CN107033163A - A kind of Yi Dushaban is to benzene methanesulfonic acid salt novel crystal forms and its preparation method and application - Google Patents

Abstract

The invention discloses a new crystal form of edoxaban p-benzene mesylate and its preparation method and application. There are characteristic peaks at 2θ=3.0±0.2° and 4.0±0.2°, the preparation method of this new crystal form is as follows: (1) Edoxaban p-benzene mesylate crystal form I is added to a mixed solvent containing alcohol and ester , to obtain mixture A, control the mol ratio of water in mixture A to edoxaban p-benzene mesylate to be (1-5):1; (2) be heated to the dissolution of edoxaban p-benzene mesylate ; (3) Filtration, cooling the resulting filtrate to 10-25 ° C, while stirring and crystallizing during the cooling process; (4) Filtration, that is. The new crystal form of the invention has high purity, high solubility, good stability and simple preparation process, and can be applied to the preparation and large-scale production of crystal form drugs.

Description

A new crystal form of edoxaban p-benzene mesylate and its preparation method and application

technical field

The invention relates to the field of pharmacy, in particular to a new crystal form of edoxaban p-benzene mesylate and its preparation method and application.

Background technique

Edoxaban is a small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., which is a factor X (FXa) blocker. During the coagulation process, activated coagulation factor X (FXa) activates prothrombin (FII) into thrombin (FIIa), which promotes the formation of fibrin, thereby forming a thrombus. Therefore, FXa has become the main target for the development of a new generation of anticoagulant drugs, through the selective, reversible and direct inhibition of FXa to achieve the purpose of inhibiting thrombus formation. Clinical development has verified that Edoxaban has good tolerance, oral absorption and anticoagulant activity, and clinical trials in Japan and Taiwan have confirmed that it inhibits venous thrombosis (VTE) in patients undergoing lower limb orthopedic surgery effectiveness and safety.

Edoxaban p-benzene mesylate chemical name: N–(5–chloro–2–pyridyl)–N’–[(1S,2R,4S)–4–(dimethylamino)formyl] –2–[[4,5,6,7–tetrahydro–5–methylthiazolo[5,4–C]–pyr–2–yl]formyl]amino)cyclohexyl]oxalamide p-phenylene mesylate. Its structural formula is as follows:

Patent documents JP2010254615, US2013035356A1 and WO2011115066A1 in the prior art have disclosed edoxaban p-benzene mesylate hydrate crystal form I and crystal form II. For polymorphic drugs, different crystal forms can have different physical and chemical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, which directly affect the quality stability of raw materials and preparations and its efficacy. The existing edoxaban has a low solubility in the crystalline form of benzene mesylate hydrate, and cannot achieve a good curative effect yet. Therefore, the development of a new crystal form of edoxaban p-benzene mesylate hydrate with high solubility and good stability is of great value for improving the clinical efficacy of the drug.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the defects that the existing edoxaban p-benzene mesylate crystal form has low solubility, is not conducive to drug absorption, and cannot achieve curative effect well, and provides a kind of edoxaban A new crystal form of p-benzenemethanesulfonate and its preparation method and application. In the present invention, the new crystal form of edoxaban p-benzene mesylate is named as Edoxaban p-benzene mesylate crystal form III, the product of crystal form III has high purity, high solubility and excellent physical and chemical properties. Good stability. The preparation method of the invention can effectively improve the product quality of the edoxaban p-benzene mesylate crystal form III, has a simple preparation process, and can be applied to the preparation and large-scale production of crystal-form drugs.

The present invention provides a crystalline form III of edoxaban p-benzene mesylate. In the powder X-ray diffraction spectrum (XRD) using a radiation source of Cu-Kα, the crystalline form III has a diffraction angle of 2θ=3.0 There are characteristic peaks at ±0.2° and 4.0±0.2°.

Preferably, in the X-ray powder diffraction pattern of the edoxaban p-benzene mesylate salt crystal form III using Cu-Kα as the radiation source, at diffraction angles 2θ=3.0±0.2°, 4.0±0.2° , 5.4±0.2°, 6.6±0.2°, 9.0±0.2°, 23.0±0.2° and 24.6±0.2° have characteristic peaks.

More preferably, the edoxaban p-benzene mesylate crystal form III has 2θ, and relative peak intensity data:

Table 1

Optimally, the X-ray powder diffraction pattern of the edoxaban p-toluene mesylate salt form III using a radiation source of Cu-Kα is shown in FIG. 1 .

Preferably, the infrared absorption spectra of the edoxaban p-benzene mesylate crystalline form III measured by KBr pellets are at 1571.70±2cm ^-1 , 1401.62±2cm ^-1 , 1190.24±2cm -1 , 817.71±2cm -1 , 817.71±2cm ^-1 There are absorption peaks at 2cm ^-1 and 633.56±2cm ^-1 .

More preferably, the infrared absorption spectra of the edoxaban p-benzene mesylate crystal form III measured by KBr pellets are at 3455.15±2cm ^-1 , 3028.44±2cm ^-1 , 2941.15±2cm -1 , 2709.04±2cm -1 , 2709.04±2cm ^-1 2cm ^-1 , 1675.97±2cm ^-1 , 1618.49±2cm ^-1 , 1571.70±2cm ^-1 , 1502.12±2cm ^{-1 , 1460.60±2cm -1} , 1401.62±2cm ^-1 , 1377.41±2cm ^-1 , 1296.20±2cm ^-1 , ^1296.20 ±2cm -1 ¹ , 1216.84±2cm ^-1 , 1190.24±2cm ^-1 , 1123.01±2cm ^-1 , 1035.31±2cm ^-1 , 1010.36±2cm ^-1 , 957.53±2cm ^-1 , 927.00±2cm ^-1 , 840.33±2cm ^-1 , There are absorption peaks at 817.71±2cm ^-1 , 771.61±2cm ^-1 , 685.70±2cm ^-1 , 633.56±2cm ^-1 , 569.05±2cm ^-1 , 497.72±2cm ^-1 , 428.57±2cm ^-1 .

Optimally, the infrared spectrum of the edoxaban p-benzene mesylate salt form III measured by KBr pellets is shown in FIG. 2 .

Preferably, the differential scanning calorimetry (DSC) spectrum of the edoxaban p-benzene mesylate salt crystal form III has endothermic peaks in the ranges of 270-273°C and 199-203°C. Among them, the endothermic peak in the range of 270-273°C is a large endothermic peak, and the endothermic peak in the range of 199-203°C is a small endothermic peak.

More preferably, the DSC spectrum of the edoxaban p-benzene mesylate salt crystal form III is shown in FIG. 3 .

Preferably, the thermogravimetric analysis (TGA) spectrum of the edoxaban p-benzene mesylate salt crystal form III is shown in FIG. 4 .

The present invention also provides a preparation method of the edoxaban p-benzene mesylate crystal form III, the preparation method comprising the following steps:

(1) Edoxaban p-benzene mesylate crystal form I is added to the mixed solvent containing alcohol and ester to obtain mixture A, and the molar ratio of water in mixture A to edoxaban p-benzene mesylate is controlled For (1-5): 1;

(2) heating the mixture A until the edoxaban p-benzene mesylate is dissolved to obtain the mixed solution B;

(3) cooling the mixed solution B to 10-25°C, while stirring and crystallizing during the cooling process;

(4) Filtration, the obtained solid is the crystalline form III of edoxaban p-benzene mesylate.

In step (1), the edoxaban p-benzene mesylate salt crystal form I is the edoxaban p-benzene mesylate salt crystal form I conventionally used in the art, preferably according to the examples in the patent document US2013035356A1 2, prepared by recrystallization using a solvent system of ethanol and water.

In step (1), the alcohol is an alcohol routinely used in the art, including chemically pure and analytically pure alcohols. The alcohol is preferably one or more of C1-C4 alcohols, more preferably one or more of methanol, ethanol, isopropanol and n-butanol.

In step (1), the esters are conventionally used in the art, including chemically pure and analytically pure esters. The ester is preferably one or more of C3-C6 esters, more preferably one or more of methyl acetate, ethyl acetate and butyl acetate.

In step (1), the mixed solvent containing alcohol and ester is preferably a mixed solvent containing methanol and ethyl acetate. Preferably, the ratio of the weight of the edoxaban p-benzene mesylate to the volume sum of the methanol and the ethyl acetate is 1: (10-50) g/mL, more preferably 1 : (20-30) g/mL; Wherein, the volume ratio (v/v) of described methyl alcohol and described ethyl acetate is preferably 1:(0.1-20), is more preferably 1:(0.5- 5).

In step (1), the water in the mixture A can come from the trace moisture contained in the edoxaban p-benzene mesylate, the moisture contained in the used alcohol and ester solvent, such as the chemical used Pure or analytically pure alcohols and esters contain traces of moisture and said edoxaban p-benzene mesylate, alcohols and esters contain moisture introduced from the environment, such as moisture introduced from the air. If the total water content in the mixture A cannot meet the requirements of the above molar ratio, if it is too little or too much, it is necessary to adjust the moisture to the allowable range by adding water or drying the material to remove moisture. The content of water in the mixture A can be detected by conventional methods in the art, such as using a moisture meter for detection.

In step (2), the heating temperature is preferably 50-60°C, more preferably 60°C. The process of the dissolution is preferably accompanied by stirring, the stirring time is preferably 30-60min, more preferably 30min; the stirring speed is preferably 120-300rpm/min, more preferably It is 170rpm/min.

In step (3), before cooling down the temperature of the mixed liquid B, it is preferable to carry out the filtering operation. The filtration is a conventional operation in the field, and the purpose of the filtration is to remove insoluble mechanical impurities in the mixed liquid B, such as iron filings and filter paper scraps.

In step (3), the cooling rate is generally 1-80°C/h, preferably 4-10°C/h, more preferably 6°C/h.

In step (3), the crystallization time is generally 1-18 hours, preferably 1-10 hours, more preferably 4 hours.

In step (3), the stirring is very important for the precipitation of edoxaban p-benzene mesylate crystal form III, if no stirring is carried out, the crystal form of crystal form III will change.

In step (4), the solid obtained after the filtration is preferably subjected to drying treatment, and the drying treatment is preferably vacuum drying treatment at 40°C.

The present invention also provides the application of the above edoxaban p-benzene mesylate crystal form III.

The present invention provides the application of the edoxaban p-benzene mesylate crystal form III in the preparation of coagulation factor X (FXa) blocker.

The present invention also provides the application of the edoxaban p-benzene mesylate crystal form III in the preparation of a drug for preventing or treating thrombosis.

On the basis of conforming to common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progress effect of the present invention is:

The inventors of the present invention have discovered Edoxaban p-benzene mesylate crystal form III through a lot of research, which has successfully improved the deficiencies in the prior art, especially the deficiencies in solubility, and Edoxaban of the present invention The p-benzenemethanesulfonate crystal form III has high purity, high solubility, excellent physical and chemical properties, and good stability. The preparation method of the present invention has simple process, and the preparation method of the present invention can effectively improve the quality of the crystal form, and can be applied to the preparation and large-scale production of medicines.

Description of drawings

Fig. 1 is the powder X-ray diffraction spectrum of edoxaban p-benzene mesylate crystal form III obtained in Example 1.

Fig. 2 is the infrared absorption spectrum of edoxaban p-benzene mesylate crystal form III obtained in Example 1.

Fig. 3 is the DSC spectrum of edoxaban p-benzene mesylate crystal form III obtained in Example 1.

Fig. 4 is the TGA spectrum of the crystalline form III of edoxaban p-benzene mesylate obtained in Example 1.

Fig. 5 is a powder X-ray diffraction pattern of edoxaban p-benzene mesylate salt crystal form I.

Fig. 6 is a powder X-ray diffraction pattern of edoxaban p-benzene mesylate salt crystal form II.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

The crystalline form I of edoxaban p-benzene mesylate used in the following examples was prepared according to the method in Example 2 in the patent document US2013035356A1, that is, it was prepared by recrystallization using a solvent system of ethanol and water.

In the following examples, the instrument and test conditions used for powder X-ray diffraction analysis are as follows: the X-diffraction instrument model is Rigaku D/Max-2200, and the radiation source is Cu-Kα; the scanning speed of the test is 4 °/min, The scan step width is 0.01°.

The instruments and test conditions used for infrared analysis are as follows: the infrared spectrophotometer model is BRWKER VECTOR 22; the test samples are prepared by KBr pellets; the scan range of the test is 400-4000cm ^-1 .

The instruments and test conditions used for DSC analysis are as follows: the model of the DSC detector is NETZSCHDSC200F3Maia; the heating rate of the test is 10°C/min, and the temperature range is 30-300°C.

The instruments and test conditions used for TGA analysis are as follows: the TGA instrument model is PerkinElMerTGA400; the heating rate of the test is 10°C/min, and the temperature range is 30-300°C.

The test conditions of HPLC analysis are as follows: the chromatographic column is Merok STAR RP-18endcapped 250×4.6mm, 5μl; mobile phase A is 0.1% perfluorobutane sulfonic acid: acetonitrile (volume ratio 75:25), mobile phase B is acetonitrile: 0.1% perfluorobutane sulfonic acid (volume ratio 70:30); the detection wavelength is 290nm; the flow rate is 1.0mL/min; the injection volume is 10μl; the column temperature is 30°C; the liquid phase conditions are shown in Table 2 below.

Table 2 liquid phase conditions

time t(min) Mobile phase A(%) Mobile phase B(%) 0 100 0 18 67 33 twenty three 0 100 30 0 100 30.1 100 0 40 100 0

Example 1

A crystalline form III of edoxaban p-benzene mesylate, the preparation method of which is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 20 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=3:2, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the mol ratio of the water in mixture A and edoxaban p-benzene mesylate is 1.5:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain a filtrate, and cool the filtrate to 25° C. at a rate of 6° C./h, while stirring and crystallizing for 4 hours during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.41 g of crystals with an HPLC purity of 99.6%.

The powder X-ray diffraction spectrum, infrared absorption spectrum, DSC spectrum and TGA spectrum of the crystal are shown in Figures 1 to 4, respectively.

As can be seen from Figure 1, Edoxaban p-benzene mesylate crystal form III has characteristic peaks at diffraction angles 2θ=3.0°, 4.0°, 5.4°, 6.6°, 9.0°, 23.0° and 24.6°, which With 2θ as shown in Table 3 below, and relative peak intensity data:

table 3

At the same time, the present invention also characterizes the powder X-ray diffraction patterns of edoxaban p-benzene mesylate salt crystal form I and crystal form II, as shown in Figure 5 and Figure 6 for details. As can be seen from Fig. 5 and Fig. 6, neither edoxaban p-benzene mesylate crystal form I nor crystal form II have characteristic peaks around 2θ=3.0° and 4.0°, thus it can be known that the basis of the present invention The XRD peak position of doxaban p-benzene mesylate salt crystal form III is obviously different from crystal form I and crystal form II, and it is obviously different from the existing crystal structure of crystal form I and crystal form II.

It can be seen from Figure 2 that the crystalline form III of edoxaban p-benzene mesylate is at 3455.15±2cm ^-1 , 3028.44±2cm ^-1 , 2914.15±2cm ^-1 , 2709.04±2cm ^-1 , 1675.79±2cm ^-1 , 1618.49±2cm ^-1 , 1571.71±2cm ^-1 , 1502.12±2cm ^-1 , 1460.60±2cm ^-1 , 1401.62±2cm ^-1 , 1377.41±2cm ^-1 , 1296.20±2cm ^-1 , 1216.48±2cm ^-1 , 1190.24 ±2cm ^-1 , 1123.01±2cm ^-1 , 1035.31±2cm ^-1 , 1010.36±2cm ^-1 , 957.53±2cm ^-1 , 927.00±2cm ^-1 , 840.33±2cm ^-1 , 817.71±2cm ^-1 , 771.61±2cm -1 Absorption peaks appeared at ^-1 , 685.70±2cm ^-1 , 633.56±2cm ^-1 , 569.05±2cm ^-1 , 497.72±2cm ^-1 , 428.57±2cm ^-1 .

As shown in Figure 3, the crystalline form III of edoxaban p-benzene mesylate has endothermic peaks in the ranges of 270-273°C and 199-203°C. As shown in Figure 4, the weight loss of edoxaban p-benzene mesylate form III was only about 2.6% when the temperature was raised from 20°C to 260°C.

Through X-ray diffraction, infrared, DSC and TGA analysis, it was confirmed that the crystal form was edoxaban p-benzene mesylate crystal form III.

Example 2

A crystalline form III of edoxaban p-benzene mesylate, the preparation method of which is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 20 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=3:2, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the molar ratio of the water in mixture A and edoxaban p-benzene mesylate is 3:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain a filtrate, and cool the filtrate to 25° C. at a rate of 6° C./h, while stirring and crystallizing for 4 hours during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.45 g of crystals, with an HPLC purity of 99.5%.

The crystal was analyzed by powder X-ray diffraction, infrared, DSC and TGA, and confirmed to be edoxaban p-benzene mesylate crystal form III.

Example 3

A crystalline form III of edoxaban p-benzene mesylate, the preparation method of which is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 20 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=3:2, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the molar ratio of the water in mixture A and edoxaban p-benzene mesylate is 5:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain a filtrate, and cool the filtrate to 25° C. at a rate of 6° C./h, while stirring and crystallizing for 4 hours during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.51 g of crystals with an HPLC purity of 99.7%.

The crystal was analyzed by powder X-ray diffraction, infrared, DSC and TGA, and confirmed to be edoxaban p-benzene mesylate crystal form III.

Example 4

A crystalline form III of edoxaban p-benzene mesylate, the preparation method of which is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity >99%) into 30 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=1:5, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the molar ratio of the water in mixture A and edoxaban p-benzene mesylate is 3:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain the filtrate, cool the filtrate to 10°C at a rate of 6°C/h, and stir and crystallize for 4h during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.32 g of crystals with an HPLC purity of 99.6%.

The crystal was analyzed by powder X-ray diffraction, infrared, DSC and TGA, and confirmed to be edoxaban p-benzene mesylate crystal form III.

Example 5

A crystalline form III of edoxaban p-benzene mesylate, the preparation method of which is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) into 25 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=1:3, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the molar ratio of the water in mixture A and edoxaban p-benzene mesylate is 1:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain the filtrate, cool the filtrate to 10°C at a rate of 6°C/h, and stir and crystallize for 4h during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.37 g of crystals, with an HPLC purity of 99.6%.

The crystal was analyzed by powder X-ray diffraction, infrared, DSC and TGA, and confirmed to be edoxaban p-benzene mesylate crystal form III.

Comparative example 1

The preparation method of this comparative example is as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 10 mL of methanol solvent (methanol content used>99.5%) to obtain mixture A, wherein the water in mixture A The mol ratio with edoxaban p-benzene mesylate is 1.5:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain the filtrate, cool the filtrate to 10°C at a rate of 6°C/h, and stir and crystallize for 4h during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.71 g of crystals with an HPLC purity of 99.6%.

The crystal was confirmed by powder X-ray diffraction to still be crystalline form I of edoxaban p-benzene mesylate.

Comparative example 2

The crystallization mode of this comparative example adopts elution crystallization, and concrete steps are as follows:

(1) Add 1g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 12mL of methanol (used methanol content>99.5%) to obtain mixture A, wherein the water in mixture A and edoxaban The mol ratio of doxaban to benzene mesylate is 1.5:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate was dissolved to obtain a mixed solution B, wherein the stirring rate was 170rpm/min;

(3) Filtrate the mixed solution B to obtain the filtrate, add 8ml of ethyl acetate dropwise to the filtrate (the content of ethyl acetate used>99.5%), the dropwise addition time is 30min, then cool down to 25°C at a rate of 6°C/h, At the same time, stirring and crystallizing for 4 hours in the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.39 g of crystals with an HPLC purity of 99.6%.

It was found that no new crystal form was detected by powder X-ray diffraction detection.

Comparative example 3

The crystallization method of this comparative example adopts evaporation crystallization, and concrete steps are as follows:

(1) Add 1 g of edoxaban p-benzene mesylate crystal form I (HPLC purity>99%) to 20 mL of a mixed solvent of methanol and ethyl acetate (volume ratio methanol:ethyl acetate=3:2, used Methanol content>99.5%, ethyl acetate content>99.5%), obtain mixture A, wherein the mol ratio of the water in mixture A and edoxaban p-benzene mesylate is 1.5:1;

(2) Heating to 60°C and stirring for 30 minutes until the edoxaban p-benzene mesylate is dissolved to obtain the mixed solution B;

(3) Filtrate the mixed solution B to obtain the filtrate, and concentrate the filtrate to 10ml at 40°C and -0.1MPa, and the concentration time is 5min;

(4) Cool the concentrated solution to 25°C at a rate of 6°C/h, while stirring and crystallizing for 4h during the cooling process;

(4) Filtration, and the resulting solid was vacuum-dried at 40° C. to obtain 0.51 g of crystals with an HPLC purity of 99.7%.

It was found that no new crystal form was detected by powder X-ray diffraction detection.

Effect Example

The solubility of the edoxaban p-benzene mesylate salt crystal form III prepared in Example 1 of the present invention in different solvents was tested at 25°C, and the edoxaban p-benzene mesylate salt crystal form I was selected as the For the control group, the test results are shown in Table 4 below. It can be seen from Table 4 that the solubility of edoxaban p-benzene mesylate crystal form III in methanol and N,N-dimethylformamide of the present invention is significantly higher than that of crystal form I. The dissolution effect of the crystal form III in Example 2-5 is the same as that in Example 1.

Table 4

Form I Form III Methanol 1g/45mL 1g/24mL N,N-Dimethylformamide 1g/28mL 1g/14mL water Slightly soluble Slightly soluble ethanol Slightly soluble Slightly soluble acetone Slightly soluble Slightly soluble Acetonitrile Slightly soluble Slightly soluble

Claims (10)

1. A kind of edoxaban p-benzene mesylate crystal form III, it is characterized in that, described edoxaban p-benzene mesylate crystal form III uses the powder X-ray that radiation source is Cu-Kα In the diffraction spectrum, there are characteristic peaks at diffraction angles 2θ=3.0±0.2° and 4.0±0.2°. 2. Edoxaban p-benzene mesylate crystal form III as claimed in claim 1, is characterized in that, said edoxaban p-benzene mesylate crystal form III is Cu-Kα when using radiation source In the X-ray powder diffraction diagram, there are diffraction angles 2θ=3.0±0.2°, 4.0±0.2°, 5.4±0.2°, 6.6±0.2°, 9.0±0.2°, 23.0±0.2° and 24.6±0.2° Characteristic peaks; Preferably, the edoxaban p-benzene mesylate crystal form III has the following 2θ, and relative peak intensity data: 3. The edoxaban p-benzene mesylate crystal form III as claimed in claim 1, wherein the edoxaban p-benzene mesylate crystal form III uses a radiation source of Cu-Kα The X-ray powder diffraction pattern is shown in FIG. 1 . 4. edoxaban p-benzene mesylate crystal form III as claimed in claim 1, is characterized in that, described edoxaban p-benzene mesylate crystal form III is measured with KBr tablet. The absorption spectrum has absorption peaks at 1571.70±2cm ^-1 , 1401.62±2cm ^-1 , 1190.24±2cm ^-1 , 817.71±2cm ^-1 and 633.56±2cm ^-1 ; Preferably, the infrared absorption spectra of the edoxaban p-benzene mesylate crystal form III measured by KBr pellets are at 3455.15±2cm ^-1 , 3028.44±2cm ^-1 , 2941.15±2cm -1 , 2709.04±2cm -1 , 2709.04±2cm ^-1 2cm ^-1 , 1675.97±2cm ^-1 , 1618.49±2cm ^-1 , 1571.70±2cm ^-1 , 1502.12±2cm ^{-1 , 1460.60±2cm -1} , 1401.62±2cm ^-1 , 1377.41±2cm ^-1 , 1296.20±2cm ^-1 , ^1296.20 ±2cm -1 ¹ , 1216.84±2cm ^-1 , 1190.24±2cm ^-1 , 1123.01±2cm ^-1 , 1035.31±2cm ^-1 , 1010.36±2cm ^-1 , 957.53±2cm ^-1 , 927.00±2cm ^-1 , 840.33±2cm ^-1 , There are absorption peaks at 817.71±2cm ^-1 , 771.61±2cm ^-1 , 685.70±2cm ^-1 , 633.56±2cm ^-1 , 569.05±2cm ^-1 , 497.72±2cm ^-1 , 428.57±2cm ^-1 ; More preferably, the infrared spectrum of the edoxaban p-benzene mesylate salt form III measured by KBr pellets is shown in FIG. 2 . 5. Edoxaban p-benzene mesylate crystal form III as claimed in claim 1, is characterized in that, the differential scanning calorimetry spectrum of described edoxaban p-benzene mesylate crystal form III is in There are endothermic peaks in the range of 270-273°C and 199-203°C; preferably, the differential scanning calorimetry spectrum of the edoxaban p-benzene mesylate crystal form III is shown in Figure 3; And/or, the thermogravimetric analysis spectrum of the edoxaban p-benzene mesylate crystal form III is shown in FIG. 4 . 6. A method for preparing edoxaban p-benzene mesylate crystal form III as described in any one of claims 1 to 5, wherein the preparation method comprises the following steps: (1) Edoxaban p-benzene mesylate crystal form I is added to the mixed solvent containing alcohol and ester to obtain mixture A, and the molar ratio of water in mixture A to edoxaban p-benzene mesylate is controlled For (1-5): 1; (2) heating the mixture A until the edoxaban p-benzene mesylate is dissolved to obtain the mixed solution B; (3) cooling the mixed solution B to 10-25°C, while stirring and crystallizing during the cooling process; (4) Filtration, the obtained solid is the crystalline form III of edoxaban p-benzene mesylate. 7. The preparation method according to claim 6, wherein in step (1), the edoxaban p-benzene mesylate crystal form I is prepared by recrystallization from a mixed solvent of ethanol and water; And/or, in step (1), the alcohol is one or more of C1-C4 alcohols, preferably one or more of methanol, ethanol, isopropanol and n-butanol; And/or, in step (1), the ester is one or more of C3-C6 esters, preferably one or more of methyl acetate, ethyl acetate and butyl acetate; And/or, in step (1), the mixed solvent that contains alcohol and ester is the mixed solvent that contains methanol and ethyl acetate, preferably, the weight of described edoxaban p-benzene mesylate and described The ratio of the volume of methanol and the ethyl acetate is 1:(10-50) g/mL, more preferably 1:(20-30) g/mL; wherein, the methanol and the ethyl acetate The volume ratio of is preferably 1:(0.1-20), more preferably 1:(0.5-5). 8. The preparation method according to claim 6, characterized in that, in step (2), the heating temperature is 50-60°C, preferably 60°C; the dissolution process is preferably accompanied by There is stirring, the stirring time is 30-60min, preferably 30min; the stirring rate is 120-300rpm/min, preferably 170rpm/min; And/or, in step (3), before cooling the mixed solution B, perform a filtering operation; And/or, in step (3), the cooling rate is 1-80°C/h, preferably 4-10°C/h, more preferably 6°C/h; And/or, in step (3), the crystallization time is 1-18 hours, preferably 1-10 hours, more preferably 4 hours; And/or, in step (4), the solid obtained after the filtration is subjected to drying treatment, and the drying treatment is preferably vacuum drying treatment at 40° C. 9. The use of edoxaban p-benzene mesylate crystal form III according to any one of claims 1 to 5 in the preparation of coagulation factor X blockers. 10. A use of the edoxaban p-benzene mesylate crystal form III according to any one of claims 1 to 5 in the preparation of a drug for preventing or treating thrombosis.