CN106977496A - A kind of crystallization preparation method of candesartan Cilexetil - Google Patents
A kind of crystallization preparation method of candesartan Cilexetil Download PDFInfo
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- CN106977496A CN106977496A CN201710145305.5A CN201710145305A CN106977496A CN 106977496 A CN106977496 A CN 106977496A CN 201710145305 A CN201710145305 A CN 201710145305A CN 106977496 A CN106977496 A CN 106977496A
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- candesartan cilexetil
- crystal formation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of crystallization preparation method of candesartan Cilexetil is less than 10 μm of candesartan Cilexetil crystal formation I crystallization preparation method the present invention relates to a kind of granularity, its product HPLC contents are up to more than 99.5%, particle diameter distribution is uniform, the one way molar yield of crystallization process is more than 85%, avoid the treatment process such as pulverizing process or spray drying, fundamentally solve the problem for the product stability decline that pulverized zone is come, avoid the quality problems such as product reunion caused by drying, method is simple and easy to apply, production cost is low, is adapted to industrialized production.
Description
Technical field
The present invention relates to crystallization technique field, more particularly to a kind of candesartan Cilexetil crystal formation I crystallization preparation method.
Background technology
Candesartan Cilexetil（No. CAS：145040-37-5）It is treatment high blood pressure disease as the pro-drug of Candesartan
Preferable medication selection one of.Compared with other depressor, candesartan Cilexetil has be discontinued after without hypertension rebound phenomenon and can keep away
The advantages of exempting from tachycardia phenomenon, is particularly suitable for use in old patient.In addition, there is polymorphism in candesartan Cilexetil, but only
There is crystal formation I as its medicinal crystal-form and be used for clinical treatment.
Candesartan Cilexetil solubility in water is relatively low, and its solute effect in human body fluid is poor, is unfavorable for drug effect
Play.In general, the size of insoluble medicine granularity and the speed of its dissolved corrosion have very strong relevance, i.e. granularity is got over
Small, drug-eluting speed is faster.By reducing the granularity of candesartan Cilexetil, its dissolution rate just can be improved, and then can reach and carry
The basic goal of high-drug-effect.
Reducing the method for candesartan Cilexetil granularity has a many kinds, and crushing is at one kind the easiest in early stage production technology
Reason mode.However, the problem of product is degraded easily occurs in crushing process for candesartan Cilexetil.To ensure candesartan Cilexetil product
Stability, most enterprises at present no longer using crushing by the way of, but crystallized by regulation and control or the mode such as drying process come
Realize the purpose for reducing candesartan Cilexetil granularity.Chinese patent 201310340686.4 is molten as crystallizing with water using lower alcohol
Agent, directly prepared sizes can be less than 20 μm of candesartan Cilexetil by way of solution is crystallized.Although avoiding powder using the method
Broken process, but its preparation method is only applicable to specific armorphous candesartan Cilexetil, due to candesartan Cilexetil crystal formation I in a solvent
Solubility be much smaller than armorphous candesartan Cilexetil, the preparation method is not particularly suited for the low candesartan Cilexetil crystal formation I of solubility
（Medicinal crystal-form）It is refined.Patent application 201310238693.3 is beaten the ethanol solution of candesartan Cilexetil using emulsifying agent
After slurry pretreatment, the candesartan Cilexetil crystal formation I products that granularity is less than 11 μm can be obtained by way of spray drying.Though this method
The product granularity so obtained is smaller, but during need peristaltic pump to convey solid-liquid mixture, easily block in material conveying process
Pipeline, and then influence the homogeneity of spray drying different periods product.In addition, spray drying device purchase and maintenance cost compared with
It is high, in addition it is also necessary to additionally to increase waste gas recovering device, can all cause the raising of production cost.Therefore, find a kind of without crushing, mistake
Journey is simple to operate, production cost is low, the small grain size candesartan Cilexetil preparation method of suitable industrialized production is particularly important.
The content of the invention
It is less than 10 μm of candesartan Cilexetil crystal formation I crystallization preparation method it is an object of the invention to provide a kind of granularity.
The technical scheme is that a kind of granularity is less than 10 μm of candesartan Cilexetil crystal formation I crystallization preparation method, its
It is characterised by：
The first step dissolves the in the mixed solvent that candesartan Cilexetil crystal formation I crude products add acetone and water；
Second step is filtered, by filtrate fast cooling to 5~10 DEG C, and candesartan Cilexetil crystal formation I crystal seed is added at this temperature,
And constant temperature stirs 1~3h；Then water is added, continues constant temperature and stirs 1~3h；
3rd step is filtered, and washs filter cake, is dried to obtain the candesartan Cilexetil crystal formation I products that granularity is less than 10 μm.
, according to the invention it is preferred to, during first step dissolving candesartan Cilexetil crystal formation I crude products, the matter of crude product and solvent for use
Amount continuously stirs dissolving 30~60 minutes than being 0.05~0.1 g/g at 20~30 DEG C.
, according to the invention it is preferred to, the mixed solvent of acetone and water described in the first step, matter of the acetone in the mixed solvent
It is 70%~90% to measure fraction.
, according to the invention it is preferred to, during second step fast cooling, rate of temperature fall is 5~10 DEG C/min, when liquid temperature is down to 5
At~10 DEG C, candesartan Cilexetil crystal formation I crystal seeds are added, amount of seed is the 1%~3% of raw material weight.
, according to the invention it is preferred to, second step adds crystal seed and constant temperature is stirred after 1~3h, and into system, stream adds initial molten
The water of 8~10 times of acetone weight in liquid, stream rate of acceleration is 1~5 g/min.
According to the present invention, the filter cake after the filtering of the 3rd step is washed with one kind in water, acetone；Collect after washing
Filter cake, is dried under 40~60 DEG C, normal pressure.
The beneficial effects of the invention are as follows there is provided a kind of candesartan Cilexetil crystal formation I crystallization preparation method, its product HPLC
Content is up to more than 99.5%, and granularity is less than 10 μm, and particle diameter distribution is uniform, the one way molar yield of crystallization process more than 85%,
The treatment process such as pulverizing process or spray drying are avoided, the difficulty for the product stability decline that pulverized zone is come fundamentally is solved
Topic, it is to avoid product caused by drying such as is reunited at the quality problems, method is simple and easy to apply, and production cost is low, is adapted to industrialized production.
Brief description of the drawings
Fig. 1 is candesartan Cilexetil crystal formation I Granularity Distribution figures.
Embodiment：
Content, is described further with reference to specific embodiment for a better understanding of the present invention, but the present invention is not only limited to
This.
Embodiment 1
5g candesartan Cilexetil crystal formations I is added and fills 100 g acetone and water mixed solvent（Mass ratio is 7:3）Crystallizer in,
The stirring and dissolving at 20 DEG C, was continuously stirred after 30 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 5 DEG C, cooling speed
Rate be 10 DEG C/min, backward crystallizer in add 0.05g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 3h, it
Stream plus 700g water in backward crystallizer, stream rate of acceleration is 1g/min.Constant temperature stirs 1h in this case afterwards.Suction filtration, is used in combination
Acetone washs filter cake, is dried under 40 DEG C of condition of normal pressure 8 hours, and crystal formation I product yields are that 85.2%, HPLC purity is
99.8%, Granularity Distribution is uniform, D100For 9.83 μm（See Fig. 1）.
Embodiment 2
10g candesartan Cilexetil crystal formations I is added and fills 100 g acetone and water mixed solvent（Mass ratio is 4:1）Crystallizer in,
The stirring and dissolving at 30 DEG C, was continuously stirred after 60 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 10 DEG C, cooling speed
Rate be 10 DEG C/min, backward crystallizer in add 0.15g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 2h, it
Stream plus 720g water in backward crystallizer, stream rate of acceleration is 5g/min.Constant temperature stirs 3h in this case afterwards.Suction filtration, is used in combination
Acetone washs filter cake, is dried under 50 DEG C of condition of normal pressure 10 hours, and crystal formation I product yields are that 88.4%, HPLC purity is
99.7%, Granularity Distribution is uniform, D100For 8.92 μm.
Embodiment 3
10g candesartan Cilexetil crystal formations I is added and fills 100 g acetone and water mixed solvent（Mass ratio is 4:1）Crystallizer in,
The stirring and dissolving at 30 DEG C, was continuously stirred after 60 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 10 DEG C, cooling speed
Rate be 10 DEG C/min, backward crystallizer in add 0.15g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 2h, it
Stream plus 720g water in backward crystallizer, stream rate of acceleration is 5g/min.Constant temperature stirs 3h in this case afterwards.Suction filtration, is used in combination
Water washing filter cake, is dried 10 hours under 60 DEG C of condition of normal pressure, and crystal formation I product yields are that 88.7%, HPLC purity is
99.7%, Granularity Distribution is uniform, D100For 8.75 μm.
Embodiment 4
8g candesartan Cilexetil crystal formations I is added and fills 120 g acetone and water mixed solvent（Mass ratio is 9:1）Crystallizer in,
The stirring and dissolving at 25 DEG C, was continuously stirred after 45 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 5 DEG C, cooling speed
Rate be 8 DEG C/min, backward crystallizer in add 0.24g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 1h, afterwards
Stream plus 864g water into crystallizer, stream rate of acceleration are 3g/min.Constant temperature stirs 2h in this case afterwards.Suction filtration, and use third
Ketone washs filter cake, is dried under 40 DEG C of condition of normal pressure 9 hours, and crystal formation I product yields are that 86.4%, HPLC purity is
99.8%, Granularity Distribution is uniform, D100For 9.93 μm.
Embodiment 5
10g candesartan Cilexetil crystal formations I is added and fills 100 g acetone and water mixed solvent（Mass ratio is 17:3）Crystallizer
In, the stirring and dissolving at 25 DEG C was continuously stirred after 60 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 8 DEG C, cooling
Speed be 10 DEG C/min, backward crystallizer in add 0.1g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 3h, it
Stream plus 800g water in backward crystallizer, stream rate of acceleration is 4g/min.Constant temperature stirs 3h in this case afterwards.Suction filtration, is used in combination
Acetone washs filter cake, is dried under 40 DEG C of condition of normal pressure 10 hours, and crystal formation I product yields are that 87.2%, HPLC purity is
99.8%, Granularity Distribution is uniform, D100For 8.62 μm.
Embodiment 6
10g candesartan Cilexetil crystal formations I is added and fills 200 g acetone and water mixed solvent（Mass ratio is 3:1）Crystallizer in,
The stirring and dissolving at 20 DEG C, was continuously stirred after 30 minutes, filtering；Filtrate is moved into crystallizer, and is cooled to 10 DEG C, cooling speed
Rate be 5 DEG C/min, backward crystallizer in add 0.2g candesartan Cilexetil crystal seeds, and at this temperature constant temperature stir 3h, afterwards
Stream plus 1200g water into crystallizer, stream rate of acceleration are 5g/min.Constant temperature stirs 3h in this case afterwards.Suction filtration, and use water
Filter cake is washed, is dried under 40 DEG C of condition of normal pressure 10 hours, crystal formation I product yields are that 87.8%, HPLC purity is 99.7%,
Granularity Distribution is uniform, D100For 9.35 μm.
Claims (4)
1. a kind of granularity is less than 10 μm of candesartan Cilexetil crystal formation I crystallization preparation method, comprise the following steps：
The first step dissolves the in the mixed solvent that candesartan Cilexetil crystal formation I crude products add acetone and water；
Second step is filtered, by filtrate fast cooling to 5~10 DEG C, and candesartan Cilexetil crystal formation I crystal seed is added at this temperature,
And constant temperature stirs 1~3h；Then water is added, constant temperature stirs 1~3h；
3rd step is filtered, and washs filter cake, is dried to obtain the candesartan Cilexetil crystal formation I products that granularity is less than 10 μm.
2. preparation method according to claim 1, it is characterised in that in the first step, crystal formation I crude products and acetone used and water
The mass ratio of mixed solvent is 0.05~0.1 g/g.
3. preparation method according to claim 1, it is characterised in that the fast cooling described in second step, rate of temperature fall is 5
~10 DEG C/min.
4. according to any described preparation method of claim 1 or 2, it is characterised in that acetone and water used in the first step it is mixed
In bonding solvent, acetone is 70%~90% in the mass fraction of in the mixed solvent.
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| CN201710145305.5A CN106977496A (en) | 2017-03-13 | 2017-03-13 | A kind of crystallization preparation method of candesartan Cilexetil |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791256A (en) * | 2009-06-19 | 2012-11-21 | 成药技术Ip控股（泽西）有限公司 | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| CN104758252A (en) * | 2014-01-03 | 2015-07-08 | 广东东阳光药业有限公司 | Candesartan cilexetil composition |
| CN106432201A (en) * | 2016-09-14 | 2017-02-22 | 威海迪素制药有限公司 | Preparation method for candesartan cilexetil crystals |
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2017
- 2017-03-13 CN CN201710145305.5A patent/CN106977496A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791256A (en) * | 2009-06-19 | 2012-11-21 | 成药技术Ip控股（泽西）有限公司 | Nanoparticulate candesartan cilexetil compositions, process for the preparation thereof and pharmaceutical compositions containing them |
| CN104758252A (en) * | 2014-01-03 | 2015-07-08 | 广东东阳光药业有限公司 | Candesartan cilexetil composition |
| CN106432201A (en) * | 2016-09-14 | 2017-02-22 | 威海迪素制药有限公司 | Preparation method for candesartan cilexetil crystals |
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