CN110041320A - A kind of preparation method of the crystallization of Azilsartan - Google Patents
A kind of preparation method of the crystallization of Azilsartan Download PDFInfo
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- CN110041320A CN110041320A CN201910334815.6A CN201910334815A CN110041320A CN 110041320 A CN110041320 A CN 110041320A CN 201910334815 A CN201910334815 A CN 201910334815A CN 110041320 A CN110041320 A CN 110041320A
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- azilsartan
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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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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention provides a kind of preparation methods of the crystallization of Azilsartan, comprising the following steps: Azilsartan is dissolved in the in the mixed solvent of alcohol and water；Distill out a part of mixed solvent；Water is added, cool down crystallization；Solid is separated, it is dry, obtain the crystallization of Azilsartan.The crystallization for the Azilsartan that the present invention is prepared is the Azilsartan of the micronization of high-purity, and particle diameter distribution is controllable and meets the requirement of pharmaceutical preparation.Compared with the Azilsartan for the micronization that mechanical crushing method is prepared, the Azilsartan shelf stability for the micronization that the present invention is prepared is more preferable.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of preparation method of the crystallization of Azilsartan.
Background technique
Azilsartan (Azilsartan) is a kind of selective angiotensin II receptor antagonist (abbreviation ARB), is had
Decompression and nervous centralis effect, can be used alone or be used together with other blood-pressure drugs, public by Japanese military field pharmacy
(Takeda) research and development are taken charge of, are got the Green Light listing in January, 2012 in Japan, trade nameThe change of Azilsartan
Scientific name is known as 2- ethyoxyl -1- { [2'- (2,5- dihydro -5- oxo -1,2,4- oxadiazoles -3- base) biphenyl -4- base] methyl } benzene
And imidazoles -7- carboxylic acid, structural formula are shown in formula I.
Azilsartan belongs to insoluble drug, almost insoluble in water.For such insoluble drug, in order to promote drug
Particle quickly dissolves, and improves bioavailability, needs to reduce drug granule partial size.Therefore, the medicinal forms of Azilsartan are micro-
Atomized particles.The method of the Azilsartan of traditional preparation micronization is but the Azilsartan powder using the means being mechanically pulverized
Thermal stability is bad when broken, and impurity can be generated in crushing process.Azilsartan mainly generates three kinds of impurity in crushing process
(referred to herein as impurity A, impurity B and impurity F), respectively as shown in Formula Il, formula III, formula IV.
The Azilsartan of micronization with high purity in order to obtain, by liquid nitrogen and A Qisha in Chinese patent CN103831159A
Smooth mixing is crushed.However, this method needs nitrogen ultra low temperature condition, operating condition is harsh, and this method is not suitable for industrialization
Large-scale production.
Therefore, it is necessary to develop, a kind of operating condition is mild, is suitble to the micronization of the preparation high-purity of industrialized production
The method of Azilsartan.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of the crystallization of Azilsartan, and this method is easy to operate, are easy to work
Industry application, and the purity is high of the crystallization of the Azilsartan of obtained micronization, thermal stability is good, and particle diameter distribution is controllable and accords with
The requirement of composite medicine preparation.
The method of the crystallization for preparing Azilsartan of the invention the following steps are included:
(1) Azilsartan is dissolved in the in the mixed solvent of alcohol and water；
(2) mixed solvent of the 5%-30% of the mixed solvent total weight is distilled out；
(3) water is added, is cooled to 0-5 DEG C of crystallization；
(4) solid is separated, it is dry, obtain the crystallization of Azilsartan.
According to the method for the present invention, wherein purity >=98% of Azilsartan described in step (1).
According to the method for the present invention, wherein the alcohol of in the mixed solvent described in step (1) can be methanol and/or ethyl alcohol,
Preferred alcohol.
According to the method for the present invention, wherein the weight ratio of the alcohol and water of in the mixed solvent described in step (1) (g/g, or
Person, Kg/Kg) it is 4:1-20:1, preferably 9:1-10:1.
According to the method for the present invention, wherein the weight ratio of mixed solvent described in step (1) and Azilsartan (g/g, or
Person, Kg/Kg) it is 30:1-80:1, preferably 40:1-50:1.
According to the method for the present invention, wherein step (1) 35-60 DEG C at a temperature of carry out, preferably in 40-60 DEG C of temperature
Degree is lower to carry out.
According to the method for the present invention, wherein distill out the 10%-20%'s of the mixed solvent total weight in step (2)
Mixed solvent.
According to the method for the present invention, wherein control speed of agitator is 100-150 revs/min in step (2).
According to the method for the present invention, wherein the water that the water being added in step (3) is 0-5 DEG C.
According to the method for the present invention, wherein the weight ratio of the water and Azilsartan that are added in step (3) (g/g, alternatively,
It Kg/Kg) is 10:1-40:1, preferably 20:1-30:1.
According to the method for the present invention, wherein cooled down in step (3) with 1-4 DEG C/min of rate, preferably with 1-2 DEG C/minute
The rate of clock cools down.
According to the method for the present invention, wherein control speed of agitator is 100-150 revs/min in step (3).
According to the method for the present invention, wherein the size distribution of the crystallization of Azilsartan obtained in step (4) be 3 μm≤
D50≤20 μm, purity are greater than 99.8%.
Without limitation, the X-ray powder diffraction (XRPD) of the crystallization of Azilsartan prepared in accordance with the method for the present invention
Map is as shown in Figure 2.
Without limitation, differential scanning calorimetry (DSC) figure of the crystallization of Azilsartan prepared in accordance with the method for the present invention
Spectrum is as shown in Figure 3.
Without limitation, thermogravimetric analysis (TGA) map of the crystallization of Azilsartan prepared in accordance with the method for the present invention is such as
Shown in Fig. 4.
The method that the present invention prepares the crystallization of Azilsartan is easy to operate, is easy to industrial applications.The present invention is prepared
Azilsartan crystallization be high-purity micronization Azilsartan, particle diameter distribution is controllable and meets wanting for pharmaceutical preparation
It asks.Compared with the Azilsartan for the micronization that mechanical crushing method is prepared, the A Qisha for the micronization that the present invention is prepared
Smooth shelf stability is more preferable.
Detailed description of the invention
Fig. 1 is the particle size distribution figure of the crystallization for the Azilsartan that embodiment 1 obtains.
Fig. 2 is the XRPD map of the crystallization for the Azilsartan that embodiment 1 obtains.
Fig. 3 is the DSC map of the crystallization for the Azilsartan that embodiment 1 obtains.
Fig. 4 is the TGA map of the crystallization for the Azilsartan that embodiment 1 obtains.
Fig. 5 is the particle size distribution figure of the crystallization for the Azilsartan that embodiment 2 obtains.
Fig. 6 is the particle size distribution figure of the crystallization for the Azilsartan that embodiment 3 obtains.
Fig. 7 is the particle size distribution figure of the Azilsartan for the crushing that comparative example 1 obtains.
Specific embodiment
The following example further explains the present invention, still, they and be not meant to limit the scope of the invention or
It limits.
Facility information used in the present invention is as follows:
The information of primary raw material used in the embodiment of the present invention is as follows:
Embodiment 1: 150 revs/min of mixing speed, the Azilsartan for crystallizing to be micronized
400Kg ethyl alcohol and 40Kg purified water are added in 1000L reaction kettle, stirring is warming up to 45-55 DEG C, and it is pure that 10Kg is added
The Azilsartan that degree is 98.5% dissolves, 150 revs/min of mixing speed is controlled, in bath temperature for insulated and stirred 5-20 minutes
60-70 DEG C, decompression precipitation goes out about 60Kg solvent, and 200Kg ice water is added, and controls 1-2 DEG C/min of rate of temperature fall, is cooled to 0-5
DEG C, keep the temperature 10 minutes, filter to obtain wet product, be dried in vacuo in 40-50 DEG C 8.6Kg Azilsartan crystallization, yield 86%, purity
99.9%.
Sample detection particle diameter distribution, is shown in Fig. 1；Sample detection XRPD, DSC and TGA are shown in Fig. 2 to Fig. 4 respectively.
The Azilsartan reported in the crystallization of Azilsartan made from embodiment 1 and patent document CN201110158635.0
Crystallization XRPD 2 θ compare it is as shown in Table 1 below.
Table 1
Embodiment 2: 110 revs/min of mixing speed, micronization Azilsartan is crystallized to obtain
360Kg ethyl alcohol, 40Kg purified water are added in 1000L reaction kettle, stirring is warming up to 50-60 DEG C, and it is pure that 10Kg is added
The Azilsartan that degree is 98.5%, insulated and stirred 5-20 minutes, filtering, filtrate controlled 110 revs/min of mixing speed, in water-bath
50-60 DEG C of temperature, decompression precipitation goes out about 80Kg solvent, and 300Kg ice water is added, and controls 1-2 DEG C/min of rate of temperature fall, is cooled to
0-5 DEG C, keep the temperature 10 minutes, be centrifuged to obtain wet product, be dried in vacuo in 40-50 DEG C 8.1Kg Azilsartan crystallization, yield 81%,
Purity 99.9%.
Sample detection particle diameter distribution, is shown in Fig. 5；Sample detection XRPD, DSC and TGA, map is consistent with Fig. 2 to Fig. 4,
This is not repeated to provide.
Embodiment 3: in ultrasonic wave, micronization Azilsartan is crystallized to obtain
500g methanol, 50g purified water are added in 1L four-hole bottle, stirring is warming up to 50-60 DEG C, 10g Azilsartan is added,
Insulated and stirred 5-20 minutes, filtering, filtrate controlled 400 revs/min of mixing speed, and at 60-70 DEG C of bath temperature, decompression precipitation goes out
About 60g solvent, four-hole bottle is put into ultrasound bath, and 200g ice water is added in four-hole bottle, is cooled to 0-5 DEG C, heat preservation 10
Minute, filter to obtain wet product, be dried in vacuo in 40-50 DEG C 8.3g Azilsartan crystallization, yield 83%, purity 99.9%.
Sample detection particle diameter distribution, is shown in Fig. 6.Sample detection XRPD, DSC and TGA, map is consistent with Fig. 2 to Fig. 4,
This is not repeated to provide.
Comparative example 1: air-stream type ultrafine pulverizer prepares Azilsartan micro mist
1.4Kg ethyl alcohol is added in 3L reaction kettle, 150g purified water is warming up to 60-65 DEG C, and 50g Azilsartan is added, and protects
Temperature 30 minutes, filtering；Filtrate controls 35-45 revs/min of mixing speed, and at 40-50 DEG C of bath temperature, decompression precipitation goes out about 700g
Solvent is cooled to 0-5 DEG C, keeps the temperature 1h, is centrifuged to obtain wet product, 46.6g Azilsartan, yield are dried in vacuo to obtain in 40-50 DEG C
93.2%, purity 99.8%.10g Azilsartan is taken, using FMS air-stream type ultrafine pulverizer, slowly charging is crushed, and obtains 6g crushing
Azilsartan.
Sample detection particle diameter distribution, is shown in Fig. 7.
The test of the related material stability of test example 1
The crystallization of Azilsartan made from Example 1, respectively at 1 month and 60 DEG C 1 Zhou Houjian of storage of 20-30 DEG C of storage
Related substance is surveyed, see Table 2 for details.
Table 2
The Azilsartan and smashed Azilsartan in comparative example 1 before crushing obtained are taken, is stored respectively at 20-30 DEG C
January and 60 DEG C storage 1 week after detect related substance, see Table 3 for details.
Table 3
By stability test above it is found that the related content of material of the crystallization for the Azilsartan that the present invention is prepared
Low, stability is more preferable.
Claims (5)
1. a kind of method for the crystallization for preparing Azilsartan, comprising the following steps:
(1) Azilsartan is dissolved in the in the mixed solvent of alcohol and water；
(2) mixed solvent of the 5%-30% of the mixed solvent total weight is distilled out；
(3) water is added, is cooled to 0-5 DEG C of crystallization；
(4) solid is separated, it is dry, obtain the crystallization of Azilsartan.
2. according to the method described in claim 1, wherein, purity >=98% of Azilsartan described in step (1)；Step (1)
Described in the alcohol of in the mixed solvent be methanol and/or ethyl alcohol, preferred alcohol；The alcohol and water of in the mixed solvent described in step (1)
Weight ratio be 4:1-20:1, preferably 9:1-10:1；The weight ratio of mixed solvent described in step (1) and Azilsartan is 30:
1-80:1, preferably 40:1-50:1；Step (1) 35-60 DEG C at a temperature of carry out, preferably 40-60 DEG C at a temperature of carry out.
3. according to the method described in claim 2, wherein, the 10%- of the mixed solvent total weight is distilled out in step (2)
20% mixed solvent；Control speed of agitator is 100-150 revs/min in step (2).
4. according to the method in claim 2 or 3, wherein the water that the water being added in step (3) is 0-5 DEG C；In step (3)
The water of addition and the weight ratio of Azilsartan are 10:1-40:1, preferably 20:1-30:1；With 1-4 DEG C/min of speed in step (3)
Rate cooling, is preferably cooled down with 1-2 DEG C/min of rate；Control speed of agitator is 100-150 revs/min in step (3).
5. according to the method in claim 2 or 3, wherein the size distribution of the crystallization of Azilsartan obtained in step (4)
For 3 μm≤D50≤20 μm, purity is greater than 99.8%.
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| CN201910334815.6A CN110041320B (en) | 2019-04-24 | 2019-04-24 | Preparation method of azilsartan crystals |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2021001140A (en) * | 2019-06-21 | 2021-01-07 | 金剛化学株式会社 | Method for producing stable azilsartan fine crystals |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102827153A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森药业股份有限公司 | Crystal form of azilsartan and preparation method thereof |
-
2019
- 2019-04-24 CN CN201910334815.6A patent/CN110041320B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827153A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森药业股份有限公司 | Crystal form of azilsartan and preparation method thereof |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021001140A (en) * | 2019-06-21 | 2021-01-07 | 金剛化学株式会社 | Method for producing stable azilsartan fine crystals |
| JP7486763B2 (en) | 2019-06-21 | 2024-05-20 | 金剛化学株式会社 | Method for producing stable fine crystals of azilsartan |
| 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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