CN103831159B - A kind of Azilsartan method of micronization - Google Patents
A kind of Azilsartan method of micronization Download PDFInfo
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- CN103831159B CN103831159B CN201410025070.2A CN201410025070A CN103831159B CN 103831159 B CN103831159 B CN 103831159B CN 201410025070 A CN201410025070 A CN 201410025070A CN 103831159 B CN103831159 B CN 103831159B
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- azilsartan
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Abstract
The invention discloses a kind of Azilsartan method of micronization, described method is included in micronization process, and the method adopting ultralow temperature to pulverize, comprises Azilsartan is mixed the step of carrying out micronization with liquid nitrogen.
Description
Technical field:
The invention belongs to medicinal chemistry art, 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-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylic acid, its structure, such as formula shown in IV, is researched and developed by Japanese Takeda Pharmaceutical Company Limited (Takeda), in 2012 in Japan's listing, there are 20mg, 40mg two kinds of specifications.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 limiting its absorption and bioavilability.According to Noyes-Whimey equation, reduce drug particles particle diameter, increase its specific area and wetability, thus reach the rapidly-soluble object promoting particle, therefore, micronization technology becomes the important channel solving insoluble drug dissolution rate problem.
Carrying out in micronization process to medicine, carrying out pulverizing with high speed machine shear pulverizer to medicine is conventional means, also the most cheap, the present inventor finds carrying out micronizing pulverizing with high speed machine shear pulverizer to Azilsartan raw material, the Azilsartan micro mist obtained with there is no the Azilsartan raw material before pulverizing and compare, had more three new impurity, impurity I, impurity II and impurity III, carry out qualitative to these three impurity, its structure is such as formula I, shown in formula II, formula III.
These impurity belong to unknown impuritie, belong to new compound, and the present invention is to this has been structural confirmation, and its spectroscopic data is as follows respectively:
(1) impurity I (removing ethyl impurity), shown in I, produces at high temperature, acidity or mechanical shearing crushing process or increases;
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 extends along with shear time and increase;
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 extends along with shear time and increase.
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)。
Obtained 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 produced in crushing process relevant with high speed machine, for this reason, the present inventor shears in crushing process at high speed machine and reduces temperature, surprised discovery, effectively can control impurity level by the temperature reduced in micronization process, ensure 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, adopts the method that ultralow temperature is pulverized.
Method of the present invention, comprises Azilsartan to mix with liquid nitrogen and carries out micronized step.
Method of the present invention is mixed with liquid nitrogen by Azilsartan, synchronously enters gas and draw formula ultrafine crusher and pulverize sample.
Preferably, method of the present invention comprises the following steps: start pulverizer, Azilsartan is added pulverizer from charge door in batches, each addition is about 5g, add after once pulverizing 10 ~ 15s and again add, meanwhile, liquid nitrogen continuous print is added pulverizer from charge door, to ensure 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 μm.
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, containing Azilsartan micro mist of the present invention.
Because three kinds of impurity of the present invention are that the present invention obtains first, the present invention's also these three compounds claimed for this reason
The preparation method of these three compounds is that the Azilsartan micro mist obtained, carries out separation and purification with preparative liquid chromatograph to Azilsartan impurity by Azilsartan raw material high speed jet mill is carried out micronizing pulverizing, 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:
High speed machine shear pulverizer is adopted to carry out mechanical shearing pulverizing to the non-micropowder samples of Azilsartan:
Detect and adopt HPLC method,
The non-micropowder samples of Azilsartan: impurity I 0.02%, impurity II do not detect, impurity III does not detect.
Azilsartan mechanical shearing pulverizes 30s: impurity I 0.11, impurity II 0.09, impurity III 0.05.
Azilsartan mechanical shearing pulverizes 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 operated by ultralow temperature micro mist, control the degraded of Azilsartan, make the potential impurity of Azilsartan in controlled range, can obtain by this kind of micro mist technique the sample meeting preparation granularity requirements simultaneously.
Accompanying drawing illustrates:
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
Detailed description of the invention:
In conjunction with specific embodiments, set forth content of the present invention further, specific embodiment is not used in for illustration of content of the present invention and limits the scope of the invention.
Embodiment 1:RF-08 type high speed machine shear pulverizer intermittence pulverizes Azilsartan 30s.
Get 200g Azilsartan and be placed in RF-08 type high speed disintegrator, intermittent pulverizing 30s, by gained micronizing Azilsartan sample censorship related substance.
Embodiment 2:RF-08 type high speed disintegrator intermittence pulverizes Azilsartan 300s.
Get 50g Azilsartan and be placed in RF-08 type high speed disintegrator, intermittent pulverizing 300s, by gained micronizing Azilsartan sample censorship related substance.
Embodiment 3: Azilsartan is synchronous with liquid nitrogen to add FDV type gas continuously and draw formula ultrafine crusher and pulverize Azilsartan.
Get Azilsartan 200g, start pulverizer, Azilsartan is added pulverizer from charge door in batches, each addition is about 5g, adds after once pulverizing 10 ~ 15s and again adds, simultaneously, liquid nitrogen continuous print is added pulverizer from charge door, to ensure that pulverizing system is in low-temperature condition, after 200g Azilsartan is pulverized completely, from the Azilsartan micro mist that discharging opening is collected.Azilsartan micro mist impurity I, impurity II and impurity III are less than 0.1%, size distribution D (90) < 10 μm.
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 DEG C 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, filter cake 60 DEG C of dryings, obtain impurity I(such 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 less than 10 DEG C, 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 washes twice with 50mL10% sodium acid carbonate 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 DEG C of reaction 4h, be cooled to stirring at room temperature 1h, filter, filter cake 60 DEG C of dryings, 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
Determined wavelength: 225nm
Sample size: 500 microlitres
The part of enrichment 36 ~ 38min, according to separation method 2 separation and purification further.
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
Determined wavelength: 225nm
Sample size: 500 microlitres
Collect the part of 37 ~ 38min, obtain impurity III.
Embodiment 8:
The related substance of sample detects:
By non-for Azilsartan micropowder samples, Azilsartan low-temperature fine powder sample, 30s sample pulverized by Azilsartan high speed disintegrator, 300s sample pulverized by Azilsartan high speed disintegrator, carries 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, Azilsartan can be obtained, by this detection, the content of impurity I, impurity II and impurity III, can know that method of the present invention can obtain the low Azilsartan of impurity I, impurity II and impurity III content, thus effectively control product quality.
Claims (8)
1. an Azilsartan method of micronization is mixed with liquid nitrogen by Azilsartan, synchronously enters gas and draw formula ultrafine crusher and pulverize sample.
2. the method for claim 1, comprise the following steps: start pulverizer, Azilsartan is added pulverizer from charge door in batches, each addition is about 5g, add after once pulverizing 10 ~ 15s and again add, meanwhile, liquid nitrogen continuous print is added pulverizer from charge door, to ensure that pulverizing system is in low-temperature condition.
3. the method for claim 1, the size distribution of gained Azilsartan micro mist is D (90) < 10 μm, and impurity I, impurity II and impurity III are less than 0.1%,
Wherein, the structure of described impurity I is as follows:
Wherein, the structure of described impurity II is as follows:
Wherein, the structure of described impurity III is as follows:
4. formula I
5. formula II compound
6. formula III compound
7. an Azilsartan micro mist, wherein impurity I, impurity II and impurity III are less than 0.1%,
Wherein, the structure of described impurity I is as follows:
Wherein, the structure of described impurity II is as follows:
Wherein, the structure of described impurity III is as follows:
8. a pharmaceutical composition, containing Azilsartan micro mist according to claim 7.
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| CN106841415B (en) * | 2016-12-20 | 2019-03-22 | 合肥拓锐生物科技有限公司 | Analysis method in relation to substance in a kind of Azilsartan raw material and its preparation |
| CN111454255B (en) * | 2020-06-03 | 2022-03-18 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| KR20130119903A (en) * | 2010-06-16 | 2013-11-01 | 다케다 야쿠힌 고교 가부시키가이샤 | Crystal of amide compound |
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| 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 |
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