CN102558275A - Alpha type polycrystalline abiraterone acetate crystal, and preparation method, application and pharmaceutical composition thereof - Google Patents
Alpha type polycrystalline abiraterone acetate crystal, and preparation method, application and pharmaceutical composition thereof Download PDFInfo
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- CN102558275A CN102558275A CN2010105945771A CN201010594577A CN102558275A CN 102558275 A CN102558275 A CN 102558275A CN 2010105945771 A CN2010105945771 A CN 2010105945771A CN 201010594577 A CN201010594577 A CN 201010594577A CN 102558275 A CN102558275 A CN 102558275A
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Abstract
The invention provides alpha type polycrystalline abiraterone acetate crystal, a preparation method and application of the alpha type polycrystalline abiraterone acetate crystal, a pharmaceutical composition containing the alpha type polycrystalline abiraterone acetate crystal, as well as X-ray diffraction patterns and infrared spectra characteristics of the alpha type polycrystalline abiraterone acetate crystal and powder of the alpha type polycrystalline abiraterone acetate crystal.
Description
Technical field
The invention belongs to medical technical field.More particularly, the present invention relates to a kind of new crystallization of polymorphic acetic acid Abiraterone, its preparation method, purposes and comprise this new polymorphic acetic acid Abiraterone crystalline pharmaceutical composition.
Background technology
Acetic acid Abiraterone (Abiraterone acetate), chemical name: danabol-5,16-diene-3-alcohol, 17-(3-pyridine)-, acetate (ester),, structural formula is following:
The acetic acid Abiraterone is the hormone synthetic inhibitor; Be a kind of orally active novel hormonal class antitumour drug, can irreversible inhibition cytopigment p450 enzyme 17-hydroxylase/C (17,20) lyase; The generation of blocking-up testis and suprarenal gland male hormone, thus be used for advanced prostate cancer.The former company of grinding is the Institute of Cancer Research (Britain).The permission merchant is Cougar Biotechnology.The right of priority patent No. of these article is GB 2265624, preferential state: Britain, priority date: on March 31st, 1992.
Summary of the invention
The object of the present invention is to provide a kind of new acetic acid Abiraterone crystallization.Contriver of the present invention carries out powder x-ray diffraction and infrared spectrum characterization through a large amount of experimental studies to the acetic acid Abiraterone crystallization that experiment makes, and has found the crystallization of a kind of novel α type polymorphic acetic acid Abiraterone, thereby has accomplished the present invention.The present invention also aims to provide a kind of prepare acetic acid Abiraterone crystalline method of the present invention, acetic acid Abiraterone of the present invention crystallization be used for treating in preparation advanced prostate cancer medicine purposes and contain acetic acid Abiraterone crystalline pharmaceutical composition of the present invention.
The invention provides the crystallization of a kind of α type polymorphic acetic acid Abiraterone; Its powder x-ray diffraction figure shows the principal character peak at the diffraction angle place shown in the following 2 θ angles: 5.74 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.5 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.3 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23.3 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.3 ° ± 0.2 °, 25.9 ° ± 0.2 °, 26.8 ° ± 0.2 °, 27.5 ° ± 0.2 °; 29.8 ° ± 0.2 ° of peak intensity is followed successively by: 34%, 57%, 11%, 70%, 70%, 57%, 22%, 100%, 65%, 24%, 51%, 34%, 31%, 42%, 14%, 14%, 17%, 11%, 13%, 27%, 12%, and the error of said peak intensity is ± 20%.
In one embodiment of the present invention, measure condition determination: Cu-Ka radiation with D/MAX-2500 type X-ray diffractometer; Its X ray diffracting spectrum has following diffraction angle (2 θ), spacing (d value), intensity (%); The error at 2 θ angles is 0.2 °, and intensity error is ± 20%.Its X-ray powder diffraction test result is as shown in table 1.
Table 1
In one embodiment of the present invention, said α type polymorphic acetic acid Abiraterone crystalline infrared spectrogram comprises following charateristic avsorption band: 3047cm
-1, 2937cm
-1, 2891cm
-1, 2855cm
-1, 1735cm
-1, 1560cm
-1, 1374cm
-1, 1245cm
-1, 1035cm
-1
According to α type polymorphic acetic acid Abiraterone provided by the invention crystallization, wherein, in a kind of embodiment preferred, said acetic acid Abiraterone crystalline infrared spectrogram is as shown in Figure 2.
In one embodiment, fusing point test is carried out in crystallization to said α type polymorphic acetic acid Abiraterone: adopt YRT-fusing point appearance, fusing point is 141.1-141.8 ℃.
The present invention also provides above-mentioned α type polymorphic acetic acid Abiraterone crystalline preparation method, and this method comprises that (1) forms solution with acetic acid Abiraterone heating for dissolving in solvent; (2) with this solution filtration, crystallisation by cooling; (3) filtration obtains crystallization and dry.
According to preparation method provided by the invention; Wherein, Said solvent can be in water, methyl alcohol, ethanol, Virahol, isopropyl ether, acetonitrile, THF, ETHYLE ACETATE, chloroform, methylene dichloride, toluene, normal hexane and the acetone one or more, is preferably in water, ethanol, Virahol, the methyl alcohol one or more.In preparing method's of the present invention step (1), the consumption of said solvent can be 2-15ml/g with the volume mass ratio of acetic acid Abiraterone, is preferably 3-10ml/g; The temperature of said heating can be 40-110 ℃, is preferably 60-80 ℃.
According to preparation method provided by the invention, wherein, the crystalline temperature can be preferably 0-30 ℃ for-5-50 ℃ in the said step (2); The crystalline time can be 1-24 hour, is preferably 6-18 hour.
According to the α type polymorphic acetic acid Abiraterone crystallization that method provided by the invention makes, its
1H-NMR,
13C-NMR and liquid phase collection of illustrative plates are seen Fig. 3,4,5.
According to α type polymorphic acetic acid Abiraterone provided by the invention crystallization and preparation method thereof, wherein, be used to prepare said acetic acid Abiraterone crystalline raw material, can prepare according to various known synthetic routes, yet the invention is not restricted to these methods.The reaction scheme of preparation can comprise following several kinds:
Route 1
Route 2
The present invention also provides a kind of pharmaceutical composition; This pharmaceutical composition comprises the α type polymorphic acetic acid Abiraterone provided by the invention crystallization as activeconstituents, the α type polymorphic acetic acid Abiraterone crystallization that perhaps makes according to preparation method provided by the invention, and one or more pharmaceutically acceptable carrier or vehicle.
Described pharmaceutical composition is applicable to oral prepns.Tablet of the present invention adopts the crystallization of α type polymorphic acetic acid Abiraterone, lactose, Microcrystalline Cellulose, starch, hydroxypropylcellulose, carboxymethylstach sodium, Magnesium Stearate to process through certain preparation technology.Every contains α type polymorphic acetic acid Abiraterone crystallization 50mg-1000mg, preferred 200-500mg.
The present invention also provides α type polymorphic acetic acid Abiraterone of the present invention crystallization to be used for treating the purposes of the medicine of cancer in preparation.Preferably, said cancer is prostate cancer and mammary cancer.
α type polymorphic acetic acid Abiraterone crystallization purity provided by the invention is high, and the product that makes is through accelerated test and the room temperature study on the stability that keeps sample for a long time, and stability is fine as a result.The result sees table 2 table 3.
The damp and hot accelerated test result of table 2 α type polymorphic acetic acid Abiraterone crystallization
The table 3 α type polymorphic acetic acid Abiraterone crystallization investigation result that keeps sample for a long time
Description of drawings
Below, specify embodiment of the present invention in conjunction with accompanying drawing, wherein:
Fig. 1 is the α type polymorphic acetic acid Abiraterone crystalline powder x-ray diffraction figure that makes;
Fig. 2 is the α type polymorphic acetic acid Abiraterone crystalline infrared spectrogram that makes;
Fig. 3 be the α type polymorphic acetic acid Abiraterone crystalline proton nmr spectra that makes (
1H-NMR) figure;
Fig. 4 be the α type polymorphic acetic acid Abiraterone crystalline carbon-13 nmr spectra that makes (
13C-NMR) figure;
Fig. 5 is the α type polymorphic acetic acid Abiraterone crystalline high-efficient liquid phase chromatogram that makes.
Embodiment
Below in conjunction with embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
Take by weighing acetic acid Abiraterone 10 grams, add in the 30ml acetone, be heated to 56 ℃ of dissolvings that reflux.Add 0.2 gram decolorizing with activated carbon then, filtered while hot naturally cools to room temperature with filtrating.Carried out crystallization in 8 hours 25 ℃ of held, filtration, drying obtain white acetic acid Abiraterone crystallization 7.1 grams then.
Embodiment 2
Take by weighing acetic acid Abiraterone 10 grams, add in the 100ml acetone, be heated to 56 ℃ of dissolvings that reflux.Add 0.2 gram decolorizing with activated carbon then, filtered while hot naturally cools to room temperature with filtrating.Carried out crystallization in 20 hours 25 ℃ of held, filtration, drying obtain white acetic acid Abiraterone crystallization 3.5 grams then.
Embodiment 3
Take by weighing acetic acid Abiraterone 10 grams, add in the 50ml Virahol, be heated to 82.5 ℃ of dissolvings that reflux.Add 0.2 gram decolorizing with activated carbon then, filtered while hot naturally cools to room temperature with filtrating.Carried out crystallization in 20 hours 25 ℃ of held, filtration, drying obtain white acetic acid Abiraterone crystallization 5.7 grams then.
Embodiment 4
Take by weighing acetic acid Abiraterone 10 grams, add in the 75ml Virahol, be heated to 82.5 ℃ of dissolvings that reflux.Add 0.2 gram decolorizing with activated carbon then, filtered while hot naturally cools to room temperature with filtrating.Carried out crystallization in 15 hours 0 ℃ of held, filtration, drying obtain white acetic acid Abiraterone crystallization 4.8 grams then.
Embodiment 5
Take by weighing acetic acid Abiraterone 10 grams, add in the 30ml acetone, be heated to 56 ℃ of dissolvings that reflux.Add 0.2 gram decolorizing with activated carbon then, filtered while hot naturally cools to room temperature with filtrating.Carried out crystallization in 18 hours 0 ℃ of held, filtration, drying obtain white acetic acid Abiraterone crystallization 8.2 grams then.
Embodiment 6
The crystallization of 50g α type polymorphic acetic acid Abiraterone, 32g lactose, 20g starch, 6g Microcrystalline Cellulose are crossed 100 mesh sieves respectively; And abundant mixing; The 2% hydroxyl methylcellulose aqueous solution joined in the said mixture granulate; Cross 20 mesh sieve system softwoods, make wet granular in 45～55 ℃ dry about 2-3 hour, with remain carboxymethylstach sodium, Magnesium Stearate joins compressing tablet in the above-mentioned dried particles.
Claims (10)
1. α type polymorphic acetic acid Abiraterone crystallization; It is characterized in that; Its powder x-ray diffraction figure shows the principal character peak at the diffraction angle place shown in the following 2 θ angles: 5.74 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.5 ° ± 0.2 °, 14.7 ° ± 0.2 °, 15.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.1 ° ± 0.2 °, 18.3 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.0 ° ± 0.2 °, 23.3 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.3 ° ± 0.2 °, 25.9 ° ± 0.2 °, 26.8 ° ± 0.2 °, 27.5 ° ± 0.2 °; 29.8 ° ± 0.2 ° of peak intensity is followed successively by: 34%, 57%, 11%, 70%, 70%, 57%, 22%, 100%, 65%, 24%, 51%, 34%, 31%, 42%, 14%, 14%, 17%, 11%, 13%, 27%, 12%, and the error of said peak intensity is ± 20%.
2. α type polymorphic acetic acid Abiraterone according to claim 1 crystallization, its powder x-ray diffraction collection of illustrative plates is as shown in Figure 1.
3. according to each described α type polymorphic acetic acid Abiraterone crystallization in the claim 1 to 2, wherein, its infrared spectrogram comprises following charateristic avsorption band: 3047cm
-1, 2937cm
-1, 2891cm
-1, 2855cm
-1, 1735cm
-1, 1560cm
-1, 1374cm
-1, 1245cm
-1, 1035cm
-1
4. according to each described α type polymorphic acetic acid Abiraterone crystallization in the claim 1 to 3, wherein, its infrared spectrogram is as shown in Figure 2.
5. each described α type polymorphic acetic acid Abiraterone crystalline preparation method among the claim 1-4, this method comprises that (1) forms solution with acetic acid Abiraterone heating for dissolving in solvent; (2) with this solution filtration, crystallisation by cooling; (3) filtration obtains crystallization and dry.
6. preparation method according to claim 5, wherein, said solvent is one or more in water, methyl alcohol, ethanol, Virahol, isopropyl ether, acetonitrile, THF, ETHYLE ACETATE, chloroform, methylene dichloride, toluene, normal hexane and the acetone.
7. according to claim 5 or 6 described preparing methods, wherein, the volume-mass ratio of solvent and acetic acid Abiraterone is 2-15mL/g in the said step (1), is preferably 3-10mL/g; The temperature of heating is 40-110 ℃, is preferably 60-80 ℃.
8. according to each described preparation method among the claim 5-7, wherein, the crystalline temperature is-5-50 ℃ in the said step (2), is preferably 0-30 ℃; The crystalline time is 1-24 hour, is preferably 6-18 hour.
9. pharmaceutical composition; This pharmaceutical composition comprises as each described α type polymorphic acetic acid Abiraterone crystallization among the claim 1-4 of activeconstituents, or the α type polymorphic acetic acid Abiraterone crystallization that makes according to each described preparation method among the claim 5-8, and one or more pharmaceutically acceptable carrier or vehicle.
10. each described α type polymorphic acetic acid Abiraterone crystallization among the claim 1-4, or the α type polymorphic acetic acid Abiraterone crystallization that makes according to each described preparation method among the claim 5-8 be used for treating the purposes of the medicine of cancer in preparation, said cancer is preferably prostate cancer and mammary cancer.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102336801A (en) * | 2011-10-31 | 2012-02-01 | 南京卡文迪许生物工程技术有限公司 | Abiraterone acetate polymorphic substance and pharmaceutical composition |
| EP2792682A1 (en) | 2013-04-19 | 2014-10-22 | Zach System | Process for producing a solid form of abiraterone acetate |
| CN105017372A (en) * | 2015-07-10 | 2015-11-04 | 武汉百科药物开发有限公司 | Crystal form of abiraterone acetate and preparation method of crystal form of abiraterone acetate |
| WO2016128891A1 (en) | 2015-02-09 | 2016-08-18 | Druggability Technologies Ip Holdco Limited | Complexes of abiraterone acetate, process for the preparation thereof and pharmaceutical compositions containing them |
| CN113307839A (en) * | 2021-06-16 | 2021-08-27 | 马苏峰 | Method for preparing abiraterone acetate crystal and abiraterone acetate crystal prepared by same |
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| WO1993020097A1 (en) * | 1992-03-31 | 1993-10-14 | British Technology Group Ltd. | 17-substituted steroids useful in cancer treatment |
| WO1995009178A1 (en) * | 1993-09-30 | 1995-04-06 | British Technology Group Limited | Synthesis of 17-(3-pyridyl) steroids |
| CN101528308A (en) * | 2006-08-25 | 2009-09-09 | 库伽尔生物科技公司 | Methods and compositions for treating cancer |
| CN101768199A (en) * | 2009-12-24 | 2010-07-07 | 深圳万乐药业有限公司 | Polymorphs of abiraterone acetate and preparation method thereof |
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2010
- 2010-12-20 CN CN2010105945771A patent/CN102558275A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993020097A1 (en) * | 1992-03-31 | 1993-10-14 | British Technology Group Ltd. | 17-substituted steroids useful in cancer treatment |
| WO1995009178A1 (en) * | 1993-09-30 | 1995-04-06 | British Technology Group Limited | Synthesis of 17-(3-pyridyl) steroids |
| CN101528308A (en) * | 2006-08-25 | 2009-09-09 | 库伽尔生物科技公司 | Methods and compositions for treating cancer |
| CN101768199A (en) * | 2009-12-24 | 2010-07-07 | 深圳万乐药业有限公司 | Polymorphs of abiraterone acetate and preparation method thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102336801A (en) * | 2011-10-31 | 2012-02-01 | 南京卡文迪许生物工程技术有限公司 | Abiraterone acetate polymorphic substance and pharmaceutical composition |
| EP2792682A1 (en) | 2013-04-19 | 2014-10-22 | Zach System | Process for producing a solid form of abiraterone acetate |
| WO2014170221A1 (en) * | 2013-04-19 | 2014-10-23 | Zach System | Process for producing a solid form of abiraterone acetate |
| CN105143241A (en) * | 2013-04-19 | 2015-12-09 | 扎克系统公司 | Process for producing a solid form of abiraterone acetate |
| CN105143241B (en) * | 2013-04-19 | 2017-11-14 | 扎克系统公司 | For the method for the abiraterone acetate for preparing solid form |
| WO2016128891A1 (en) | 2015-02-09 | 2016-08-18 | Druggability Technologies Ip Holdco Limited | Complexes of abiraterone acetate, process for the preparation thereof and pharmaceutical compositions containing them |
| CN105017372A (en) * | 2015-07-10 | 2015-11-04 | 武汉百科药物开发有限公司 | Crystal form of abiraterone acetate and preparation method of crystal form of abiraterone acetate |
| CN113307839A (en) * | 2021-06-16 | 2021-08-27 | 马苏峰 | Method for preparing abiraterone acetate crystal and abiraterone acetate crystal prepared by same |
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Application publication date: 20120711 |