CN103831159A - Azilsartan micronization method - Google Patents
Azilsartan micronization method Download PDFInfo
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- CN103831159A CN103831159A CN201410025070.2A CN201410025070A CN103831159A CN 103831159 A CN103831159 A CN 103831159A CN 201410025070 A CN201410025070 A CN 201410025070A CN 103831159 A CN103831159 A CN 103831159A
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- azilsartan
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- micro mist
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Abstract
The invention discloses an azilsartan micronization method. According to the method, during micronization, an ultralow temperature crushing method is adopted, and the method comprises the steps of mixing azilsartan with liquid nitrogen, and performing micronization operation.
Description
Technical field:
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of Azilsartan method of micronization.
Background technology:
Azilsartan, chemistry 2-ethyoxyl-1-[[2 '-(4 by name, 5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid, its structure, suc as formula shown in IV, is researched and developed by Japanese Wu Tian drugmaker (Takeda), in Japan's listing, there were 20mg, two kinds of specifications of 40mg in 2012.Be used for the treatment of vascular hypertension as Angiotensin Ⅱ receptor antagonist, there are wide market prospects.
Azilsartan belongs to insoluble drug, almost insoluble in water, and for this type of insoluble drug, drug-eluting becomes the key factor that limits its absorption and bioavilability.According to Noyes-Whimey equation, reduce drug particles particle diameter, increase its specific area and wetability, thereby reach the rapidly-soluble object that promotes particle, therefore, micronization technology becomes the important channel that solves insoluble drug dissolution rate problem.
Medicine is carried out in micronization process, with high speed machine shear pulverizer, medicine being pulverized is conventional means, also the most cheap, the inventor finds, with high speed machine shear pulverizer, Azilsartan raw material is being carried out to micronizing pulverizing, the Azilsartan micro mist obtaining with do not have pulverize before Azilsartan raw material compare, had more three new impurity, impurity I, impurity II and impurity III, these three impurity are carried out qualitative, its structure is suc as formula shown in I, formula II, formula III.
These impurity belong to unknown impuritie, belong to new compound, and the present invention has carried out structural confirmation to this, and its spectroscopic data is as follows respectively:
(1) impurity I (removing ethyl impurity), shown in I, produces or increases at high temperature, acidity or mechanical shearing crushing process;
1h-NMR(400MHz, DMSO-d6): δ 5.432 (2H, s), 7.039～7.684 (11H, m), 11.412 (1H, s), 12.404 (1H, s), 13.137 (1H, s).
(2) impurity II (ethyl ester impurity), shown in II, produces at mechanical shearing crushing process, and along with shear time extends and increases;
1h-NMR(400MHz, DMSO-d6): δ 1.139～1.174 (3H, t, J=7.2), 1.377～1.412 (3H, t, 6.8), 4.154～4.207 (2H, q, 7.2), 4.576～4.629 (2H, q, J=6.8), 5.551 (2H, s), 6.960～7.705 (11H, m).
(3) impurity III (N-ethyl impurity), shown in III, produces at mechanical shearing crushing process, and along with shear time extends and increases.
1H-NMR（400MHz，DMSO-d6）：δ0.565～0.601(3H,t,J=7.2),1.161～1.197(3H,t,J=7.2),1.354～1.389(3H,t,J=6.8),2.928～2.982(2H,q,J=7.2),4.159～4.212(2H,q,7.2),4.558～4.611(2H,q,6.8),5.555(2H,s),6.995～7.757(11H,m)。
Obtain the sample of three impurity by preparation liquid phase separation, and carried out nuclear-magnetism structural identification, obtain the structural information of impurity; Relevant nuclear magnetic spectrum is shown in accompanying drawing 1-3.
Analyze its source, may to shear the heat producing in crushing process relevant with high speed machine, for this reason, the inventor shears in crushing process and reduces temperature at high speed machine, surprised discovery, can effectively control impurity level by the temperature reducing in micronization process, guarantee that the granularity of Azilsartan meets preparation stripping requirement simultaneously.
Summary of the invention:
Content of the present invention relates to Azilsartan method of micronization.The method is simple to operate, and device therefor is easy to get, can continued operation, and Control of Impurities effect is better, and can reach the granularity requirements in Azilsartan pharmaceutical preparation.
Azilsartan method of micronization of the present invention, comprises following content:
A kind of Azilsartan method of micronization, described method is included in micronization process, the method that adopts ultralow temperature to pulverize.
Method of the present invention, comprises Azilsartan is mixed with liquid nitrogen and carries out micronized step.
Method of the present invention is that Azilsartan is mixed with liquid nitrogen, synchronously enters gas and draws formula ultrafine crusher sample is pulverized.
Preferably, method of the present invention comprises the following steps: start pulverizer, Azilsartan is added to pulverizer from charge door in batches, each about 5g of addition, add after once pulverizing 10～15s and again add, meanwhile, continuous liquid nitrogen added to pulverizer from charge door, to guarantee that pulverizing system is in low-temperature condition.
Method of the present invention, the size distribution of gained Azilsartan micro mist is D (90) < 10 μ m.
Method of the present invention, in gained Azilsartan micro mist, impurity I, impurity II and impurity III are less than 0.1%.
The invention provides a kind of Azilsartan micro mist, wherein impurity I, impurity II and impurity III are less than 0.1%.
The present invention also provides a kind of pharmaceutical composition, contains Azilsartan micro mist of the present invention.
Because three kinds of impurity of the present invention are that the present invention obtains first, also claimed these three compounds of the present invention for this reason
The preparation method of these three compounds is by Azilsartan raw material high speed jet mill is carried out to micronizing pulverizing, and the Azilsartan micro mist obtaining carries out separation and purification to Azilsartan impurity with preparative liquid chromatograph, obtains this three compounds.
The present invention has carried out experimental check to Azilsartan related substance in micronization process, and experimental result is as follows:
Adopt high speed machine shear pulverizer to Azilsartan not micro mist sample carry out mechanical shearing pulverizing:
Detect the HPLC method that adopts,
Azilsartan is micro mist sample not: impurity I 0.02%, impurity II do not detect, impurity III does not detect.
Azilsartan mechanical shearing is pulverized 30s: impurity I 0.11, impurity II 0.09, impurity III 0.05.
Azilsartan mechanical shearing is pulverized 300s: impurity I 0.35, impurity II 0.27, impurity III 0.14.
Azilsartan and liquid nitrogen mixing low temp are pulverized: impurity I 0.06, impurity II 0.04, impurity III do not detect.
Beneficial effect of the present invention comprises:
Find the potential impurity in Azilsartan micronization process, and operate by ultralow temperature micro mist, control the degraded of Azilsartan, make the potential impurity of Azilsartan in controlled range, can obtain meeting the sample of preparation granularity requirements simultaneously by this kind of micro mist technique.
Accompanying drawing explanation:
Accompanying drawing 1: Azilsartan impurity I nucleus magnetic hydrogen spectrum
Accompanying drawing 2: Azilsartan impurity II nucleus magnetic hydrogen spectrum
Accompanying drawing 3: Azilsartan impurity III nucleus magnetic hydrogen spectrum
Accompanying drawing 4: Azilsartan low-temperature grinding granularity Detection collection of illustrative plates
The specific embodiment:
In conjunction with specific embodiments, further set forth content of the present invention, specific embodiment is used for illustrating content of the present invention and is not used in and limits the scope of the invention.
The intermittent Azilsartan 30s that pulverizes of embodiment 1:RF-08 type high speed machine shear pulverizer.
Get 200g Azilsartan and be placed in RF-08 type high speed disintegrator, the intermittent 30s that pulverizes, by gained micronizing Azilsartan sample censorship related substance.
The intermittent Azilsartan 300s that pulverizes of embodiment 2:RF-08 type high speed disintegrator.
Get 50g Azilsartan and be placed in RF-08 type high speed disintegrator, the intermittent 300s that pulverizes, by gained micronizing Azilsartan sample censorship related substance.
Embodiment 3: Azilsartan is synchronizeed with liquid nitrogen and added continuously FDV type gas to draw formula ultrafine crusher Azilsartan is pulverized.
Get Azilsartan 200g, start pulverizer, Azilsartan is added to pulverizer from charge door in batches, each about 5g of addition, adds after once pulverizing 10～15s and again adds, simultaneously, continuous liquid nitrogen added to pulverizer from charge door, to guarantee that pulverizing system is in low-temperature condition, after 200g Azilsartan is pulverized completely, the Azilsartan micro mist of collecting from discharging opening.Azilsartan micro mist impurity I, impurity II and impurity III are less than 0.1%, size distribution D (90) < 10 μ m.
Embodiment 4:
The preparation method of compound:
Get Azilsartan (shown in IV) 2g, add in 20mL1mol/L hydrochloric acid, stir and be warming up to 60 ℃ of reaction 3h, be cooled to stirring at room temperature 1h, filter, filter cake adds stirring at room temperature 30min in 5mL methyl alcohol, filter, 60 ℃ of filter cakes are dry, obtain impurity I(suc as formula shown in I).
Embodiment 5:
The preparation method of compound:
Get Azilsartan 5g, add in 50mL carrene, add 1.1g pyridine, stir temperature control below 10 ℃, be added dropwise to 1.6g thionyl chloride reaction 3h, add 2mL methyl alcohol, rise to room temperature reaction 3h, with 50mL0.1mol/L salt acid elution organic layer twice, organic layer is used 50mL10% sodium acid carbonate washed twice again, divide and get organic layer evaporate to dryness, obtain impurity II.
Embodiment 6:
The preparation method of compound:
Get Azilsartan 5g, add in 20mLDMF, be warming up to 130 ℃ of reaction 4h, be cooled to stirring at room temperature 1h, filter, 60 ℃ of filter cakes are dry, and gained sample obtains impurity III through separation and purification.
Embodiment 7:
Instrument and equipment: Waters prepares liquid phase
Separation method 1:
Mobile phase: A: methyl alcohol, B: water
| Time | A（%） | B（%） |
| 0 | 40 | 60 |
| 5 | 40 | 60 |
| 30 | 80 | 20 |
| 40 | 80 | 20 |
| 40.01 | 95 | 5 |
| 43.00 | 95 | 5 |
| 47.00 | 40 | 60 |
Flow velocity: 17.06ml/min
Running time: 45min
Detect wavelength: 225nm
Sample size: 500 microlitres
The part of enrichment 36～38min, according to the further separation and purification of separation method 2.
Separation method 2:
Mobile phase: A: acetonitrile, B: water
| Time | A（%） | B（%） |
| 0 | 25 | 75 |
| 5 | 25 | 75 |
| 30 | 58 | 42 |
| 38 | 58 | 42 |
| 38.01 | 95 | 5 |
| 42.00 | 95 | 5 |
| 42.01 | 25 | 75 |
Flow velocity: 17.06ml/min
Running time: 45min
Detect wavelength: 225nm
Sample size: 500 microlitres
The part of collecting 37～38min, obtains impurity III.
Embodiment 8:
The related substance of sample detects:
By Azilsartan, micro mist sample, Azilsartan low-temperature fine powder sample, Azilsartan high speed disintegrator are not pulverized 30s sample, Azilsartan high speed disintegrator is pulverized 300s sample, carry out HPLC detection according to following condition:
Azilsartan sample concentration: 0.3mg/mL
Gradient condition: mobile phase A: 0.5% triethylamine solution (phosphoric acid regulates pH2.8); Mobile phase B: acetonitrile
Detect in order to upper chromatographic condition, can obtain Azilsartan, the content of impurity I, impurity II and impurity III, can know that by this detection method of the present invention can obtain impurity I, impurity II and the low Azilsartan of impurity III content, thereby effectively control product quality.
Claims (10)
1. an Azilsartan method of micronization, described method is included in micronization process, the method that adopts ultralow temperature to pulverize.
2. the method for claim 1, comprises Azilsartan is mixed with liquid nitrogen and carries out micronized step.
3. the method for claim 1, is that Azilsartan is mixed with liquid nitrogen, synchronously enters gas and draws formula ultrafine crusher sample is pulverized.
4. the method for claim 1, comprise the following steps: start pulverizer, Azilsartan is added to pulverizer from charge door in batches, each about 5g of addition, add after once pulverizing 10～15s and again add, meanwhile, continuous liquid nitrogen added to pulverizer from charge door, to guarantee that pulverizing system is in low-temperature condition.
5. the method for claim 1, the size distribution of gained Azilsartan micro mist is D (90) < 10 μ m, impurity I, impurity II and impurity III are less than 0.1%.
6. formula I compound
7. formula II compound
8. formula III compound
9. an Azilsartan micro mist, wherein impurity I, impurity II and impurity III are less than 0.1%.
10. a pharmaceutical composition, contains Azilsartan micro mist claimed in claim 9.
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| CN201410025070.2A CN103831159B (en) | 2014-01-20 | 2014-01-20 | A kind of Azilsartan method of micronization |
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| CN201410025070.2A CN103831159B (en) | 2014-01-20 | 2014-01-20 | A kind of Azilsartan method of micronization |
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| CN103831159B CN103831159B (en) | 2016-04-13 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106841415A (en) * | 2016-12-20 | 2017-06-13 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of Azilsartan raw material and its preparation |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011158880A1 (en) * | 2010-06-16 | 2011-12-22 | 武田薬品工業株式会社 | Crystal of amide compound |
| CN102580097A (en) * | 2012-03-16 | 2012-07-18 | 江苏先声药物研究有限公司 | Medicinal composition containing azilsartan |
| CN102895205A (en) * | 2012-11-09 | 2013-01-30 | 重庆市力扬医药开发有限公司 | Rapidly-dissolved azilsartan pharmaceutical preparation |
-
2014
- 2014-01-20 CN CN201410025070.2A patent/CN103831159B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011158880A1 (en) * | 2010-06-16 | 2011-12-22 | 武田薬品工業株式会社 | Crystal of amide compound |
| CN102580097A (en) * | 2012-03-16 | 2012-07-18 | 江苏先声药物研究有限公司 | Medicinal composition containing azilsartan |
| CN102895205A (en) * | 2012-11-09 | 2013-01-30 | 重庆市力扬医药开发有限公司 | Rapidly-dissolved azilsartan pharmaceutical preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106841415A (en) * | 2016-12-20 | 2017-06-13 | 合肥拓锐生物科技有限公司 | About the analysis method of material in a kind of Azilsartan raw material and its preparation |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
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Effective date of registration: 20160831 Address after: 100028 Beijing City, Chaoyang District Shuguang Sirirath A Phoenix Plaza No. 5 block 27 layer Patentee after: BEIJING PHARMACEUTICAL GROUP Co.,Ltd. Address before: 100124 Beijing city Chaoyang District Baiziwan West No. 402 Business Center No. 2 Fu Jinhai floor 21 Patentee before: CHINA RESOURES SAIKE PHARMACEUTICAL Co.,Ltd. |
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