KR20200106737A - Crystal of Edoxaban benzenesulfonate monohydrate and its preparing method - Google Patents

Abstract

The present invention provides a crystal form of edoxaban benzenesulfonate monohydrate and a method for manufacturing the same. A novel crystal form benzenesulfonate monohydrate according to the present invention is easy to prepare, has high purity, and also has properties of excellent stability and hygroscopicity. The present invention provides: a crystal form of benzenesulfonate monohydrate of chemical formula 2 which is pharmaceutically acceptable and physicochemically improved, thereby being able to be usefully used as an agent for preventing and/or treating thrombosis diseases as an anticoagulant; and the method for manufacturing the same.

Description

Crystal of Edoxaban benzenesulfonate monohydrate and its preparation method {Crystal of Edoxaban benzenesulfonate monohydrate and its preparing method}

The present invention relates to a novel edoxaban benzenesulfonate monohydrate crystal form and a method for preparing the same.

Edoxaban represented by the following Formula 1, chemical name N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2- Compounds that are {[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethandiamide are activated blood clotting As a compound exhibiting an inhibitory effect on factor X (FXa), it is useful as a drug for preventing and/or treating thrombosis diseases.

[Formula 1]

In the (crystalline) form of the salt related to the edoxaban compound represented by the above formula (1), Korean Patent No. 10-1708528 discloses crystalline forms for forms 1 and 2 for edoxaban p-toluenesulfonic acid salt monohydrate. In addition, crystals are prepared by a slurry stirring method, a recrystallization method using a single solvent, a recrystallization method using an aqueous solvent, and a freeze drying-solvent vapor exposure method. In particular, the freeze drying-solvent vapor exposure method It is a method of manufacturing an amorphous form. In addition, Korean Patent No. 10-1424843 mentions edoxaban p-toluenesulfonic acid salt monohydrate and hydrochloride, but it does not describe specific crystal forms and preparation methods, but only with respect to formulations showing dissolution properties. Are doing. In addition, US Patent Registration No. US 8394821B2 refers only to the edoxaban tartaric acid crystal form.

On the other hand, the known edoxaban crystalline form is present in the form of a hydrate or hydrochloride, so that it absorbs moisture when exposed to the air, and thereby exhibits a side effect of formation of impurities. Semi-crystalline forms are unstable in the air and may be pharmaceutically dangerous due to impurities produced.

Korean Patent No. 10-1708528 Korean Patent No. 10-1424843 US Patent Registration No. 8394821

The problem to be solved by the present invention is a stable compound that is stable against moisture (hygroscopicity) and hardly generates impurities even for long-term storage, and thus a novel edoxaban benzenesulfonate monohydrate crystal form having useful forms and properties in terms of drugs To provide.

Another object of the present invention is to provide a method for producing a novel edoxaban benzenesulfonate monohydrate crystal form having a higher yield and purity than the known method for preparing edoxaban p-toluenesulfonate monohydrate.

The present invention is pharmaceutically acceptable and improved physicochemically to provide an anticoagulant that can be usefully used as a prophylactic and/or therapeutic agent for thrombosis diseases, and a method for preparing the same.

[Formula 2]

Edoxaban benzenesulfonate monohydrate crystal form according to the present invention has a 2θ diffraction angle of 5.2±0.2°, 10.4±0.2°, 12.3±0.2°, 13.4±0.2°, 13.9±0.2 in powder X-ray diffraction (XRD) analysis. °, 14.6±0.2°, 17.3±0.2°, 17.9±0.2°, 18.9±0.2°, 19.9±0.2°, 21.0±0.2°, 21.6±0.2°, 22.0±0.2°, 22.7±0.2°, 23.2±0.2 It has diffraction patterns of °, 24.3±0.2°, and 24.4±0.2°.

In addition, the preparation method of edoxaban benzenesulfonate monohydrate crystal form according to the present invention is, A) benzenesulfonic acid hydrate is dissolved in an organic solvent in a (suspension) solution of edoxaban free base, water, and an organic solvent, and then added. Thereby dissolving the entire reactant and producing crystals; B) including the step of aging the crystal obtained in step A).

More specifically, steps A) and B) are as follows.

A) dissolution of the entire reactant and formation of crystals

In the step A), the reaction mixture comprising the free base of edoxaban represented by Formula 1 and a mixed solvent of water and an organic solvent is heated to a temperature of about 50 to 60°C, and then benzenesulfonic acid is added to the reaction mixture. The hydrate is dissolved in an organic solvent and added at a temperature of 55 to 60°C. After that, the reaction mixture is cooled to room temperature and allowed to stand for 30 minutes or longer to form crystals.

The amount of the benzenesulfonic acid hydrate in step A) is 1.0 to 2.0 equivalents, preferably 1.0 to 1.1 equivalents, based on the free base of edoxaban.

As the organic solvent, acetone, acetonitrile, methanol, ethanol, isopropanol, or a mixed solvent thereof may be used, preferably methanol, ethanol, isopropanol, and more preferably ethanol.

The amount of the'mixed solvent of organic solvent and water' added to the edoxaban free base is 8 to 11 ml/g based on the amount (g) of the edoxaban free base, and the ratio of organic solvent:water in the mixed solvent (volume ratio) Is 3:1~9:1. In addition, the amount of the organic solvent that dissolves the benzenesulfonic acid hydrate is 0.15 to 0.25% by volume based on the organic solvent of the mixed solvent.

B) Crystal ripening stage

Next, in the step of B) aging the crystal, a mixed solvent of an organic solvent and water is additionally mixed with the reaction mixture containing the edoxaban benzenesulfonate monohydrate crystal obtained in step A, followed by stirring at room temperature for a certain period of time, and cooling again to After aging by stirring for a period of time, the precipitated crystals are filtered to obtain a crystalline form of edoxaban benzenesulfonate monohydrate.

The organic solvent:water ratio (volume ratio) of the mixed solvent of the above B) crystal aging step is 3:1 to 9:1, and the amount of the mixed solvent is 30 to 70 (volume)% of the amount of the mixed solvent used in step A). The predetermined time required for stirring the above room temperature and cooling is 30 minutes to 5 hours, and preferably 1 to 2 hours. The above cooling temperature is 0 to 10°C, preferably 0 to 5°C, and when the cooling temperature is 5°C or higher or the stirring time in cooling is 1 hour or less, the yield is lowered.

The edoxaban benzenesulfonate monohydrate crystalline form of the present invention is easier to prepare, has high purity, and exhibits excellent properties such as stability and hygroscopicity compared to the crystalline form of other salts. In addition, the manufacturing method of the edoxaban benzenesulfonate monohydrate crystal form of the present invention has the advantage of being able to easily prepare the edoxaban benzenesulfonate monohydrate crystalline form having the above excellent properties in high yield.

1 is an X-ray diffraction spectrum of edoxaban benzenesulfonate monohydrate crystal form according to this study.
2 is a hydrogen nuclear magnetic resonance spectrum of a crystalline form of edoxaban benzenesulfonate monohydrate according to this study.
3 is a differential scanning calorie spectrum for a crystalline form of edoxaban benzenesulfonate monohydrate according to this study.
4 is an X-ray diffraction spectrum of a crystalline form of edoxaban oxalate monohydrate, which is a comparative example for this study.
5 is an X-ray diffraction spectrum for a crystalline form of edoxaban citrate monohydrate, which is a comparative example for this study.
6 is an X-ray diffraction spectrum for a crystalline form of edoxaban (-)-10-campasulfonic acid salt monohydrate, which is a comparative example for this study.

Hereinafter, examples, etc. will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples.

In addition, below, in order to prepare for the edoxaban benzenesulfonate monohydrate crystalline form of the present invention, edoxaban oxalate monohydrate crystalline form, edoxaban citrate monohydrate crystalline form and edoxaban (- )-10-Campasulfonic acid salt monohydrate crystalline form was prepared, and a known edoxaban p-toluenesulfonic acid salt monohydrate was prepared as a comparative example, and then edoxaban benzenesulfonate monohydrate crystalline form of the present invention and the above comparative example And the hygroscopicity and stability of each crystalline form of the comparative example were measured.

Comparative example

[Comparative Example 1]

Form I of edoxaban p-toluenesulfonate monohydrate was prepared according to the method of Example described in Korean Patent No. 10-1708528 (yield: 86%, purity 99.900%).

Example

[Example 1]

N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanodiamide·benzenesulfonate monohydrate crystalline form

3.0 g of edoxaban free base was suspended in 25.5 ml of ethanol and 4.5 ml of water, and the solution was heated to 60° C. and 0.95 g (1.1 eq) of benzenesulfonic acid hydrate was dissolved in 4.5 ml of ethanol to the suspension of the free base of edoxaban. Added. After that, the reaction mixture was cooled to room temperature and allowed to stand for 1 hour. To the reaction mixture in which crystals were formed, 12.75 ml of ethanol and 2.25 ml of water were added, and the reaction mixture was stirred at room temperature for 2 hours, and then cooled to 2°C. Stir for hours. The resulting crystals were filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystals (yield: 90%, purity: 99.986%).

[Comparative Example 1]

N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanodiamide·oxalate monohydrate crystalline form

3.0 g of edoxaban free base was dissolved in 25.5 ml of ethanol, 4.5 ml of water, and 12 ml of dichloromethane. 0.54 g (1.1 eq) of oxalic acid was dissolved in 4.5 ml of ethanol and added to the edoxaban free base solution. Then, it stirred at room temperature for 2 hours, cooled, and stirred for 2 hours. Filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystal (yield: 77%, purity: 99.977%).

[Comparative Example 2]

N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanadiamide citrate monohydrate crystalline form

3.0 g of edoxaban free base was dissolved in 25.5 ml of ethanol, 4.5 ml of water, and 12 ml of dichloromethane. 0.83 g (1.1 eq) of citric acid was dissolved in 4.5 ml of ethanol and added to the edoxaban free base solution. Then, it stirred at room temperature for 2 hours, cooled, and stirred for 2 hours. Filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystal (yield: 60%, purity: 99.931%).

[Comparative Example 3]

N-(5-chloropyridin-2-yl)-N'-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6 ,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanadiamide·(-)-10-campasulfonic acid salt monohydrate crystalline form

3.0 g of edoxaban free base was dissolved in 25.5 ml of ethanol, 4.5 ml of water, and 12 ml of dichloromethane. 1.40g (1.1eq) of (-)-10-campasulfonic acid was dissolved in 4.5ml of ethanol and added to the edoxaban free base solution. Then, it stirred at room temperature for 2 hours, cooled, and stirred for 2 hours. Filtered and dried under vacuum at 50° C. for 12 hours to obtain the title crystal (yield: 40%, purity: 99.846%).

[Crystal form analysis]

end. Powder X-ray diffraction (XRD) analysis

As a result of performing powder X-ray diffraction analysis on the edoxaban benzenesulfonate monohydrate crystal form obtained in Example 1, 2θ diffraction angles were 5.2, 10.4°, 12.3°, 13.4°, 13.9°, as shown in FIG. Peaks were shown at 14.6°, 17.3°, 17.9°, 18.9°, 19.9°, 21.0°, 21.6°, 22.0°, 22.7°, 23.2°, 24.3°, and 24.4°, respectively, at this time, powder X-ray diffraction (XRD) The measurement conditions of the spectrum are as follows.

1) Device: Rigaku's MiniFlex 600/X Source: Cu

2) Tube voltage: 40 kV/Tube current: 15mA

3) Diverging slit: 1°/Scattering slit: 1°/Receiving slit: 0.15mm

4) Scanning range: 3 to 40°2θ/sampling interval 0.04°C

5) Scan speed: 10°/min

I. Hydrogen nuclear magnetic resonance analysis

Hydrogen nuclear magnetic resonance spectrum analysis was performed on the edoxaban benzenesulfonate monohydrate crystal form obtained in Example 1, and the results are attached to FIG. 2. The crystals were 10.31 (s, 1H), 10.14 (1H, br), 9.16 (d, 1H), 8.76 (d, 1H), 8.46 (t, 1H), 8.01 (d, 2H), 7.58 (m, 2H) ), 7.30(m, 3H), 4.42(m, 1H), 4.00(m, 1H), 3.18(m, 2H), 2.98(s, 3H), 2.92(s, 4H), 2.78(s, 3H) , 2.04 (m, 2H), 1.71 (m, 3H), 1.50 (m, 1H) showed peaks, respectively. The measurement conditions for the hydrogen nuclear magnetic resonance (NMR) are as follows.

1) Device: Agilent 400MR

2) Measurement range: -1.0 ~ 15 ppm

3) Number of scans: 4 times

All. Differential Scanning Calorie (DSC) Analysis

Differential scanning calorimetry (DSC) analysis was performed on the edoxaban benzenesulfonate monohydrate crystal form obtained in Example 1, and the results are attached to FIG. 3. As shown in FIG. 3, the crystalline form showed an onset temperature of 249°C and an endothermic peak of 251°C. The measurement conditions of the differential scanning calorimeter spectrum are as follows.

1) Device: Q20(TA instrument)

2) Measurement range: 10 to 300℃/Temperature increase interval: 10℃/min

la. Hygroscopicity test

The form of the pharmaceutically preferable compound is preferably a form that does not absorb moisture even in an environment of high humidity while maintaining the initial form. Therefore, in order to confirm the hygroscopicity of the edoxaban benzenesulfonate monohydrate crystalline form obtained in Example 1 and the crystalline form of the other salts of Comparative Examples and Comparative Examples, each of the crystalline compounds at 25°C temperature and 50% relative humidity. The water content (KF moisture %) was measured according to the time. The results are shown in Table 1 below.

Early 12 hours 24 hours 48 hours Edoxaban free base 0.11% 0.13% 0.14% 0.17% Edoxaban
p-toluenesulfonate monohydrate
(Theoretical moisture 2.44%) 2.45% 2.46% 2.49% 2.50% Edoxaban
Benzenesulfonate monohydrate
(Theoretical moisture 2.49%) 2.48% 2.49% 2.49% 2.48% Edoxaban
Oxalate monohydrate
(Theoretical moisture 2.74%) 4.13% 4.24% 4.53% 4.88% Edoxaban citrate monohydrate
(Theoretical moisture 2.56%) 3.16% 3.22% 3.24% 3.29% Edoxaban
(-)-10-campasulfonic acid salt monohydrate
(Theoretical moisture 2.25%) 3.21% 3.35% 3.58% 3.74%

* The above theoretical moisture represents the content (%) of the molecular weight of the hydrate contained in the molecular weight of the total molecular structure.

As shown in Table 1, the edoxaban benzenesulfonate monohydrate crystalline form of the present invention does not exhibit hygroscopicity at all. It was shown that the water content remained at a similar level even after 24 or 48 hours compared to the initial water content, and unlike the benzene sulfonate monohydrate crystalline form, the crystalline form of other salts increased the moisture content in the air as time passed. can see.

In case of convention, related substances (impurities, etc.) increase, and the color of the product becomes discolored.This discoloration is related to the generation of impurities, so there is a problem of stability.Thus, among the crystalline forms of each salt in Table 1 above, benzene, which does not show a convention Sulfonate monohydrate is the most stable compound.

hemp. Stability test

When the edoxaban benzenesulfonate monohydrate crystalline form of the present invention and the crystalline form of other salts were stored at room temperature, they were analyzed by HPLC and shown in Table 2.

RRT 1 RRT 1.34 RRT 2.61 Edoxaban free base Room temperature storage 99.966 0.009 0.009 Room temperature storage 1 week 99.963 0.009 0.011 Room temperature storage 2 weeks 99.961 0.009 0.013 Edoxaban
p-toluenesulfonate monohydrate Room temperature storage 99.976 0.003 0.012 Room temperature storage 1 week 99.974 0.002 0.015 Room temperature storage 2 weeks 99.970 0.002 0.017 Edoxaban
Benzenesulfonate monohydrate Room temperature storage 99.989 0.002 0.006 Room temperature storage 1 week 99.986 0.002 0.006 Room temperature storage 2 weeks 99.986 0.002 0.006 Edoxaban
Oxalate
1 luggage Room temperature storage 99.981 0.002 0.008 Room temperature storage 1 week 99.977 0.002 0.012 Room temperature storage 2 weeks 99.975 0.002 0.014 Edoxaban
Citrate monohydrate Room temperature storage 99.922 0.002 0.016 Room temperature storage 1 week 99.919 0.002 0.016 Room temperature storage 2 weeks 99.918 0.002 0.017 Edoxaban (-)-10-campasulfonic acid salt monohydrate Room temperature storage 99.991 0.002 0.003 Room temperature storage 1 week 99.986 0.002 0.005 Room temperature storage 2 weeks 99.984 0.002 0.007

-RRT 1: the location of the HPLC peak where the crystalline form of the salt appears (area%)

-RRT 1.34: HPLC peak position where impurities contained in the crystalline form of the salt appear when the position of the HPLC peak where the crystalline form of the salt appears is set to “1” (area %)

-RRT 2.61: HPLC peak position where impurities contained in the crystalline form of the salt appear when the position of the HPLC peak where the crystalline form of the salt appears is set to “1” (area%)

As can be seen from Table 2 above, it can be seen that the edoxaban benzenesulfonate monohydrate crystalline form of the present invention is a material that is very stable compared to the monohydrate crystalline form of other salts at room temperature. In particular, certain related substances (impurities) of RRT 2.61 hardly increase in the benzenesulfonate monohydrate crystalline form, indicating that a certain purity is maintained.The edoxaban benzenesulfonate monohydrate crystalline form of the present invention is easy to store and store. Excellent stability. This stability is also shown to be consistent with the results of the above hygroscopicity test.

Claims (5)

In powder X-ray diffraction (XRD) analysis, the diffraction angle of 2θ is 5.2±0.2, 10.4±0.2°, 12.3±0.2°, 13.4±0.2°, 13.9±0.2°, 14.6±0.2°, 17.3±0.2°, 17.9±0.2. Diffraction patterns of °, 18.9±0.2°, 19.9±0.2°, 21.0±0.2°, 21.6±0.2°, 22.0±0.2°, 22.7±0.2°, 23.2±0.2°, 24.3±0.2°, 24.4±0.2 Edoxaban benzenesulfonate monohydrate crystalline form.
A) mixing (suspension) of edoxaban free base of water and an organic solvent by dissolving benzenesulfonic acid hydrate in an organic solvent and adding it to the reaction solution to dissolve the entire reactant and to produce crystals; B) including the aging step of the crystal, wherein the B) aging step of the crystal comprises the step of aging the crystal obtained in step A) above at room temperature and a cooling temperature of 0 ~ 10 ℃, respectively, the edoxaban of claim 1 Method for producing benzenesulfonate monohydrate crystal form.
The method of claim 2, wherein the organic solvent is methanol, ethanol, isopropanol, or a mixture thereof.
The method of claim 2, wherein the cooling temperature in the step of aging in B) is 0 to 5° C., wherein the edoxaban benzenesulfonate monohydrate crystalline form is produced.
The method according to any one of claims 2 to 4, wherein the mixing ratio of water and organic solvent in the mixed reaction solution used in step A) is 1:3 to 1:9 (water: organic solvent) (volume ratio). A method for producing edoxaban benzenesulfonate monohydrate crystal form, characterized in that.

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