CN103319473A

CN103319473A - Two crystal forms of azilsartan and preparation method thereof

Info

Publication number: CN103319473A
Application number: CN2013102757454A
Authority: CN
Inventors: 徐云根; 周海平; 刘伟; 何广卫
Original assignee: HEFEI YIGONG MEDICINE CO Ltd
Current assignee: HEFEI YIGONG MEDICINE CO Ltd
Priority date: 2013-07-02
Filing date: 2013-07-02
Publication date: 2013-09-25

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to two crystal forms of azilsartan and a preparation method thereof. For the crystal form B of the azilsartan, in a X-ray powder diffraction pattern, 2theta has characteristic peaks near 7.46 degrees, 8.43 degrees, 9.38 degrees, 10.96 degrees, 18.90 degrees, 21.06 degrees, 21.98 degrees, 22.71 degrees, 23.11 degrees and 24.89 degrees. For the crystal form C, in the X-ray powder diffraction pattern, 2theta has characteristic peaks near 9.52 degrees, 11.64 degrees, 13.51 degrees, 20.85 degrees, 21.83 degrees, 22.40 degrees, 23.44 degrees, 25.17 degrees, 26.17 degrees and 29.06 degrees. The crystal form B and crystal form C of the azilsartan have better stability and fluidity and are beneficial to long-time storage.

Description

Polymorphic of Azilsartan and preparation method thereof

Technical field

The invention belongs to the pharmaceutical chemistry technical field, be specifically related to two kinds of crystal formations of Azilsartan and preparation method thereof.

Background technology

Azilsartan, chemistry 2-oxyethyl group-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl) biphenyl-4-yl by name] methyl] benzoglyoxaline-7-carboxylic acid, (I) is as follows for structural formula:

This medicine is a kind of selectivity angiotensin II receptor antagonists by the exploitation of Japanese Wu Tian company, gets permission the listing in Japan in January, 2012, is used for the treatment of hypertension.In addition, as the Azilsartan (Azilsartan medoxomil, TAK-491) of its prodrug, also obtained drugs approved by FDA on February 25th, 2011.Azilsartan is by being hydrolyzed into Azilsartan and bringing into play drug effect at gi tract after oral, and Thomson Reuters society prediction Azilsartan in the time of 2014 can reach 700,010,330 dollars of year sale.These show that all this medicine is having unique advantage aspect the treatment hypertension.

Chinese patent CN92105152C discloses a certain solvate of Azilsartan and preparation method: use re-crystallizing in ethyl acetate, obtain containing the solvate of 0.5 molecule ethyl acetate and 0.2 molecular water, fusing point is 156～157 ℃.In addition, and document (J.Med.Chem.1996,39, the fusing point of 5228-5235.) having reported Azilsartan is 212～214 ℃, but does not carry out crystal formation research; WO2012107814A1 discloses the preparation method of Azilsartan, is crystal type or solvate but also do not illustrate.Chinese patent CN102827153A discloses with dehydrated alcohol and has carried out the crystal formation (hereinafter referred to as crystal form A) that the method for recrystallization obtains, and the characteristic peak of PXRD is expressed as 9.01 °, 12.60 °, 18.21 ° with 2 θ (± 0.2 °); Be preferably 9.01 °, 12.60 °, 18.21 °, 19.21 °, 21.37 °, 24.42 °, 25.25 °, 26.58 °.Chinese patent CN102766139A also discloses the crystal formation that multiple recrystallization method prepares Azilsartan, but compares PXRD collection of illustrative plates and other data, and what obtain also is crystal form A.

In sum, the Azilsartan crystal formation kind of bibliographical information is few at present, but this medicine antihypertensive effect is remarkable, and market outlook are vast, therefore further its crystal formation research is very important.

Summary of the invention

The invention discloses two kinds of crystal formations of Azilsartan, be called for short crystal form B and crystal C.

The Azilsartan crystal form B is in X-ray powder diffraction figure, and angle represents with 2 θ, at 7.46 °, 8.43 °, 9.38 °, 10.96 °, 18.90 °, 21.06 °, 21.98 °, 22.71 °, 23.11 °, has characteristic peak near 24.89 °.General 2 θ can have ± 0.2 ° of deviation.Its X-ray powder diffraction figure collection of illustrative plates as shown in Figure 1.

Occur an endotherm(ic)peak near the differential scanning calorimetric thermogram of Azilsartan crystal form B is presented at 163.8 ℃, and an exothermic peak occurs at 185～195 ℃.As shown in Figure 2.

The invention discloses the preparation method of Azilsartan crystal form B, comprise: with the mixed solvent recrystallization of Azilsartan with DMF (DMF) and acetone, vacuum-drying and get final product, wherein, the volume ratio of DMF and acetone is 1:5～1:10 in the mixed solvent.

Azilsartan crystal C of the present invention, it is in X-ray powder diffraction figure, and angle represents with 2 θ, at 9.52 °, 11.64 °, 13.51 °, 20.85 °, 21.83 °, 22.40 °, 23.44 °, 25.17 °, 26.17 °, has characteristic peak near 29.06 °.Its X-ray powder diffraction figure collection of illustrative plates as shown in Figure 3.

An endotherm(ic)peak appears in the Azilsartan crystal C near its differential scanning calorimetric thermogram is presented at 122.3 ℃.See Fig. 4.

The invention discloses the preparation method of Azilsartan crystal C, comprising: with the mixed solvent recrystallization of Azilsartan with DMF and Virahol, vacuum-drying and get final product, wherein, the volume ratio of DMF and Virahol is 1:3～1:10.

Stability test shows, Azilsartan crystal form B of the present invention and crystal C are more stable than crystal form A, are conducive to prolonged preservation.And the flowability of crystal form B and crystal C is also better.The preparation method of crystal form B disclosed by the invention and crystal C is simple to operate, and solvent load is few and nontoxic, and production cost is low, has clear superiority aspect industrialization.

Description of drawings

Fig. 1 is the X-ray powder diffraction figure of Azilsartan crystal form B.

Fig. 2 is the dsc analysis figure of Azilsartan crystal form B.

Fig. 3 is the X-ray powder diffraction figure of Azilsartan crystal C.

Fig. 4 is the dsc analysis figure of Azilsartan crystal C.

Embodiment

Embodiment 1

The preparation of Azilsartan crystal form B:

Azilsartan 3g is added in the 50ml eggplant-shape bottle, add 3ml DMF and 18ml acetone, induction stirring is heated to 65 ℃ of all dissolvings, and stopped heating and stirring approximately were cooled to room temperature in 30 minutes, at room temperature placed 2 hours, placed 5 hours at 0～5 ℃ again.The a small amount of washing with acetone of suction filtration, filter cake, 35 ℃ of vacuum-drying 12 hours obtains white crystal 2.3g.

X-ray powder diffraction figure sees Fig. 1, and dsc analysis figure sees Fig. 2.

Embodiment 2

The preparation of Azilsartan crystal C:

Azilsartan 3g is added in the 25ml eggplant-shape bottle, add 3ml DMF, induction stirring also is heated to 85 ℃ of dissolvings, drips Virahol to saturated (12ml), and stopped heating and stirring were cooled to room temperature in 30 minutes.There is a small amount of solid to separate out in the process of cooling, places after 2 hours under the room temperature, spend the night 0～5 ℃ of placement again.The a small amount of washed with isopropyl alcohol of suction filtration, filter cake, 35 ℃ of vacuum-drying 12 hours obtains white crystal 2.5g.

X-ray powder diffraction figure sees Fig. 3, and dsc analysis figure sees Fig. 4.

Claims

1. the crystal form B of an Azilsartan is characterized in that: in X-ray powder diffraction figure, angle represents with 2 θ, at 7.46 °, and 8.43 °, 9.38 °, 10.96 °, 18.90 °, 21.06 °, 21.98 °, 22.71 °, 23.11 °, have characteristic peak near 24.89 °.

2. the crystal form B of claim 1, its X-ray powder diffraction figure collection of illustrative plates such as Fig. 1.

3. an endotherm(ic)peak appears in the crystal form B of claim 1 near its differential scanning calorimetric thermogram is presented at 163.8 ℃, and an exothermic peak occurs at 185～195 ℃.

4. method for preparing the crystal form B of claim 1 comprises: with the mixed solvent recrystallization of Azilsartan with DMF and acetone, and vacuum-drying and get final product, wherein the volume ratio of DMF and acetone is 1:5～1:10.

5. the crystal C of an Azilsartan is characterized in that: in X-ray powder diffraction figure, angle represents with 2 θ, at 9.52 °, and 11.64 °, 13.51 °, 20.85 °, 21.83 °, 22.40 °, 23.44 °, 25.17 °, 26.17 °, have characteristic peak near 29.06 °.

6. the crystal C of claim 5, its X-ray powder diffraction figure collection of illustrative plates such as Fig. 3.

7. an endotherm(ic)peak appears in the crystal C of claim 5 near its differential scanning calorimetric thermogram is presented at 122.3 ℃.

8. method for preparing the crystal C of claim 5, it comprises: with the mixed solvent recrystallization of Azilsartan with DMF and Virahol, vacuum-drying and get final product, wherein, the volume ratio of DMF and Virahol is 1:3～1:10.