CN101560176A - Amorphous atorvastatin calcium and preparation method thereof - Google Patents
Amorphous atorvastatin calcium and preparation method thereof Download PDFInfo
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- CN101560176A CN101560176A CNA2008101041376A CN200810104137A CN101560176A CN 101560176 A CN101560176 A CN 101560176A CN A2008101041376 A CNA2008101041376 A CN A2008101041376A CN 200810104137 A CN200810104137 A CN 200810104137A CN 101560176 A CN101560176 A CN 101560176A
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- atorvastatincalcuim
- atorvastatin calcium
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Abstract
The invention discloses amorphous atorvastatin calcium the x diffraction figure of which has a diffraction peak at 28.0, 15.5, 9.8 and 4.7. The invention also discloses a preparation method of the amorphous atorvastatin calcium, which comprises the following steps: dissolving the atorvastatin calcium in an alcoholic solvent; dropwise adding water under the stirring condition or dropwise adding an atorvastatin calcium solution into the water under the stirring condition, and precipitating atorvastatin calcium solids; and then, filtering the solvent to obtain the amorphous atorvastatin calcium.
Description
Technical field
The present invention relates to a kind of new amorphous atropic Fa Tating calcium (atorvastatin calcium), and preparation method thereof.
Background technology
The chemical name of atorvastatincalcuim is [R-(R
*, R
*)]-2-(4-fluorophenyl)-beta-dihydroxyl-5-(1-first and second bases)-3-phenyl-4-[(phenyl amino) carbonyl]-1H-pyrroles-1-enanthic acid.Atorvastatincalcuim is a medicine complete synthesis, that highly selective suppresses the HMG-CoA reductase enzyme, and U.S. Warner-Lambert (afterwards incorporating Pfizer into) development was gone on the market in Britain, the U.S. with 1997, was third generation statins.Atorvastatincalcuim is a Statins blood lipid regulation medicine, is used for the treatment of the control of hypercholesterolemia and combined hyperlipidemia familial, coronary heart disease and cerebral apoplexy.
The method and the key intermediate that are used to prepare atorvastatin are disclosed in United States Patent (USP) 5,003,080,5,097,045,5,103,024,5,124,428,5,149,837,5,155,251,5,216,174,5,245,174,5,248,793,5,280,126,5, in 342,952 and 5,397,792.
Atorvastatincalcuim can exist with unbodied or two kinds of forms of crystallization shape, and wherein the atorvastatincalcuim with definite crystallization shape is disclosed among the WO97/03958.
In the prior art, disclose the four kinds of not syncrystallization of atorvastatincalcuim shape things, WO97/03958 relates to atorvastatincalcuim crystallized form (III), and is public in WO97/03959
Opened atorvastatincalcuim crystallized form (I), (II) and (IV), crystallization shape atorvastatincalcuim (I), (II), (III) and preparation method (IV) are open by prior art.
With comparing of crystallization shape, unbodied atorvastatincalcuim has many advantages, and unbodied atorvastatincalcuim has variable dissolution characteristics and obtains variable biological utilisation in some cases.In some treatments, some other has more superiority some bioavailability characteristic ratio.
In disclosed CN1379760A, CN1196679C, WO02083638, WO02057228, WO02083637, WO03078693, WO03068739, WO03018547, WO0142209, WO0071116 and WO0128999 patent, all introduced the preparation method of amorphous and noncrystalline shape atorvastatincalcuim and hydrate thereof.
Summary of the invention
The invention provides a kind of unformed atorvastatincalcuim, it has following X-RAY grating spectrum feature:
Instrument model: Bruker-AXS D8 Advance
Ccanspeed：0.5?Increment：0.25
Radiation: copper target emission
Start sweep voltage: 40KV
Anodic current: 40mA
Sample: smooth-flat-surface, thickness 0.5mm
The mensuration of X-ray diffraction characterizes the orderly of crystalline material based on the diffraction and the interference of dot matrix atom; Lattice structure shows that by the reflection (maximum interference) of X ray picture because their disordered structure, the capable material of amorphous does not demonstrate spike in diffraction, and they only characterize with flat curve.Use X-ray diffraction, so people can have no the crystal form or the non-crystalline state of ambiguous experimental material.
Of the present inventionly further provide a kind of method for preparing amorphous atorvastatin calcium, it has been eliminated the problems of the prior art and has been convenient to commercial-scale application.
The invention provides a kind of method for preparing amorphous atorvastatin calcium, the atorvastatincalcuim of atorvastatincalcuim crude product or crystallized form is dissolved in ethanol, methyl alcohol, Virahol, propyl carbinol or its mixture, add suitable elutriation and go out the precipitation of atorvastatincalcuim, by filtering or the centrifugal solid that obtains, solid vacuum-drying obtains unbodied atorvastatincalcuim.
Unbodied atorvastatincalcuim provided by the invention, compared with prior art, the yield height, simple to operate, be of value to suitability for industrialized production.
The method for preparing amorphous atorvastatin calcium that this patent provides comprises:
(1) atorvastatincalcuim with atorvastatincalcuim crude product or crystallized form is dissolved in the alcohol;
(2) adding entry or the atorvastatincalcuim drips of solution is added to the water is precipitated out;
(3) by filter or centrifugal remove to desolvate obtain amorphous atorvastatin calcium;
The available alcoholic solvent of the present invention can be selected from ethanol, methyl alcohol, Virahol, propyl carbinol or its mixture, preferred alcohol; Anti-solvent is a water; Precipitation and centrifugal separation obtains amorphous atorvastatin calcium.
Description of drawings:
Fig. 1 does not have the X diffracting spectrum of capable atorvastatincalcuim surely, and transverse axis is represented 2 θ, and Z-axis is represented the intensity at peak.
The X-ray powder diffraction figure of product sees accompanying drawing 1
Embodiment
Embodiment 1
Add the 300ml dehydrated alcohol to the 2L there-necked flask, stir atorvastatincalcuim crude product 30g down, heat solid is molten entirely.Stop heating, be cooled to 35 ℃-40 ℃, stir and drip 300ml water down in filtrate, dropwised a large amount of white solids in about 20 minutes to separate out, static crystallization was added into 300ml water and stirred 10 minutes in 2 hours, and is centrifugal, filter cake with 1L wash white solid.35 ℃ of vacuum-dryings of filter cake got white solid 27.5 grams in 20 hours, and yield is 91.7%.
Add the 300ml anhydrous methanol to the 2L there-necked flask, stir adding crystallization shape atorvastatincalcuim 30g down, heat solid is molten entirely.Stop heating, be cooled to 35 ℃-40 ℃, stir and drip 300ml water down in filtrate, dropwised a large amount of white solids in about 20 minutes to separate out, static crystallization was added into 300ml water and stirred 10 minutes in 2 hours, and is centrifugal, filter cake with 1L wash white solid.35 ℃ of vacuum-dryings of filter cake got white solid 27.0 grams in 20 hours, and yield is 90%.
Embodiment 3
Add the 300ml Virahol to the 2L there-necked flask, stir adding shape atorvastatincalcuim crude product 30g down, heat solid is molten entirely.Stop heating, be cooled to 35 ℃-40 ℃, stir and drip filtrate down in 300ml water, dropwised a large amount of white solids in about 20 minutes to separate out, static crystallization was added into 300ml water and stirred 10 minutes in 2 hours, and is centrifugal, filter cake with 1L wash white solid.35 ℃ of vacuum-dryings of filter cake got white solid 27.0 grams in 20 hours, and yield is 90%.
Claims (5)
1. the atorvastatincalcuim of an amorphous form, its x diffraction data is: 28.0,15.5,9.8,4.7.
2. the preparation method of atorvastatincalcuim according to claim 1 may further comprise the steps:
(a) atorvastatincalcuim is dissolved in the alcoholic solvent;
(b) stir dropping entry down, or under stirring the atorvastatincalcuim drips of solution is added to the water, separate out the atorvastatincalcuim solid;
(c) filter out solvent and obtain unbodied atorvastatincalcuim.
3. method according to claim 2, wherein alcoholic solvent is ethanol, methyl alcohol, Virahol, propyl carbinol or its mixture.
4. method according to claim 2 is characterized in that anti-solvent is a water.
5. method according to claim 2, wherein said amorphous atropic Fa Tating calcium obtains by filtration or centrifugation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101041376A CN101560176A (en) | 2008-04-16 | 2008-04-16 | Amorphous atorvastatin calcium and preparation method thereof |
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| CNA2008101041376A CN101560176A (en) | 2008-04-16 | 2008-04-16 | Amorphous atorvastatin calcium and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311377A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Refining method capable of obtaining atorvastatin calcium in form of crystal |
| CN106432033A (en) * | 2016-10-21 | 2017-02-22 | 江苏阿尔法药业有限公司 | Preparation method of amorphous atorvastatin calcium |
-
2008
- 2008-04-16 CN CNA2008101041376A patent/CN101560176A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102311377A (en) * | 2010-06-29 | 2012-01-11 | 山东新华制药股份有限公司 | Refining method capable of obtaining atorvastatin calcium in form of crystal |
| CN106432033A (en) * | 2016-10-21 | 2017-02-22 | 江苏阿尔法药业有限公司 | Preparation method of amorphous atorvastatin calcium |
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Application publication date: 20091021 |