises PANALYTICAL E, Cu-K α, a sample table is a flat plate, an incident light path is BBHD, a diffraction light path is PLXCEL, voltage is 45kv, current is 40mA, a divergence slit is 1/4, an anti-divergence slit is 1, a cable slit is 0.04rad, step length is 0.5s, and a scanning range is 3-50 degrees, and characteristic peaks in a corresponding X-ray powder diffraction diagram (Cu-K α) are shown in attached figure 1 and table 1 in detail.

Table 1 PXRD peaks for crystalline form D of pyrazolo-pyridinone compounds

The DSC thermal analysis tester and the test conditions of the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-350 ℃; heating rate:10 ℃/min; segment gas N₂(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.

The TGA/DSC test results of the crystalline forms of the pyrazolo-pyridinone compounds prepared according to the process of the invention are shown in figure 2. DSC results show that the crystal form of the pyrazolo-pyridinone compound prepared by the invention does not contain solvent and water.

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

Compared with the pyrazolo-pyridinone compound crystal form D reported at present, the pyrazolo-pyridinone compound crystal form D prepared by the method has the following advantages:

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

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

(3) The dissolution rate is high. Compared with the tablet prepared by the existing crystal form, the tablet prepared by the crystal form D of the pyrazolo-pyridinone compound has the advantages of quick dissolution of the active ingredients of the pyrazolo-pyridinone compound and high dissolution proportion.

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

Drawings

FIG. 1: an X-ray powder diffraction pattern of crystalline form D of the pyrazolo-pyridinone compound.

FIG. 2: a Differential Scanning Calorimetry (DSC) profile of crystalline form D of a pyrazolo-pyridone compound.

Detailed Description

The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and obvious changes and modifications made by those of ordinary skill in the art in light of the present invention are also encompassed within the scope of the present invention, the pyrazolo-pyridone compound being apixaban.

Example 1:

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

(2) slowly cooling the solution in the step (1) to 45 ℃, adding 110g of mixed solvent (100g of acetone and 10g of purified water), and stirring for 4 hours under heat preservation;

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

Example 2:

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

(2) slowly cooling the solution in the step (1) to 40 ℃, adding 210g of mixed solvent (180g of acetonitrile +30g of purified water), and stirring for 2 hours under heat preservation;

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

Example 3:

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

(2) slowly cooling the solution in the step (1) to 30 ℃, adding 305g of mixed solvent (300g of ethylene glycol dimethyl ether and 5g of purified water), and stirring for 6 hours under heat preservation;

(3) and (3) cooling the solution obtained in the step (2) to-2 ℃, stirring and crystallizing for 1h, filtering, collecting precipitated crystals, and drying in vacuum at 55 ℃ to obtain 9.45g of 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 a pyrazolo-pyridinone compound is added to a 150g N-methylpyrrolidone solution and heated to 120 ℃ to completely dissolve it;

(2) slowly cooling the solution in the step (1) to 45 ℃, adding 26g of mixed solvent (25g of isopropyl ether and 1g of purified water), and stirring for 5 hours under heat preservation;

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

Example 5:

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

(2) slowly cooling the solution in the step (1) to 40 ℃, adding 500g of mixed solvent (450g of benzyl alcohol and 50g of purified water), and stirring for 3 hours under heat preservation;

(3) and (3) cooling the solution obtained in the step (2) to-8 ℃, stirring for crystallization for 2h, filtering, collecting precipitated crystals, and drying in vacuum at 55 ℃ to obtain 9.35g of pyrazolo-pyridone compound crystal form D compound with the yield of 93.5% and the HPLC purity of 99.93%.

Example 6:

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

(2) slowly cooling the solution in the step (1) to 30 ℃, adding 180g of mixed solvent (140g of acetone and 40g of purified water), and stirring for 5 hours under heat preservation;

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

Example 7:

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

(2) slowly cooling the solution in the step (1) to 20 ℃, adding 180g of mixed solvent (90g of benzyl alcohol and 90g of dichloromethane), and stirring for 8 hours under heat preservation;

(3) and (3) cooling the solution obtained in the step (2) to-5 ℃, stirring and crystallizing for 5h, filtering, collecting precipitated crystals, and drying in vacuum at 55 ℃ to obtain 9.14g of 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 a pyrazolo-pyridinone compound is added to a solution of 80g N-methylpyrrolidone and heated to 130 ℃ to completely dissolve it;

(2) slowly cooling the solution in the step (1) to 60 ℃, adding 860g of mixed solvent (800g of ethylene glycol and 60g of purified water), and stirring for 1h under heat preservation;

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

Example 9:

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

(2) slowly cooling the solution in the step (1) to 50 ℃, adding 420g of mixed solvent (300g of propylene glycol and 120g of purified water), and stirring for 3 hours under heat preservation;

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

Example 10:

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

(2) slowly cooling the solution in the step (1) to 70 ℃, adding 500g of mixed solvent (400g of tetrahydrofuran and 100g of purified water), and stirring for 2 hours under heat preservation;

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

Example 11:

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

(2) slowly cooling the solution in the step (1) to 70 ℃, adding 350g of mixed solvent (200g of formamide and 150g of purified water), and stirring for 2 hours under heat preservation;

(3) and (3) cooling the solution obtained in the step (2) to 5 ℃, stirring for crystallization for 1.5h, filtering, collecting precipitated crystals, and drying in vacuum at 55 ℃ to obtain 8.91g of 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 (100g of tetrahydrofuran and 200g of purified water), and stirring for 2 hours under heat preservation;

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

Comparative example 1:

adding 10g of apixaban and 50g of N, N-dimethylformamide at room temperature, stirring, heating to 80-90 ℃, dissolving and clarifying, adding 1% of activated carbon for decolorizing for 30 minutes, and performing hot filtration to obtain a clarified solution; and (3) keeping the temperature of the obtained apixaban clear solution at 80 ℃, dropwise adding 20g of isopropanol at the rotating speed of 30 r/min, stirring for growing crystals for 20 minutes, continuously keeping the temperature, dropwise adding 80g of isopropanol, stirring for 1 hour after dropwise adding for 90 minutes, naturally cooling to room temperature, filtering, washing a solid with 10g of isopropanol, and drying the solid at 70 ℃ in vacuum to obtain an apixaban white glossy solid with the yield of 80.1% and the purity of HPLC (high performance liquid chromatography) of 90.0%.

Comparative example 2:

3.5g of apixaban is taken to be put into a round-bottom flask with proper volume, 1000ml of acetonitrile is added, stirring and dissolving are carried out at the reflux temperature,

filtering to remove impurities, and freeze-drying the filtrate in a freeze dryer at-80 ℃ to obtain 3.0g of apixaban crystal I, wherein the yield is 85.7 percent, and the HPLC purity is 97.2 percent.

Comparative example 3:

taking 2g of apixaban into a round-bottom flask with a proper volume, adding 500ml of acetonitrile, stirring and dissolving at a reflux temperature, filtering to remove impurities, quickly removing the solvent from the filtrate by using a rotary evaporator, and drying at room temperature to obtain 1.72g of apixaban crystal II, wherein the yield is 86.2 percent, and the HPLC purity is 97.7 percent.

Comparative example 4:

adding non-B crystal form apixaban (2g) into a 500ml reaction bottle, adding tetrahydrofuran (350ml), stirring and heating to solid

Dissolving the whole body, cooling to below 40 ℃, adding Apixaban B crystal form seed crystal, slowly cooling to room temperature, adding 100ml of water,

continuously cooling to 0 ℃ for crystallization, performing suction filtration and drying to obtain 1.63g of Apixaban B crystal form product, wherein the yield is 81.5 percent, and the HPLC purity is as follows: 95.6 percent.

Comparative example 5:

adding 5.0g of apixaban crude product into a mixed solvent of 50ml of acetonitrile and 50ml of ethanol, heating to dissolve, cooling to 0-5 ℃ for crystallization for 2h, performing suction filtration, and performing vacuum drying at 50 ℃ to obtain 4.0g of white gamma-crystal form apixaban, wherein 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-propylene glycol, stirring and heating to 120 ℃, continuously heating and stirring for 0.5h after complete dissolution, stopping heating, naturally cooling to separate out crystals, adding 10ml of water when the temperature in the reaction bottle is 55 ℃, continuously stirring, cooling to room temperature in an ice water bath, stirring and crystallizing for 2h, performing suction filtration, washing with water (3 × 5ml), and performing vacuum drying at 65 ℃ for 30h to obtain 0.86g of apixaban gamma crystal form product, wherein the yield is 86.0%, and the HPLC purity is 96.8%.

Comparative example 7:

adding 17g of apixaban crude product into a three-neck flask filled with 120ml of ethyl acetate, heating to 70 ℃, stirring for 2 hours, cooling the suspension to 40 ℃, and shearing the suspension for 10 minutes at the rotating speed of 10000 rpm by a high-speed shearing machine. Filtering, and vacuum drying the obtained filter cake at 50 ℃ for 3 hours to obtain 12.3g of white apixaban crystal form I with the yield of 72.4 percent. HPLC purity: 95.1 percent.

Comparative example 8:

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

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

Comparative example 9:

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

Comparative example 10:

apixaban (0.5g) was added to acetic acid (2ml), heated to 80 ℃ and stirred to form a solution. Ethyl acetate (10ml) was slowly added to the solution, and after a large amount of solid had precipitated, it was slowly cooled to 30 ℃ and stirred for 3 hours. Filtration and vacuum drying of the collected solid at 80 ℃ gave apixaban (0.35g) in 70% yield and 97.8% HPLC purity.

Solubility test

The specific solubility test is referred to the chinese pharmacopoeia 2015. The Apixaban excesses of examples 1-12 and comparative examples 1-10 were precisely weighed, placed in vials, added with water, 0.1mol/L hydrochloric acid, and a phosphate buffer solution of pH6.8, to prepare an Apixaban saturated solution, shaken to dissolve, filtered, and measured for absorbance at a wavelength of 280nm by UV-visible spectrophotometry (general rule 0401) to calculate the solubility, the results are shown in Table 2.

Table 2 solubility of different crystalline forms of apixaban in different media

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

Dissolution test

1000 Apixaban tablets (specification: 5 mg/tablet) were prepared by dry granulation using the Apixaban crystals prepared in examples 1 to 12 and comparative examples 1 to 10, respectively, according to the formulation ratio of Table 3.

TABLE 3 pharmaceutical formulation ratios containing crystalline form of apixaban

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

TABLE 4 dissolution rates of tablets prepared with different crystalline forms of apixaban in 0.1mol/L hydrochloric acid

Through experiments, all the tablets prepared from the apixaban crystal form D prepared by the scheme of the invention have similar dissolution effect. As can be seen from Table 4, the tablets prepared by the apixaban crystal form prepared by the technology of the invention have higher dissolution rate in 0.1mol/L hydrochloric acid solution compared with the tablets prepared by the existing apixaban crystal form.

Claims

1. A crystalline form D of a pyrazolo-pyridone compound having 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 ° as an X-ray diffraction pattern expressed in terms of 2 Θ, using radiation of Cu-K α.

2. Form D according to claim 1, wherein the compound crystals 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 °, 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 ° in an X-ray diffraction pattern, expressed in terms of 2 Θ, using Cu-K α radiation.

3. Form D according to claim 2, wherein the compound crystal is characterized by an X-ray diffraction pattern, expressed in 2 Θ, using Cu-K α radiation having 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 °, 30.3 ± 0.3 ± 0.2 °.

4. Form D according to claim 1, wherein the compound is crystallized using Cu-K α radiation and has characteristic peaks according to the X-ray powder diffraction pattern shown in figure 1.

5. Form D according to claim 1, characterized by an exothermic peak at 176 ± 2 ℃ and an endothermic peak at 239 ± 2 ℃ as measured by differential scanning calorimetry.

6. A preparation method of the crystal form D as claimed in any one of claims 1 to 5, characterized by comprising the following specific preparation steps:

7. A process for preparing form D according to claim 6, wherein the mass ratio of pyrazolo-pyridinone compound to N-methylpyrrolidone in step (1) is 1: 5 to 20.

8. The method for preparing the crystalline form D according to claim 6, wherein the amount of the organic solvent A used in the step (2) is 2.5 to 45 times the mass of the pyrazolo-pyridinone compound.

9. The method 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, dichloromethane, acetic acid, preferably from one or more of benzyl alcohol, isopropyl ether, ethylene glycol dimethyl ether, acetone, acetonitrile, dichloromethane, more preferably from one or more of benzyl alcohol, isopropyl ether, acetone, ethylene glycol dimethyl ether, acetonitrile.

10. A pharmaceutical composition comprising the pyrazolo-pyridinone compound of any one of claims 1 to 5 in crystalline form D, together with other pharmaceutically acceptable excipient components.