CN102040596A - Dasatinib polymorph and preparation method thereof - Google Patents
Dasatinib polymorph and preparation method thereof Download PDFInfo
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- CN102040596A CN102040596A CN2009101969878A CN200910196987A CN102040596A CN 102040596 A CN102040596 A CN 102040596A CN 2009101969878 A CN2009101969878 A CN 2009101969878A CN 200910196987 A CN200910196987 A CN 200910196987A CN 102040596 A CN102040596 A CN 102040596A
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Abstract
The invention discloses a dasatinib polymorph and a preparation method thereof. The invention is characterized in that: a powder diffraction pattern of the crystal comprises three or more than three 2theta values of 7.2 degrees, 10.6 degrees, 12.2 degrees, 14.5 degrees, 16.4 degrees, 20.0 degrees, 22.8 degrees and 23.7+/-0.2 degrees. In addition, the invention also discloses a method for preparing the dasatinib polymorph. The dasatinib polymorph is easy for industrial production and is a novel pharmaceutically acceptable and stable dasatinib polymorph.
Description
Technical field
The present invention relates to Dasatinib polymorph and preparation method thereof.
Background technology
Dasatinib (Dasatinib), commodity are called Sprycel, are a kind of oral tyrosine kinase inhibitors by Bristol-Myers Squibb Co.'s research and development.This medicine is in the June 28 in 2006 of preferentially examining by U.S. FDA, be used for all stadium patients, also be used for the treatment of simultaneously other therapy resistances or the Philadelphia chromosome male acute lymphoblastic leukemia adult patient (ph+ALL) that do not tolerate to treatment failure previously or adult's chronic myelogenous leukemia (CML) of not tolerating.
Dasatinib has the disclosed monohydrate H1-7 of CN1980909A crystal formation, propyl carbinol solvate BU-2 crystal formation, alcohol solvent compound E2-1 crystal formation, pure product N-6 crystal formation and pure product T1N1-7 crystal formation at present, the crystallized form of the various salt of the disclosed Dasatinib of WO2007035874 (such as mesylate, hydrobromate, salicylate etc.), and WO2009053854 discloses the multiple crystal formation (comprising isopropanol solvent compound, Virahol-crystal formations such as dimethylsulfoxide solvent compound) of Dasatinib.
Summary of the invention
The object of the present invention is to provide a kind of Dasatinib polymorph and preparation method thereof, to overcome the above-mentioned defective that prior art exists.
Dasatinib polymorph of the present invention is the crystal formation of pure product form, is designated as the I type;
Further, described Dasatinib polymorph is characterised in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 3 or 3: 7.2 °, and 10.6 °, 12.2 °, 14.5 °, 16.4 °, 20.0 °, 22.8 °, 23.7 ± 0.2 °; Dsc (DSC) is analyzed collection of illustrative plates has the feature endotherm(ic)peak at about 285～287 ℃; Thermogravimetric analysis (TGA) collection of illustrative plates is weightless about below 1%.
The preparation method of the Dasatinib polymorph that the present invention is above-mentioned comprises the steps:
With raw material Dasatinib under 30～70 ℃ of conditions dry 1～8 hour, remove solvent, can obtain the Dasatinib of I type;
Said raw material Dasatinib is selected from more than one in II type Dasatinib polymorph, III type Dasatinib polymorph or the IV type Dasatinib polymorph;
Described Dasatinib II type polymorphic form for dichloromethane solvent compound crystal formation, is characterized in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.9 °, 11.8 °, 12.4 °, 14.8 °, 17.7 °, 18.6 °, 21.6 °, 22.9 °, 23.7 °, 25.4 ± 0.2 °; The DSC collection of illustrative plates has the feature endotherm(ic)peak at about 80～160 ℃ and 285～287 ℃; The TGA collection of illustrative plates shows weightless about 14%.
The preparation method of the Dasatinib II type polymorphic form that the present invention is above-mentioned comprises the steps:
1) the crude product Dasatinib is suspended in the methylene dichloride, 20～40 ℃ were stirred 0.5～1 hour down;
2) filter, the filter cake washed with dichloromethane promptly obtains II type Dasatinib.
3) or with Dasatinib be dissolved in the aqueous organic solvent, obtain Dasatinib solution.
4) this drips of solution is added in the methylene dichloride.
5) filter, promptly obtain II type Dasatinib.
Described aqueous organic solvent is selected from methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, tetrahydrofuran (THF), ethylene glycol, methyl-sulphoxide, N, dinethylformamide and their mixture thereof, preferred methyl-sulphoxide.
The Dasatinib III type polymorphic form that the present invention is above-mentioned, be isopropyl ether solvate crystal formation, it is characterized in that the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.9 °, 11.9 °, 15.0 °, 16.6 °, 21.5 °, 22.9 °, 24.0 °, 24.5 ± 0.2 °; The DSC collection of illustrative plates has the feature endotherm(ic)peak at about 110～160 ℃ and 285～288 ℃; TGA shows collection of illustrative plates weightless about 13%.
The preparation method of the Dasatinib III type polymorphic form that the present invention is above-mentioned comprises the steps:
1) the crude product Dasatinib is suspended in the isopropyl ether, 30～70 ℃ were stirred 0.5～1 hour down.
2) filter, promptly obtain II type Dasatinib.
3) or with Dasatinib be dissolved in the aqueous organic solvent, obtain Dasatinib solution.
4) this drips of solution is added in the isopropyl ether.
5) filter, promptly obtain II type Dasatinib.
The aqueous organic solvent definition is the same.
The Dasatinib IV type polymorphic form that the present invention is above-mentioned is N, dinethylformamide solvate crystal formation, it is characterized in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.5 °, and 5.9 °, 12.4 °, 14.8 °, 16.5 °, 22.2 °, 22.8 °, 24.8 °, 25.4 ± 0.2 °; The DSC collection of illustrative plates has the feature endotherm(ic)peak at about 115～139 ℃ and 285～287 ℃; TGA shows collection of illustrative plates weightless about 8.67%.
The preparation method of the Dasatinib IV type polymorphic form that the present invention is above-mentioned comprises the steps:
1) the crude product Dasatinib is suspended in N, in the dinethylformamide, 40～90 ℃ were stirred 0.5～1 hour down.
2) with the speed of per hour the falling 10 ℃ crystallization of slowly lowering the temperature.Filter, promptly obtain II type Dasatinib.
3) or with ethyl acetate be added drop-wise in the solution that step 1) obtains, separate out crystal under stirring.
4) filter, promptly obtain II type Dasatinib.
Dasatinib polymorph of the present invention is easy to suitability for industrialized production, is a kind of pharmaceutically acceptable, stable Dasatinib new crystal, is suitable for further preparing various formulations, the bioavailability height of preparation finished product.
Description of drawings
Fig. 1 is Dasatinib I type polymorphic form X-RD figure;
Fig. 2 is Dasatinib I type polymorphic form DSC figure;
Fig. 3 is Dasatinib I type polymorphic form TGA figure;
Fig. 4 is Dasatinib II type polymorphic form X-RD figure;
Fig. 5 is Dasatinib II type polymorphic form DSC figure;
Fig. 6 is Dasatinib II type polymorphic form TGA figure;
Fig. 7 is Dasatinib III type polymorphic form X-RD figure;
Fig. 8 is Dasatinib III type polymorphic form DSC figure;
Fig. 9 is Dasatinib III type polymorphic form TGA figure;
Figure 10 is Dasatinib IV type polymorphic form X-RD figure;
Figure 11 is Dasatinib IV type polymorphic form DSC figure;
Figure 12 is Dasatinib IV type polymorphic form TGA figure.
Embodiment
The present invention is further detailed explanation below in conjunction with drawings and Examples:
Embodiment 1
The preparation of II type Dasatinib polymorph
The 5g Dasatinib is joined in the dichloromethane solvent of 25ml, about 2～3 hours of temperature rising reflux is reduced to room temperature, filters, and the filter cake natural air drying obtains the Dasatinib polymorph of 6.3g II type.
The preparation of II type Dasatinib polymorph
The 5g Dasatinib is dissolved in the 30ml dimethyl sulfoxide (DMSO), slowly is added drop-wise in the methylene dichloride of 300ml then, drip off after-filtration, the filter cake natural air drying obtains the Dasatinib polymorph of 6.1g II type.
Embodiment 3
The preparation of the Dasatinib of III type
The 3g Dasatinib is dissolved in the 20ml dimethyl sulfoxide (DMSO), slowly is added drop-wise in the isopropyl ether of 180ml then, drip off after-filtration, the filter cake natural air drying obtains the Dasatinib polymorph of 3.5g III type.
Embodiment 4
The preparation of the Dasatinib of III type
The 3g Dasatinib is dissolved in the 90ml dimethyl sulfoxide (DMSO), slowly is added drop-wise in the isopropyl ether of 300ml then, drip off after-filtration, the filter cake natural air drying obtains the Dasatinib polymorph of 3.4g III type.
Embodiment 5
The preparation of the Dasatinib of III type
The 50g Dasatinib is joined in the isopropyl ether of 250ml, about 2～3 hours of temperature rising reflux is reduced to room temperature, filters, and drying under reduced pressure is 4 hours under the filter cake room temperature, obtains the Dasatinib polymorph of 63.2g III type.
Embodiment 6
The preparation of the Dasatinib polymorph of IV type
The 5g Dasatinib is joined to add thermosol among the DMF of 30ml clear, with the speed of per hour the falling 10 ℃ crystallization of slowly lowering the temperature, 0 ℃ of drying under reduced pressure of filter 23 4 hours obtains 5.5g IV type Dasatinib polymorph.
Embodiment 7
The preparation of the Dasatinib polymorph of IV type
The 5ml ethyl acetate slowly is added drop-wise to stirring and crystallizing in the DMF solution of the 3.5ml that contains the 0.5g Dasatinib, filters, drying under reduced pressure is 4 hours under the filter cake room temperature, obtains the Dasatinib polymorph of 0.36g IV type.
The preparation of the Dasatinib polymorph of I type
II type Dasatinib polymorph, III type Dasatinib polymorph or IV type Dasatinib Dasatinib polymorph that embodiment 1～7 preparation method is obtained, under 30 ℃, 40 ℃, 70 ℃ conditions dry 2 hours, 4 hours, 8 hours respectively, remove the Dasatinib polymorph that solvent can obtain the I type.
Embodiment 9
The II type Dasatinib polymorph that embodiment 1 is prepared, the III type Dasatinib polymorph that embodiment 3 prepares under 40 ℃ of conditions dry 4 hours, are removed the Dasatinib polymorph that solvent can obtain the I type.
The weight ratio of II type Dasatinib polymorph and III type Dasatinib polymorph is 1: 1.
Claims (22)
1. polymorphic form that is designated as Dasatinib I type.
2. the polymorphic form of Dasatinib I type according to claim 1 is characterized in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 3 or 3: 7.2 °, and 10.6 °, 12.2 °, 14.5 °, 16.4 °, 20.0 °, 22.8 °, 23.7 ± 0.2 °.
3. the polymorphic form of Dasatinib I type according to claim 1 is characterized in that, dsc is analyzed collection of illustrative plates has the feature endotherm(ic)peak at 285～287 ℃.
4. the polymorphic form of Dasatinib I type according to claim 1 is characterized in that, the thermogravimetric analysis collection of illustrative plates is weightless about below 1%.
5. according to the preparation method of the polymorphic form of each described Dasatinib I type of claim 1～4, it is characterized in that, comprise the steps: the raw material Dasatinib is removed solvent, can obtain the polymorphic form of Dasatinib I type.
6. method according to claim 5 is characterized in that, said raw material Dasatinib is selected from more than one in II type Dasatinib polymorph, III type Dasatinib polymorph or the IV type Dasatinib polymorph.
7. one kind is designated as Dasatinib II type polymorphic form, it is characterized in that, this polymorphic form is a dichloromethane solvent compound crystal formation.
8. Dasatinib II type polymorphic form according to claim 7, it is characterized in that the powder diffraction spectrum of described polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.9 °, 11.8 °, 12.4 °, 14.8 °, 17.7 °, 18.6 °, 21.6 °, 22.9 °, 23.7 °, 25.4 ± 0.2 °.
9. Dasatinib II type polymorphic form according to claim 7 is characterized in that the DSC collection of illustrative plates has the feature endotherm(ic)peak at about 80～160 ℃ and 285～287 ℃.
10. Dasatinib II type polymorphic form according to claim 7 is characterized in that, the TGA collection of illustrative plates shows weightless about 14%.
11. the preparation method according to each described Dasatinib II type polymorphic form of claim 7～10 comprises the steps:
1) the crude product Dasatinib is suspended in the methylene dichloride, 20～40 ℃ were stirred 0.5～1 hour down;
2) filter, the filter cake washed with dichloromethane promptly obtains II type Dasatinib.
3) or with Dasatinib be dissolved in the aqueous organic solvent, obtain Dasatinib solution.
4) this drips of solution is added in the methylene dichloride.
5) filter, promptly obtain II type Dasatinib.
12. method according to claim 11 is characterized in that, described aqueous organic solvent is selected from methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, tetrahydrofuran (THF), ethylene glycol, methyl-sulphoxide, N, dinethylformamide and their mixture thereof.
13. one kind is designated as Dasatinib III type polymorphic form, it is characterized in that, this polymorphic form is an isopropyl ether solvate crystal formation.
14. Dasatinib III type polymorphic form according to claim 13 is characterized in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.9 °, and 11.9 °, 15.0 °, 16.6 °, 21.5 °, 22.9 °, 24.0 °, 24.5 ± 0.2 °.
15. Dasatinib III type polymorphic form according to claim 13 is characterized in that the DSC collection of illustrative plates has the feature endotherm(ic)peak at about 110～160 ℃ and 285～288 ℃.
16. Dasatinib III type polymorphic form according to claim 13 is characterized in that, TGA shows collection of illustrative plates weightless about 13%.
17. prepare the method for each described Dasatinib III type polymorphic form of claim 13～16, comprise the steps:
1) the crude product Dasatinib is suspended in the isopropyl ether, 30～70 ℃ were stirred 0.5～1 hour down.
2) filter, promptly obtain II type Dasatinib.
3) or with Dasatinib be dissolved in the aqueous organic solvent, obtain Dasatinib solution.
4) this drips of solution is added in the isopropyl ether.
5) filter, promptly obtain II type Dasatinib.
The aqueous organic solvent definition is the same.
18. one kind is designated as Dasatinib IV type polymorphic form, it is characterized in that this polymorphic form is N, dinethylformamide solvate crystal formation.
19. Dasatinib IV type polymorphic form according to claim 18, it is characterized in that, the powder diffraction spectrum of this polymorphic form comprises and is selected from following 2 θ values more than 4 or 4: 5.5 °, and 5.9 °, 12.4 °, 14.8 °, 16.5 °, 22.2 °, 22.8 °, 24.8 °, 25.4 ± 0.2 °.
20. Dasatinib IV type polymorphic form according to claim 18 is characterized in that the DSC collection of illustrative plates has the feature endotherm(ic)peak at about 115～139 ℃ and 285～287 ℃.
21. Dasatinib IV type polymorphic form according to claim 18 is characterized in that, TGA shows collection of illustrative plates weightless about 8.67%.
22. the preparation method of each described Dasatinib III type polymorphic form of claim 18～21 comprises the steps:
1) the crude product Dasatinib is suspended in N, in the dinethylformamide, 40～90 ℃ were stirred 0.5～1 hour down.
2) with the speed of per hour the falling 10 ℃ crystallization of slowly lowering the temperature.Filter, promptly obtain II type Dasatinib.
3) or with ethyl acetate be added drop-wise in the solution that step 1) obtains, separate out crystal under stirring.
4) filter, promptly obtain II type Dasatinib.
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030745A (en) * | 2010-11-26 | 2011-04-27 | 江苏先声药物研究有限公司 | Dasatinib solvate and preparation method thereof |
| CN102250084A (en) * | 2010-02-08 | 2011-11-23 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and pharmaceutical composition thereof |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
| CN103664929A (en) * | 2012-08-30 | 2014-03-26 | 石药集团中奇制药技术（石家庄）有限公司 | Dasatinib polycrystalline form medicament and preparation method thereof |
| CN103819469A (en) * | 2012-11-16 | 2014-05-28 | 重庆医药工业研究院有限责任公司 | Crystal form of dasatinib and preparation method for crystal form of dasatinib |
| CN104130251A (en) * | 2011-07-29 | 2014-11-05 | 江苏奥赛康药业股份有限公司 | Dasatinib compound and preparation method thereof |
| CN104997737A (en) * | 2015-08-05 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Composition dry suspension of medicine dasatinib tablet for treating leukemia |
| CN105030778A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Dasatinib composition granule serving as medicine for treating leukemia |
| CN105055327A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Dasatinib composite granules capable of treating leukaemia |
| CN105055367A (en) * | 2015-08-18 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | SprycelTM composition capsule medicine for treating leukemia |
| CN105130979A (en) * | 2015-08-10 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug dasatinib compound for treatment of leukemia and preparation method thereof |
| CN105237529A (en) * | 2015-10-29 | 2016-01-13 | 四川协力制药有限公司 | Refining method for high-purity anhydrous dasatinib |
| CN105408329A (en) * | 2013-07-25 | 2016-03-16 | 巴斯夫欧洲公司 | Salts of dasatinib in crystalline form |
| WO2017134615A1 (en) * | 2016-02-03 | 2017-08-10 | Dr. Reddy's Laboratories Limited | Solid state forms of dasatinib and processes for their preparation |
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| CN111108104A (en) * | 2017-07-07 | 2020-05-05 | 拜康有限公司 | Polymorphic forms of dasatinib |
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2009
- 2009-10-10 CN CN2009101969878A patent/CN102040596A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102250084A (en) * | 2010-02-08 | 2011-11-23 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and pharmaceutical composition thereof |
| CN102030745A (en) * | 2010-11-26 | 2011-04-27 | 江苏先声药物研究有限公司 | Dasatinib solvate and preparation method thereof |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
| CN104130251A (en) * | 2011-07-29 | 2014-11-05 | 江苏奥赛康药业股份有限公司 | Dasatinib compound and preparation method thereof |
| CN103664929A (en) * | 2012-08-30 | 2014-03-26 | 石药集团中奇制药技术（石家庄）有限公司 | Dasatinib polycrystalline form medicament and preparation method thereof |
| CN103664929B (en) * | 2012-08-30 | 2016-08-03 | 石药集团中奇制药技术（石家庄）有限公司 | Dasatinib polycrystalline form medicament and preparation method |
| CN103819469A (en) * | 2012-11-16 | 2014-05-28 | 重庆医药工业研究院有限责任公司 | Crystal form of dasatinib and preparation method for crystal form of dasatinib |
| CN105408329A (en) * | 2013-07-25 | 2016-03-16 | 巴斯夫欧洲公司 | Salts of dasatinib in crystalline form |
| CN105055327A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Dasatinib composite granules capable of treating leukaemia |
| CN104997737A (en) * | 2015-08-05 | 2015-10-28 | 青岛蓝盛洋医药生物科技有限责任公司 | Composition dry suspension of medicine dasatinib tablet for treating leukemia |
| CN105130979A (en) * | 2015-08-10 | 2015-12-09 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug dasatinib compound for treatment of leukemia and preparation method thereof |
| CN105055367A (en) * | 2015-08-18 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | SprycelTM composition capsule medicine for treating leukemia |
| CN105030778A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Dasatinib composition granule serving as medicine for treating leukemia |
| CN105237529A (en) * | 2015-10-29 | 2016-01-13 | 四川协力制药有限公司 | Refining method for high-purity anhydrous dasatinib |
| WO2017134615A1 (en) * | 2016-02-03 | 2017-08-10 | Dr. Reddy's Laboratories Limited | Solid state forms of dasatinib and processes for their preparation |
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| JP2019504090A (en) * | 2016-02-03 | 2019-02-14 | ドクター レディズ ラボラトリーズ リミテッド | Solid state forms of dasatinib and their preparation process |
| US10464933B2 (en) | 2016-02-03 | 2019-11-05 | Dr. Reddy's Laboratories Limited | Solid state forms of dasatinib and processes for their preparation |
| CN111108104A (en) * | 2017-07-07 | 2020-05-05 | 拜康有限公司 | Polymorphic forms of dasatinib |
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Application publication date: 20110504 |