WO2017029584A1 - Amorphous form of bosutinib - Google Patents
Amorphous form of bosutinibDownload PDFInfo
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- WO2017029584A1 WO2017029584A1PCT/IB2016/054820IB2016054820WWO2017029584A1WO 2017029584 A1WO2017029584 A1WO 2017029584A1IB 2016054820 WIB2016054820 WIB 2016054820WWO 2017029584 A1WO2017029584 A1WO 2017029584A1
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- bosutinib
- amorphous form
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- aqueous layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Definitions
- the present inventionprovides an amorphous form of bosutinib, a process for its preparation, its pharmaceutical composition, and a method of use thereof.
- Bosutinib monohydrateis chemically designated as 3-quinolinecarbonitrile, 4- [(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-, hydrate (1 : 1), as depicted by Formula I.
- Chinese Patent Publication No. 104447542discloses crystalline bosutinib monohydrate with particular XRD peaks.
- the present inventionprovides an amorphous form of bosutinib.
- the present inventionprovides an amorphous form of bosutinib.
- the present inventionalso provides a process for the preparation of an amorphous form of bosutinib.
- the present inventionalso provides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
- the present inventionalso provides use of an amorphous form of bosutinib for treating cancer, for example, chronic myelogenous leukemia (CML).
- CMLchronic myelogenous leukemia
- Figure 1is an X-ray powder diffraction (XRPD) pattern of an amorphous form of bosutinib.
- Figure 2is a Differential Scanning Calorimetry (DSC) thermogram of an amorphous form of bosutinib.
- treatingrefers to adding, dissolving, slurrying, stirring, reacting, condensing, or combinations thereof.
- baseincludes sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonia solution, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, and sodium bicarbonate.
- polar aprotic solventincludes polar solvents insoluble in water, for example, dichloromethane, methyl acetate, ethyl acetate, propyl acetate, and dichloroethane.
- acidincludes hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and phosphoric acid.
- isolatedrefers to precipitation, crystallization, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying may be carried out under reduced pressure, vacuum tray drying, spray drying, or air drying.
- a first aspect of the present inventionprovides an amorphous form of bosutinib.
- the amorphous form of bosutinibis characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
- XRPDX-ray powder diffraction
- the amorphous form of bosutinibis characterized by a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.
- DSCdifferential scanning calorimetry
- the amorphous form of bosutinibis further characterized by a DSC thermogram having an endothermic peak at about 79.9°C.
- a second aspect of the present inventionprovides a process for the preparation of an amorphous form of bosutinib comprising the steps of:
- step ii)stirring the product of step i) with water, a polar aprotic solvent, and an acid; iii) separating the reaction mixture of step ii) into an organic layer and an aqueous layer;
- 7-(3-chloropropoxy)-4-((2,4- dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrileis treated with N- methyl piperazine in the presence of triethylamine and dimethyl sulfoxide.
- 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrileis treated with N-methyl piperazine at a temperature of about 95°C to about 120°C.
- the polar aprotic solventis selected from the group consisting of ethyl acetate, methyl acetate, and propyl acetate.
- the acidis concentrated hydrochloric acid.
- the concentrated hydrochloric acidis added to adjust the pH of the reaction mixture to about 0.7 to about 1.0.
- the baseis an aqueous sodium bicarbonate solution.
- the aqueous sodium bicarbonate solutionis added to adjust the pH of the aqueous layer to about 7.5 to about 8.0.
- the isolation of the amorphous bosutinibcan be carried out by precipitation, cooling, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out by drying under reduced pressure, vacuum tray drying, spray drying or air drying. Drying can be carried out at a temperature of about 40°C to about 45°C for about 12 hours to about 16 hours.
- the isolation of the amorphous bosutinibis carried out by filtration, followed by washing with water, and then drying at a temperature of about 40°C to about 45 °C for about 14 hours.
- the pH of the reaction mixtureis adjusted to 0.8 with concentrated hydrochloric acid at 25°C to 30°C, and then the mixture is stirred for 5 minutes. On standing, the reaction mixture separates into organic and aqueous layers, which are separated. The pH of the aqueous layer is adjusted to 7.8 with the addition of an aqueous sodium bicarbonate solution. The reaction mixture is cooled to 10°C to 15°C, and then stirred for 2 hours. The obtained solid is filtered, then washed with deionized water, and then dried under reduced pressure at 40°C to 45°C for 14 hours to obtain the amorphous form of bosutinib.
- a third aspect of the present inventionprovides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
- the pharmaceutical compositionis in the form of tablets, capsules, powder, solution, or suspension.
- compositioncomprising mixing the amorphous form of bosutinib together with pharmaceutically acceptable carriers, excipients, and/or diluents.
- pharmaceutical compositioncomprising the amorphous form of bosutinib as a solid dispersion or as nanoparticles with at least one polymeric component.
- a fourth aspect of the present inventionprovides the use of an amorphous form of bosutinib for treating cancer, for example, CML.
- the starting material, 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrilecan be prepared by any method known in the art, such as the processes described in U.S. Patent No. 6,002,008 and Journal of Medicinal Chemistry 44(23):3965-3977 (2001).
- X-ray diffraction patternswere recorded using a PANalytical ® X'pert PRO with X'celerator ® as the detector, 0.02 as step size, and 3-40° 2 ⁇ as range, using CuKa radiation.
- DSC endothermswere recorded using a Mettler Toledo ® Star 6 , SW 11.0, with Temperature range 30°C to 300°C, Heating rate: 10°C/min., and Nitrogen flow: 20.0 mL/min.
- the reaction masswas cooled, and then deionized water (50 mL) was added at 25 °C to 30°C, and then the mixture was stirred for 70 minutes.
- the solid material obtainedwas filtered, and then washed with deionized water (20 mL).
- the wet solid obtainedwas added to deionized water (25 mL), followed by the addition of ethyl acetate (25 mL).
- the pH of the reaction masswas adjusted to 0.8 with concentrated hydrochloric acid ( ⁇ 2 mL) within 5 minutes at 25 °C to 30°C.
- the reaction masswas stirred at 25°C to 30°C for 5 minutes ,and then the layers were separated.
- the productwas isolated in an aqueous layer.
- the pH of the aqueous layerwas adjusted to 7.8 within 10 minutes with an aqueous sodium bicarbonate solution (3.5 g sodium bicarbonate in 52 mL of water).
- the reaction masswas cooled to 10°C to 15°C, and then stirred for 2 hours, followed by filtration, and then washing with deionized water (20 mL).
- the wet material obtainedwas dried under reduced pressure at 40°C to 45 °C for 14 hours to obtain the title product.
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
Description
AMORPHOUS FORM OF BOSUTINIB
Field of the Invention
The present invention provides an amorphous form of bosutinib, a process for its preparation, its pharmaceutical composition, and a method of use thereof.
Background of the Invention
Bosutinib monohydrate is chemically designated as 3-quinolinecarbonitrile, 4- [(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-, hydrate (1 : 1), as depicted by Formula I.
Formula I
U.S. Patent Nos. 6,002,008 and RE42,376 disclose bosutinib generically.
U.S. Patent Nos. 7,767,678 and 8,445,496 disclose crystalline forms I to VI of bosutinib.
Chinese Patent Publication No. 104447542 discloses crystalline bosutinib monohydrate with particular XRD peaks.
In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance. Inventing a new polymorphic form is very important in the development of pharmaceuticals. The present invention provides an amorphous form of bosutinib.
Summary of the Invention
The present invention provides an amorphous form of bosutinib.
The present invention also provides a process for the preparation of an amorphous form of bosutinib. The present invention also provides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
The present invention also provides use of an amorphous form of bosutinib for treating cancer, for example, chronic myelogenous leukemia (CML).
Brief Description of the Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of an amorphous form of bosutinib.
Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of an amorphous form of bosutinib.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term "treating," as used herein, refers to adding, dissolving, slurrying, stirring, reacting, condensing, or combinations thereof.
The term "base," as used herein, includes sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonia solution, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, and sodium bicarbonate.
The term "polar aprotic solvent," as used herein, includes polar solvents insoluble in water, for example, dichloromethane, methyl acetate, ethyl acetate, propyl acetate, and dichloroethane.
The term "acid," as used herein, includes hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and phosphoric acid.
The term "isolating," as used herein, refers to precipitation, crystallization, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying may be carried out under reduced pressure, vacuum tray drying, spray drying, or air drying.
The term "precipitation," as used herein, refers to the formation/separation of a solid phase from the liquid phase in a solution or a mixture. A first aspect of the present invention provides an amorphous form of bosutinib.
According to one embodiment of this aspect, the amorphous form of bosutinib is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
In another embodiment, the amorphous form of bosutinib is characterized by a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.
In another embodiment, the amorphous form of bosutinib is further characterized by a DSC thermogram having an endothermic peak at about 79.9°C.
A second aspect of the present invention provides a process for the preparation of an amorphous form of bosutinib comprising the steps of:
i) treating 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6- methoxyquinoline-3-carbonitrile with N-methyl piperazine;
ii) stirring the product of step i) with water, a polar aprotic solvent, and an acid; iii) separating the reaction mixture of step ii) into an organic layer and an aqueous layer;
iv) precipitating the aqueous layer of step iii) with a base; and
v) isolating the amorphous form of bosutinib.
According to one embodiment of this aspect, 7-(3-chloropropoxy)-4-((2,4- dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile is treated with N- methyl piperazine in the presence of triethylamine and dimethyl sulfoxide.
In another embodiment, 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile is treated with N-methyl piperazine at a temperature of about 95°C to about 120°C.
In another embodiment, the polar aprotic solvent is selected from the group consisting of ethyl acetate, methyl acetate, and propyl acetate.
In another embodiment, the acid is concentrated hydrochloric acid.
In another embodiment, the concentrated hydrochloric acid is added to adjust the pH of the reaction mixture to about 0.7 to about 1.0.
In another embodiment, the base is an aqueous sodium bicarbonate solution. In another embodiment, the aqueous sodium bicarbonate solution is added to adjust the pH of the aqueous layer to about 7.5 to about 8.0.
In another embodiment, the isolation of the amorphous bosutinib can be carried out by precipitation, cooling, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out by drying under reduced pressure, vacuum tray drying, spray drying or air drying. Drying can be carried out at a temperature of about 40°C to about 45°C for about 12 hours to about 16 hours.
The isolation of the amorphous bosutinib is carried out by filtration, followed by washing with water, and then drying at a temperature of about 40°C to about 45 °C for about 14 hours.
Accordingly, 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6- methoxyquinoline-3-carbonitrile is treated with N-methyl piperazine in the presence of triethylamine and dimethyl sulfoxide at a temperature of 105°C to 110°C. On completion of the reaction, the reaction mass is cooled, then filtered, followed by washing of the solid material with deionized water. The wet solid is added to deionized water, followed by the addition of ethyl acetate to give a reaction mixture. The pH of the reaction mixture is adjusted to 0.8 with concentrated hydrochloric acid at 25°C to 30°C, and then the mixture is stirred for 5 minutes. On standing, the reaction mixture separates into organic and aqueous layers, which are separated. The pH of the aqueous layer is adjusted to 7.8 with the addition of an aqueous sodium bicarbonate solution. The reaction mixture is cooled to 10°C to 15°C, and then stirred for 2 hours. The obtained solid is filtered, then washed with deionized water, and then dried under reduced pressure at 40°C to 45°C for 14 hours to obtain the amorphous form of bosutinib.
A third aspect of the present invention provides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients. The pharmaceutical composition is in the form of tablets, capsules, powder, solution, or suspension.
One embodiment of this aspect provides a process for manufacturing a
pharmaceutical composition comprising mixing the amorphous form of bosutinib together with pharmaceutically acceptable carriers, excipients, and/or diluents. There is also provided a pharmaceutical composition comprising the amorphous form of bosutinib as a solid dispersion or as nanoparticles with at least one polymeric component.
A fourth aspect of the present invention provides the use of an amorphous form of bosutinib for treating cancer, for example, CML.
The starting material, 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile can be prepared by any method known in the art, such as the processes described in U.S. Patent No. 6,002,008 and Journal of Medicinal Chemistry 44(23):3965-3977 (2001).
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
Method:
X-ray diffraction patterns were recorded using a PANalytical® X'pert PRO with X'celerator® as the detector, 0.02 as step size, and 3-40° 2Θ as range, using CuKa radiation.
DSC endotherms were recorded using a Mettler Toledo® Star6, SW 11.0, with Temperature range 30°C to 300°C, Heating rate: 10°C/min., and Nitrogen flow: 20.0 mL/min.
The following example is for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLE
Preparation of an amorphous form of bosutinib:
7-(3-Chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6- methoxyquinoline-3-carbonitrile (5 g) was added to dimethyl sulfoxide (10 mL), followed by the addition of N-methyl piperazine (1.3 g) and triethylamine (0.65 g) at 25°C. The reaction mixture was heated to 105°C to 110°C for 12 hours and then triethylamine (0.65 g) was further added. The reaction mixture was stirred for another 6 hours. On completion of the reaction, the reaction mass was cooled, and then deionized water (50 mL) was added at 25 °C to 30°C, and then the mixture was stirred for 70 minutes. The solid material obtained was filtered, and then washed with deionized water (20 mL). The wet solid obtained was added to deionized water (25 mL), followed by the addition of ethyl acetate (25 mL). The pH of the reaction mass was adjusted to 0.8 with concentrated hydrochloric acid (~2 mL) within 5 minutes at 25 °C to 30°C. The reaction mass was stirred at 25°C to 30°C for 5 minutes ,and then the layers were separated. The product was isolated in an aqueous layer. The pH of the aqueous layer was adjusted to 7.8 within 10 minutes with an aqueous sodium bicarbonate solution (3.5 g sodium bicarbonate in 52 mL of water). The reaction mass was cooled to 10°C to 15°C, and then stirred for 2 hours, followed by filtration, and then washing with deionized water (20 mL). The wet material obtained was dried under reduced pressure at 40°C to 45 °C for 14 hours to obtain the title product.
Dry weight: 3.9 g
Yield: 78%
Claims
1. An amorphous form of bosutinib.
2. The amorphous form of bosutinib according to claim 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
3. The amorphous form of bosutinib according to claim 1, characterized by a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.
4. The amorphous form of bosutinib according to claim 1, characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 79.9°C.
5. A process for the preparation of an amorphous form of bosutinib comprising the steps of:
i) treating 7-(3-chloropropoxy)-4-((2,4-dichloro-5-methoxyphenyl)amino)-6- methoxyquinoline-3-carbonitrile with N-methyl piperazine;
ii) stirring the product of step i) with water, a polar aprotic solvent, and an acid; iii) separating the reaction mixture of step ii) into an organic layer and an
aqueous layer;
iv) precipitating the aqueous layer of step iii) with a base; and
v) isolating the amorphous form of bosutinib.
6. The process according to claim 5, wherein 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile is treated with N-methyl piperazine in the presence of triethylamine and dimethylsulfoxide.
7. The process according to claim 5, wherein the polar aprotic solvent is selected from the group consisting of ethyl acetate, methyl acetate, and propyl acetate.
8. The process according to claim 5, wherein the acid is concentrated hydrochloric acid.
9. The process according to claim 8, wherein the concentrated hydrochloric acid is added to adjust the pH of the reaction mixture to about 0.7 to about 1.
10. The process according to claim 5, wherein the base is an aqueous sodium bicarbonate solution.
11. The process according to claim 10, wherein the aqueous sodium bicarbonate solution is added to adjust the pH of the aqueous layer to about 7.5 to about 8.
12. A pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
13. The use of an amorphous form of bosutinib for treating cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2559DE2015 | 2015-08-19 | ||
| IN2559/DEL/2015 | 2015-08-19 |
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| Publication Number | Publication Date |
|---|---|
| WO2017029584A1true WO2017029584A1 (en) | 2017-02-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IB2016/054820CeasedWO2017029584A1 (en) | 2015-08-19 | 2016-08-10 | Amorphous form of bosutinib |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321505A (en)* | 2019-10-25 | 2021-02-05 | 杭州中美华东制药有限公司 | Bosutinib crystal form and preparation method thereof |
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|---|---|---|---|---|
| WO2004075898A1 (en)* | 2003-02-21 | 2004-09-10 | Wyeth | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury |
| WO2005047259A1 (en)* | 2003-11-06 | 2005-05-26 | Wyeth | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (cml) |
| WO2007005462A1 (en)* | 2005-07-01 | 2007-01-11 | Wyeth | Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile and methods of preparing the same |
| WO2015123758A1 (en)* | 2014-02-20 | 2015-08-27 | Apotex Inc. | Bosutinib forms and preparation methods thereof |
- 2016
- 2016-08-10WOPCT/IB2016/054820patent/WO2017029584A1/ennot_activeCeased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004075898A1 (en)* | 2003-02-21 | 2004-09-10 | Wyeth | 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alkoxy-3-quinolinecarbonitriles for the treatment of ischemic injury |
| WO2005047259A1 (en)* | 2003-11-06 | 2005-05-26 | Wyeth | 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (cml) |
| WO2007005462A1 (en)* | 2005-07-01 | 2007-01-11 | Wyeth | Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile and methods of preparing the same |
| WO2015123758A1 (en)* | 2014-02-20 | 2015-08-27 | Apotex Inc. | Bosutinib forms and preparation methods thereof |
Non-Patent Citations (2)
| Title |
|---|
| BOSCHELLI, DH ET AL.: "Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. Issue 23, 2001, pages 3965 - 3977* |
| WITHBROE, GJ ET AL.: "A Robust, Streamlined Approach to Bosutinib Monohydrate", ORGANIC PROCESS RESEARCH & DEVELOPMENT;, vol. 17, no. 3, 15 March 2013 (2013-03-15), pages 500 - 504, XP055133427* |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321505A (en)* | 2019-10-25 | 2021-02-05 | 杭州中美华东制药有限公司 | Bosutinib crystal form and preparation method thereof |
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