CN104341408A - Novel crystal form of azilsartan and preparation method thereof - Google Patents
Novel crystal form of azilsartan and preparation method thereof Download PDFInfo
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- CN104341408A CN104341408A CN201310336655.1A CN201310336655A CN104341408A CN 104341408 A CN104341408 A CN 104341408A CN 201310336655 A CN201310336655 A CN 201310336655A CN 104341408 A CN104341408 A CN 104341408A
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- KGSXMPPBFPAXLY-UHFFFAOYSA-N CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(N1)=NOC1=O Chemical compound CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(N1)=NOC1=O KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The invention relates to a novel crystal form (called form B) of a latest-generation antihypertensive drug, namely, 1-[[2'-(2,5-dihydro-5-oxo-1,2,4oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid (generic name: azilsartan), and a preparation method thereof. The azilsartan is found to have a polycrystalline state for the first time, and the novel crystal form is in a semi-stable state. As proved by research, a semi-stable-state product has high crystal form stability, can be preserved at the room temperature for six months, and is free from change in a powder-X diffraction pattern and constant in HPLC (High Performance Liquid Chromatography) purity. The novel crystal form which can be applied to further medicinal development is provided for the project development.
Description
Technical field
The present invention relates to a kind of latest generation antihypertensive drug 1-[[2 '-(2,5-dihydro-5-oxo-1,2,4 oxadiazole-3-bases) [1,1 '-xenyl]-4-base] methyl] new crystal of-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid (general by name: Azilsartan), it is called as Type B and preparation method thereof.
Background technology
The chemistry of Azilsartan is called 1-[[2 '-(2,5-dihydro-5-oxo-1,2,4 oxadiazole-3-base) [1,1 '-xenyl]-4-base] methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid, and structural formula is such as formula shown in [I].
Azilsartan is Japanese military field pharmaceutical development, in April, 2012 Japan's listing.Be a kind of Angiotensin Ⅱ receptor antagonist, the smooth class treatment of the sand for latest generation hypertension drug, can be used alone or use together with other Altace Ramipril, being considered the next-generation of candesartan Cilexetil.Its prodrug is Azilsartan, Azilsartan ester is for the comparatively significant curative effect that reduced blood pressure, 1291 Patient Participation, the experiment reaching for six weeks compare the effect of the valsartan of the Azilsartan of 40 milligrams, 80 milligrams and the olmesartan medoxomill (being researched and developed by the first pharmacy Sankyo Co., Ltd) of 40 milligrams or 320 milligrams, and the Azilsartan of 40 milligrams can reduce the blood pressure of 13.4mmHg as a result, the Azilsartan of 80 milligrams is then 14.5mmHg, the olmesartan medoxomill of 40 milligrams is 12mmHg, the valsartan of 320 milligrams is then 10.2mmHg.
CN102827153 mentions crystal formation of a kind of Azilsartan and preparation method thereof, document is with the powder-X diffracting spectrum of this crystal formation, and document does not have this crystal formation of name, due to except this patent documentation, not yet have other bibliographical informations of Azilsartan crystal formation at present, we name document crystal formation to be crystal form A.Show after deliberation, with the Azilsartan product that currently reported Azilsartan process for refining and other all regular refiner methods obtain, all have and report consistent powder-diffractogram with document CN102827153, fusing point is 190-195 DEG C, with former to grind the fusing point declaring the Azilsartan product mentioned in file consistent.
Different from known open source literature, the new crystal B that this patent is mentioned, have and relate to the diverse powder of crystal formation-X diffracting spectrum with document CN102827153, mensuration fusing point is 170-175 DEG C.
As everyone knows, the crystalline polymorph of certain drug and the druggability of medicine have relation closely, and drug crystal forms affects the dissolution rate of the stability of medicine, solubleness, preparation, and then affects the bioavailability of medicine.Generally, for oral administration solid poorly water soluble drugs, product crystal formation fusing point is higher, stability better, but the bioavailability of the solvability of corresponding product and preparation is on the low side.Therefore, in drug research and development process, very general as the situation of drug crystal forms using metastable-state crystal.
Summary of the invention
The invention provides the crystal polymorph (Type B) of Azilsartan, the powder x-ray diffraction data that it provides with reference to the accompanying drawings and DSC data characterize.
Present invention also offers the method preparing Azilsartan crystal form B, the method comprises dissolves Azilsartan alkaline solution, and alkaline solution refers generally to alkali-metal inorganic salt, comprises hydroxide radical salt, carbonate and supercarbonate, general preferred sodium hydroxide.Because the stability of Azilsartan in alkaline solution is limited, therefore the concentration of alkaline solution used is lower, generally not higher than 0.5mol/L, and in dissolution process control temperature < 30 DEG C, buck amount used is can dissolved product be advisable completely.After product dissolves, add acetonitrile, acetonitrile content is generally the 5%-100% of buck amount, and acetonitrile content is too much, easily causes acetonitrile residual (after deliberation, multiple Conventional solvents contacts with Azilsartan, and solvent all can remain, cause product is residual moltenly to exceed standard).Therefore preferably acetonitrile content is 10%-25%.Add acid liquid and regulate PH, object is dissociated for making Azilsartan product, thus separates out product in a solvent.Generally, PH=7 just has product to separate out, and pH value only affects product yield, and preferred PH=1-2, product yield is higher.
Beneficial effect of the present invention: this patent Late Cambrian Azilsartan exists polycrystalline state, and new crystal is metastable state, shows after deliberation, this metastable state product stability of crystal form is good, room temperature places 6 months, and powder-X diffractogram is unchanged, and product HPLC purity also remains unchanged.For this project development provides a kind of new crystal for further medicinal exploitation newly.
Accompanying drawing explanation
Fig. 1: the HPLC figure of Azilsartan crystal form B of the present invention
Fig. 2: the powder-X-ray diffractogram [the XRPD figure of Azilsartan crystal form B] of Azilsartan crystal form B of the present invention.
Fig. 3: thermogravimetric analysis (TGA) figure [thermogravimetric analysis (DSC) figure of Azilsartan crystal form B of the present invention] of Azilsartan crystal form B of the present invention.
Fig. 4: dsc (DSC) figure [dsc (DSC) figure of Azilsartan crystal form B of the present invention] of Azilsartan crystal form B of the present invention.
embodiment
Subordinate's embodiment, only for illustration of this patent, does not limit the protection domain of this patent.
Embodiment 1:
The preparation of the crystal form B of Azilsartan
Add the sodium hydroxide solution of 5L0.04mol/L in 10L there-necked flask, mechanical stirring, add 450g1-[[2 '-(2,5-dihydro-5-oxo-1,2,4 oxadiazole-3-bases) [1,1 '-xenyl]-4-base] methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid.(whole process temperature control is to T < 20 DEG C), stirs and makes dissolution of solid, add acetonitrile 0.5L, stir, obtain clear transparent solutions, add the hydrochloric acid of 1mol/L, adjust PH=1-2, separate out a large amount of solid, stir 30min, suction filtration, filter cake is extremely neutral with water wash, product 45 DEG C of forced air dryings, to constant weight, obtain target crystal form B product 423.7g, yield: 94.2%.
Embodiment 2:
The preparation of the crystal form B of Azilsartan
Add the sodium hydroxide solution of 3L0.1mol/L in 10L there-necked flask, mechanical stirring, add 450g1-[[2 '-(2,5-dihydro-5-oxo-1,2,4 oxadiazole-3-bases) [1,1 '-xenyl]-4-base] methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid.Stirring makes dissolution of solid, adds acetonitrile 3L, stirs, obtain clear transparent solutions, add the hydrochloric acid of 1mol/L, adjust PH=5-6, separate out a large amount of solid, stir 30min, suction filtration (whole process temperature control is to T < 20 DEG C), filter cake is with water wash to neutral, and product 45 DEG C of forced air dryings are to constant weight, obtain target product 393.5g, yield: 87.4%.
Claims (10)
1. the new crystal (crystal form B) and preparation method thereof of an Azilsartan (shown in formula I structure):
。
2. as claimed in claim 1, the crystal form B of Azilsartan, is characterized in that: reflection angle 2 θ of the X-ray powder diffraction pattern of this crystal is 4.76,9.42,11.06,14.05,16.40,19.47,21.24,21.73,22.10,22.58,24.02,24.66,25.10,25.59,26.31,28.41 have charateristic avsorption band.
3. as claimed in claim 1, Azilsartan crystal form B has X-diffracting spectrum as shown in Figure 1.
4. as claimed in claim 1, Azilsartan crystal form B has thermogravimetric (TG) as shown in Figure 2 and analyzes collection of illustrative plates, and crystal form B is the crystalline hydrate that Azilsartan contains 1.75%.
5. new crystal according to claim 1, it has means of differential scanning calorimetry (DSC) analysis chart as shown in Figure 3.
6. the preparation method of crystal form B as claimed in claim 1, is characterized in that: dissolved by Azilsartan alkali aqueous solution, add organic solvent, and adjust PH to separate out product with acid liquid, drying obtains crystal formation product.
7. the preparation method of crystal form B as claimed in claim 2, is characterized in that: alkali aqueous solution is the aqueous solution that inorganic metal alkali and organic amine alkali etc. can make product dissolve.
8. the preparation method of crystal form B as claimed in claim 2, is characterized in that: organic solvent is acetonitrile.
9. the preparation method of crystal form B as claimed in claim 2, is characterized in that: acid liquid is to regulate the inorganic acid liquid of water liquid PH < 7 or organic acid liquid.
10. the preparation method of crystal form B as claimed in claim 2, is characterized in that: regulate PH≤7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201310336655.1A CN104341408A (en) | 2013-08-02 | 2013-08-02 | Novel crystal form of azilsartan and preparation method thereof |
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| CN201310336655.1A CN104341408A (en) | 2013-08-02 | 2013-08-02 | Novel crystal form of azilsartan and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
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| JP2012140443A (en) * | 1998-11-27 | 2012-07-26 | Case Western Reserve Univ | Composition and method for treatment of alzheimer's disease, central nervous system injury, and inflammatory disease |
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| WO2012157980A2 (en) * | 2011-05-19 | 2012-11-22 | Hanmi Fine Chemical Co., Ltd. | Manufacturing method of azilsartan |
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| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan and preparation and uses thereof |
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| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan and preparation and uses thereof |
| WO2013088384A2 (en) * | 2011-12-15 | 2013-06-20 | Jubilant Life Sciences Limited | Solid state forms of azilsartan and azilsartan medoxomil monopotassium and preparation thereof |
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
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| CN103113364A (en) * | 2012-08-27 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of azilsartan polymorphism |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
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Effective date of registration: 20161124 Address after: 266001 Qingdao economic and Technological Development Zone, unity Road, No. 3601, Shandong Applicant after: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. Address before: 210016 Jiangsu Province, Nanjing city Zhongshan Road No. 323, 2 (former banshanyuan No. 12 Building 1 layer 1) Applicant before: JIANGSU CAREPHAR PHARMACEUTICAL CO., LTD. |
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Application publication date: 20150211 |