WO2010067374A2 - Polymorphs of dasatinib - Google Patents
Polymorphs of dasatinib Download PDFInfo
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- WO2010067374A2 WO2010067374A2 PCT/IN2008/000822 IN2008000822W WO2010067374A2 WO 2010067374 A2 WO2010067374 A2 WO 2010067374A2 IN 2008000822 W IN2008000822 W IN 2008000822W WO 2010067374 A2 WO2010067374 A2 WO 2010067374A2
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- dasatinib
- solvate
- solution
- dimethylformamide
- crystalline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel polymorphs of dasatinib, processes for its preparation and to pharmaceutical compositions containing it.
- Dasatinib are antineoplastic agents, which were disclosed in WO Patent Publication No. 00/62778 and U.S. Patent No. 6,596,746.
- Dasatinib chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, is represented by the following structure:
- Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice.
- polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules.
- Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
- Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
- XRD X-ray diffraction
- DSC Differential Scanning Calorimetry
- IR Infrared spectrometry
- Solid solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
- Dasatinib can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
- dasatinib monohydrate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 18.0, 18.4, 19.2, 19.6, 21.2, 24.5, 25.9 and 28.0 ⁇ 0.2 degrees.
- dasatinb monohydrate can be obtained in dasatinib, by heating and dissolving the dasatinib in an ethanol and water mixture. Crystallizing the monohydrate from the ethanol and water mixture and cooled to get dasatinib monohydrate.
- dasatinib crystalline butanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 5.9, 12.0, 13.0, 17.7, 24.1 and 24.6 ⁇ 0.2 degrees.
- dasatinib crystalline ethanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 5.8, 11.3, 15.8, 17.2, 19.5, 24.1, 25.3 and 26.2 ⁇ 0.2 degrees.
- dasatinib crystalline neat form (N-6) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 6.8, 11.1, 12.3, 13.2, 13.7, 16.7, 21.0, 24.3 and 24.8 ⁇ 0.2 degrees.
- dasatinib crystalline neat form (T1H1-7) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 8.0, 9.7, 11.2, 13.3, 17.5, 18.9, 21.0 and 22.0 ⁇ 0.2 degrees.
- U.S. Patent application No. 2006/0094728 disclosed ethanolate form (T1E2-1) of dasatinib, characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at approximately 7.2, 12.0, 12.8, 18.0, 19.3 and 25.2 ⁇ 0.2 degrees.
- Another object of the present invention is to provide process for preparing the novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate, dasatinib isopropyl acetate solvate and known crystalline dasatinib monohydrate.
- Still another object of the present invention is to provide pharmaceutical compositions containing the novel crystalline form of dasatinib.
- dasatinib dimethyl formamide solvate characterized by peaks in the powder x- ray diffraction spectrum having 2 ⁇ angle positions at about 5.7, 11.5, 14.5, 17.3 and 25.1 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of dasatinib dimethylformamide solvate is shown in figure 1.
- a process for preparing dasatinib dimethylformamide solvate which comprises crystallizing dasatinib dimethylformamide solvate from a solution of dasatinib in N,N-dimethylformamide solvent.
- N,N-dimethylformamide may alone be present as solvent in the solution or N,N-dimethylformamide in combination with water or any other solvent or solvents may be present.
- N 1 N- dimethylformamide in combination with ethyl acetate or acetone may be present in the solution.
- dasatinib dimethyl sulfoxide solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 11.1, 15.1, 17.8, 19.0, 23.4 and 24.3 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of dasatinib dimethyl sulfoxide solvate is shown in figure 2.
- a process for preparing dasatinib dimethyl sulfoxide solvate which comprises crystallizing dasatinib dimethyl sulfoxide solvate from a solution of dasatinib in a solvent mixture comprising dimethyl sulfoxide and ethyl acetate.
- dasatinib toluene solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.8, 11.8, 15.3, 21.6 and 24.6 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of dasatinib toluene solvate is shown in figure 3.
- a process for preparing dasatinib toluene solvate which comprises crystallizing dasatinib toluene solvate from a solution of dasatinib in toluene.
- dasatinib isopropyl acetate solvate characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.7, 6.0, 6.7, 12.2, 13.1, 17.1 and 21.8 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of dasatinib isopropyl acetate solvate is shown in figure 4.
- a process for preparing dasatinib isopropyl acetate solvate which comprises crystallizing dasatinib isopropyl acetate solvate from a solution of dasatinib in isopropyl acetate.
- dasatinib form I The crystalline form designated as dasatinib form I, characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 7.1, 11.9, 12.2, 14.3, 16.4, 16.7, 19.0 and 24.1 ⁇ 0.2 degrees.
- the powdered x-ray diffractogram (PXRD) of crystalline dasatinib form I is shown in figure 5.
- the crystalline dasatinib form I may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern. Thus, for example, a peak at 14.3 ⁇ 0.2 degrees 2 ⁇ is present in the PXRD of the crystalline dasatinib form I of the present invention, but is absent in the PXRD of the dasatinib crystalline neat form (N-6) disclosed in the US Patent Application No. 2005/0215795 Al
- a process for preparation of crystalline dasatinib form I which comprises crystallizing dasatinib form I from a solution of dasatinib in a solvent mixture of ethyl acetate and methanol, or acetone and methanol.
- a process for preparation of crystalline dasatinib monohydrate which comprises crystallizing dasatinib monohydrate from a solution of dasatinib dimethylformamide solvate in water.
- a process for preparation of crystalline dasatinib monohydrate which comprises crystallizing dasatinib monohydrate from a solution of dasatinib in a solvent mixture of dimethyl sulfoxide and water.
- Dasatinib used as non-solvated, solvated, hydrated forms as starting material of the invention may be obtained from known procedures.
- the solvates of the present invention are useful intermediates for obtaining pure dasatinib.
- the solvates and novel form of dasatinib of the present invention can be used to obtain known polymorphs of dasatinib.
- composition comprising crystalline dasatinib form I.
- the pharmaceutical dosage form may preferably be in solid dosage form.
- Figure 1 is an X-ray powder diffraction pattern of dasatinib dimethylformamide solvate.
- Figure 2 is an X-ray powder diffraction pattern of dasatinib dimethyl sulfoxide solvate.
- Figure 3 is an X-ray powder diffraction pattern of dasatinib toluene solvate.
- Figure 4 is an X-ray powder diffraction pattern of dasatinib isopropyl acetate solvate.
- Figure 5 is an X-ray powder diffraction pattern of crystalline dasatinib form I.
- X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-k ⁇ radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40KV and 35 mA.
- Dasatinib (5 gm) obtained according to reference example was dissolved in ethyl acetate (300 ml) at 25 0 C and heated to reflux temperature. To the solution was added methanol (100 ml) and stirred for 30 minutes at reflux temperature to form clear solution. The solution was slowly cooled to room temperature and then cooled to O 0 C, stirred for 1 hour at O 0 C. The solid was collected by filtration and the solid was washed with mixture of ethyl acetate and methanol (20 ml, 3:1), and then dried the solid at 50 0 C under vacuum to obtain 3.5 gm of crystalline dasatinib form I.
- Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in acetone (100 ml) and methanol (250 ml) and heated to reflux temperature, stirred for 30 minutes at reflux temperature to form clear solution. The solution was cooled to room temperature and then cooled to 20 0 C, stirred for 1 hour at 20 0 C. The solid was collected by filtration and the solid was washed with mixture of acetone (10 ml) and methanol (25 ml), and then dried the solid at 50 0 C under vacuum to obtain 4 gm of crystalline dasatinib form I (HPLC purity: 99.85%).
- Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) at 25 0 C and heated to 65 0 C to form clear solution. To the solution was slowly added acetone (50 ml) at 65 0 C and stirred for 1 hour at 65 0 C. The solution was slowly cooled to 25 0 C and stirred for 1 hour at 25 0 C. The contents are filtered and the solid obtained was washed with mixture of dimethylformamide and acetone (15 ml, 1:2), and then dried the solid at 50 0 C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.94%).
- Dasatinib (5 gm) was dissolved in dimethylformamide (25 ml) at 25 0 C and heated to 65 0 C to form clear solution. Ethyl acetate (50 ml) was added slowly to the solution at 65 0 C and stirred for 1 hour at 65 0 C. The solution was slowly cooled to 25 0 C, stirred for 1 hour at 25 0 C and filtered. The solid obtained was washed with mixture of dimethylformamide and ethyl acetate (30 ml, 1:2), and then dried the solid at 50 0 C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate.
- Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 65 0 C to form a clear solution. The solution was cooled to 25 0 C and then cooled to 5 0 C, stirred for 4 hour at 5 0 C. The solid was collected by filtration and the solid was washed with chilled dimethylformamide (10 ml), and then dried the solid at 50 0 C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.9%).
- Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 65 0 C to form a clear solution. Water (50 ml) was added slowly to the solution at 65 0 C and stirred for 1 hour at 65 0 C. The solution was cooled to 25 0 C and stirred for 30 minutes at 25 0 C. The solid was collected by filtration and the solid was washed with mixture of dimethylformamide and water (15 ml, 1 :2), and then dried the solid at 50 0 C under vacuum to obtain 4.7 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.93%).
- Dasatinib dimethylformamide solvate (4.7 gm) obtained as in example 6 was dissolved in water (50 ml) and heated to 75 0 C, stirred for 4 hours at 75 0 C. The solution was cooled to 25 0 C, stirred for 30 minutes at 25 0 C and filtered. The solid obtained was washed with water (15 ml), and then dried at 50 0 C under vacuum to obtain 4.7 gm of dasatinib monohydrate.
- Dasatinib (20 gm) was dissolved in dimethyl sulfoxide (100 ml) at 25 0 C and heated to 65 0 C to form clear solution. To the solution was slowly added water (200 ml) at 65 0 C and stirred for 1 hour at 65 0 C. The solution was slowly cooled to 25 0 C and stirred for 30 minutes at 25 0 C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and water (30 ml, 1 :2), and then dried the solid at 50 0 C under vacuum to obtain 19.5 gm of dasatinib monohydrate.
- Dasatinib (5 gm) was dissolved in isopropyl acetate (65 ml) and heated to 80 0 C, stirred for 1 hour at 80 0 C to form a clear solution. The solution was cooled to 25 0 C, stirred for 1 hour at 25 0 C and filtered. The solid obtained was washed with isopropyl acetate (15 ml) to obtain 5 gm of dasatinib isopropyl acetate solvate.
- Dasatinib (6 gm) was dissolved in toluene (100 ml) and heated to reflux temperature, stirred for 2 hours at reflux temperature to form a clear solution. The solution was slowly cooled to 25 0 C. The contents are filtered and the solid obtained was washed with toluene (20 ml) to obtain 5.5 gm of dasatinib toluene solvate.
- Dasatinib (5 gm) was dissolved in dimethyl sulfoxide (20 ml) at 25 0 C and heated to 65 0 C. To the solution was slowly added ethyl acetate (200 ml) at 65 0 C and the solution was slowly cooled to O 0 C, stirred for 2 hours at O 0 C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and ethyl acetate (55 ml, 1 :10), and then dried the solid at 50 0 C under vacuum to obtain 4 gm of dasatinib dimethyl sulfoxide solvate.
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Abstract
The present invention provides a novel crystalline form I of dasatinib, process for its preparation and to pharmaceutical composition containing it. The present invention also provides dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate and dasatinib isopropyl acetate solvate, processes for its preparation. The present invention further provides a process for preparation of crystalline dasatinib monohydrate.
Description
POLYMORPHS OF DASATINIB
FIELD OF THE INVENTION
The present invention relates to novel polymorphs of dasatinib, processes for its preparation and to pharmaceutical compositions containing it.
BACKGROUND OF THE INVENTION
Dasatinib are antineoplastic agents, which were disclosed in WO Patent Publication No. 00/62778 and U.S. Patent No. 6,596,746. Dasatinib, chemically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazolecarboxamide, is represented by the following structure:
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Dasatinib can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. Patent Application No. 2005/0215795 A1 (herein after referred to as the 795 patent application) described five crystalline forms of dasatinib (monohydrate, butanol solvate, ethanol solvate, neat form (N-6) and neat form (T1H1-7)), characterized by powder X-ray diffraction (P-XRD) pattern.
According to the '795 patent application, dasatinib monohydrate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 18.0, 18.4, 19.2, 19.6, 21.2, 24.5, 25.9 and 28.0 ± 0.2 degrees. As per the process exemplified in the '795 patent application, dasatinb monohydrate can be obtained in dasatinib, by heating and dissolving the dasatinib in an ethanol and water mixture. Crystallizing the monohydrate from the ethanol and water mixture and cooled to get dasatinib monohydrate.
According to the '795 patent application, dasatinib crystalline butanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.9, 12.0, 13.0, 17.7, 24.1 and 24.6 ± 0.2 degrees.
According to the 795 patent application, dasatinib crystalline ethanol solvate is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 5.8, 11.3, 15.8, 17.2, 19.5, 24.1, 25.3 and 26.2 ± 0.2 degrees.
According to the 795 patent application, dasatinib crystalline neat form (N-6) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 6.8, 11.1, 12.3, 13.2, 13.7, 16.7, 21.0, 24.3 and 24.8 ± 0.2 degrees.
According to the 795 patent application, dasatinib crystalline neat form (T1H1-7) is characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 8.0, 9.7, 11.2, 13.3, 17.5, 18.9, 21.0 and 22.0 ± 0.2 degrees.
U.S. Patent application No. 2006/0094728 disclosed ethanolate form (T1E2-1) of dasatinib, characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at approximately 7.2, 12.0, 12.8, 18.0, 19.3 and 25.2 ± 0.2 degrees.
We have discovered novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate and dasatinib isopropyl acetate solvate.
Another object of the present invention is to provide process for preparing the novel crystalline form of dasatinib, dasatinib dimethylformamide solvate, dasatinib dimethyl sulfoxide solvate, dasatinib toluene solvate, dasatinib isopropyl acetate solvate and known crystalline dasatinib monohydrate.
Still another object of the present invention is to provide pharmaceutical compositions containing the novel crystalline form of dasatinib.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention there is provided dasatinib dimethyl formamide solvate, characterized by peaks in the powder x- ray diffraction spectrum having 2Θ angle positions at about 5.7, 11.5, 14.5, 17.3 and 25.1 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of dasatinib dimethylformamide solvate is shown in figure 1.
According to another aspect of the present invention there is provided a process for preparing dasatinib dimethylformamide solvate which comprises crystallizing dasatinib dimethylformamide solvate from a solution of dasatinib in N,N-dimethylformamide solvent.
According to the invention, N,N-dimethylformamide may alone be present as solvent in the solution or N,N-dimethylformamide in combination with water or any other solvent or solvents may be present. For example, N1N- dimethylformamide in combination with ethyl acetate or acetone may be present in the solution.
According to another aspect of the present invention there is provided dasatinib dimethyl sulfoxide solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 11.1, 15.1, 17.8, 19.0, 23.4 and 24.3 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of dasatinib dimethyl sulfoxide solvate is shown in figure 2.
According to another aspect of the present invention there is provided a process for preparing dasatinib dimethyl sulfoxide solvate which comprises crystallizing dasatinib dimethyl sulfoxide solvate from a solution of dasatinib in a solvent mixture comprising dimethyl sulfoxide and ethyl acetate.
According to another aspect of the present invention there is provided dasatinib toluene solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.8, 11.8, 15.3, 21.6 and 24.6 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of dasatinib toluene solvate is shown in figure 3.
According to another aspect of the present invention there is provided a process for preparing dasatinib toluene solvate which comprises crystallizing dasatinib toluene solvate from a solution of dasatinib in toluene.
According to another aspect of the present invention there is provided dasatinib isopropyl acetate solvate, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.7, 6.0, 6.7, 12.2, 13.1, 17.1 and 21.8± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of dasatinib isopropyl acetate solvate is shown in figure 4.
According to another aspect of the present invention there is provided a process for preparing dasatinib isopropyl acetate solvate which comprises crystallizing dasatinib isopropyl acetate solvate from a solution of dasatinib in isopropyl acetate.
According to another aspect of the present invention there is provided a novel crystalline form of dasatinib. The crystalline form designated as dasatinib form I, characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 7.1, 11.9, 12.2, 14.3, 16.4, 16.7, 19.0 and 24.1 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of crystalline dasatinib form I is shown in figure 5.
The crystalline dasatinib form I may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern. Thus, for example, a peak at 14.3 ± 0.2 degrees 2Θ is present in the PXRD of the crystalline dasatinib form I of the present invention, but is absent in the PXRD of the dasatinib crystalline neat form (N-6) disclosed in the US Patent Application No. 2005/0215795 Al
According to another aspect of the present invention there is provided a process for preparation of crystalline dasatinib form I which comprises crystallizing dasatinib form I from a solution of dasatinib in a solvent mixture of ethyl acetate and methanol, or acetone and methanol.
According to another aspect of the present invention there is provided a process for preparation of crystalline dasatinib monohydrate which comprises crystallizing dasatinib monohydrate from a solution of dasatinib dimethylformamide solvate in water.
According to another aspect of the present invention there is provided a process for preparation of crystalline dasatinib monohydrate which comprises crystallizing dasatinib monohydrate from a solution of dasatinib in a solvent mixture of dimethyl sulfoxide and water.
Dasatinib used as non-solvated, solvated, hydrated forms as starting material of the invention may be obtained from known procedures.
The solvates of the present invention are useful intermediates for obtaining pure dasatinib. The solvates and novel form of dasatinib of the present invention can be used to obtain known polymorphs of dasatinib.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising crystalline dasatinib form I.
The pharmaceutical dosage form may preferably be in solid dosage form.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffraction pattern of dasatinib dimethylformamide solvate.
Figure 2 is an X-ray powder diffraction pattern of dasatinib dimethyl sulfoxide solvate.
Figure 3 is an X-ray powder diffraction pattern of dasatinib toluene solvate.
Figure 4 is an X-ray powder diffraction pattern of dasatinib isopropyl acetate solvate.
Figure 5 is an X-ray powder diffraction pattern of crystalline dasatinib form I.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-kα radiation. Approximately 1 gm of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and
a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40KV and 35 mA.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
Reference Example
2-(6-Cholro-2-methylpyrimidin-4-yl-amino)-N-(2-chloro-6-methylphenyl) thiazole-5-carboxamide (15 gm) was added to 1-(2-hydroxyethyl)piperazine at 250C and heated to 850C, stirred for 2 hours 30 minutes at 850C. To the solution was added water (500 ml) at 800C and slowly cooled to 250C, stirred for 1 hour at 250C. The solid was collected by filtration and the solid was washed with water (50 ml), and then dried the solid at 550C under vacuum to obtain 15 gm of dasatinib.
Example 1
Dasatinib (5 gm) obtained according to reference example was dissolved in ethyl acetate (300 ml) at 250C and heated to reflux temperature. To the solution was added methanol (100 ml) and stirred for 30 minutes at reflux temperature to form clear solution. The solution was slowly cooled to room temperature and then cooled to O0C, stirred for 1 hour at O0C. The solid was collected by filtration and the solid was washed with mixture of ethyl acetate and methanol (20 ml, 3:1), and then dried the solid at 500C under vacuum to obtain 3.5 gm of crystalline dasatinib form I.
Example 2
Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in acetone (100 ml) and methanol (250 ml) and heated to reflux temperature, stirred for 30 minutes at reflux temperature to form clear solution. The solution was cooled to room temperature and then cooled to 200C, stirred for 1 hour at 200C. The solid was collected by filtration and the solid was washed with mixture of acetone (10 ml) and methanol (25 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of crystalline dasatinib form I (HPLC purity: 99.85%).
Example 3
Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added acetone (50 ml) at 650C and stirred for 1 hour at
650C. The solution was slowly cooled to 250C and stirred for 1 hour at 250C. The contents are filtered and the solid obtained was washed with mixture of dimethylformamide and acetone (15 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.94%).
Example 4
Dasatinib (5 gm) was dissolved in dimethylformamide (25 ml) at 250C and heated to 650C to form clear solution. Ethyl acetate (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with mixture of dimethylformamide and ethyl acetate (30 ml, 1:2), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate.
Example 5
Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. The solution was cooled to 250C and then cooled to 50C, stirred for 4 hour at 50C. The solid was collected by filtration and the solid was washed with chilled dimethylformamide (10 ml), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.9%).
Example 6
Dasatinib (5 gm, HPLC purity: 99.2%) was dissolved in dimethylformamide (25 ml) and heated to 650C to form a clear solution. Water (50 ml) was added slowly to the solution at 650C and stirred for 1 hour at 650C. The solution was cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethylformamide and water (15 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 4.7 gm of dasatinib dimethylformamide solvate (HPLC purity: 99.93%).
Example 7
Dasatinib dimethylformamide solvate (4.7 gm) obtained as in example 6 was dissolved in water (50 ml) and heated to 750C, stirred for 4 hours at 750C. The solution was cooled to 250C, stirred for 30 minutes at 250C and filtered. The
solid obtained was washed with water (15 ml), and then dried at 500C under vacuum to obtain 4.7 gm of dasatinib monohydrate.
Example 8
Dasatinib (20 gm) was dissolved in dimethyl sulfoxide (100 ml) at 250C and heated to 650C to form clear solution. To the solution was slowly added water (200 ml) at 650C and stirred for 1 hour at 650C. The solution was slowly cooled to 250C and stirred for 30 minutes at 250C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and water (30 ml, 1 :2), and then dried the solid at 500C under vacuum to obtain 19.5 gm of dasatinib monohydrate.
Example 9
Dasatinib (5 gm) was dissolved in isopropyl acetate (65 ml) and heated to 800C, stirred for 1 hour at 800C to form a clear solution. The solution was cooled to 250C, stirred for 1 hour at 250C and filtered. The solid obtained was washed with isopropyl acetate (15 ml) to obtain 5 gm of dasatinib isopropyl acetate solvate.
Example 10
Dasatinib (6 gm) was dissolved in toluene (100 ml) and heated to reflux temperature, stirred for 2 hours at reflux temperature to form a clear solution. The solution was slowly cooled to 250C. The contents are filtered and the solid obtained was washed with toluene (20 ml) to obtain 5.5 gm of dasatinib toluene solvate.
Example 11
Dasatinib (5 gm) was dissolved in dimethyl sulfoxide (20 ml) at 250C and heated to 650C. To the solution was slowly added ethyl acetate (200 ml) at 650C and the solution was slowly cooled to O0C, stirred for 2 hours at O0C. The solid was collected by filtration and the solid was washed with mixture of dimethyl sulfoxide and ethyl acetate (55 ml, 1 :10), and then dried the solid at 500C under vacuum to obtain 4 gm of dasatinib dimethyl sulfoxide solvate.
Claims
1. A dasatinib dimethylformamide solvate, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.7, 11.5, 14.5, 17.3 and 25.1 + 0.2 degrees.
2. A process for the preparation of dasatinib dimethylformamide solvate as defined in claim 1 , which comprises crystallizing dasatinib dimethylformamide solvate from a solution of dasatinib in N1N- dimethylformamide solvent.
3. The process as claimed in claim 2, wherein the N,N-dimethylformamide in combination with water or any other solvent or solvents.
4. The process as claimed in claim 3, wherein the solvent used in the process is ethyl acetate or acetone.
5. A dasatinib dimethyl sulfoxide solvate, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 11.1, 15.1 , 17.8, 19.0, 23.4 and 24.3 ± 0.2 degrees.
6. A process for the preparation of the dasatinib dimethyl sulfoxide solvate as defined in claim 5, which comprises crystallizing dasatinib dimethyl sulfoxide solvate from a solution of dasatinib in a solvent mixture comprising dimethyl sulfoxide and ethyl acetate.
7. A dasatinib toluene solvate, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.8, 11.8, 15.3, 21.6 and 24.6 ± 0.2 degrees.
8. A process for the preparation of the dasatinib toluene solvate as defined in claim 7, which comprises crystallizing dasatinib toluene solvate from a solution of dasatinib in toluene.
9. A dasatinib isopropyl acetate solvate, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.7, 6.0, 6.7, 12.2, 13.1, 17.1 and 21.8 ± 0.2 degrees.
10. A process for the preparation of the dasatinib isopropyl acetate as defined in claim 9, which comprises crystallizing dasatinib isopropyl acetate solvate from a solution of dasatinib in isopropyl acetate.
11. A crystalline dasatinib form I, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 7.1, 11.9, 12.2, 14.3, 16.4, 19.0 and 24.1 ± 0.2 degrees.
12. A process for the preparation of the crystalline dasatinib form I as claimed in claim 11 , which comprises crystallizing dasatinib form I from a solution of dasatinib in a solvent mixture of ethyl acetate and methanol, or acetone and methanol.
13. A process for the preparation of the crystalline dasatinib monohydrate which comprises which comprises crystallizing dasatinib monohydrate from a solution of dasatinib dimethylformamide solvate in water.
14. A process for the preparation of the crystalline dasatinib monohydrate which comprises crystallizing dasatinib monohydrate from a solution of dasatinib in a solvent mixture of dimethyl sulfoxide and water.
15. A pharmaceutical composition comprising crystalline dasatinib form I of claim 11 and a pharmaceutically acceptable excipient.
16. The pharmaceutical composition as claimed in claim 15, wherein the pharmaceutical composition of crystalline dasatinib form I is a solid dosage form.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
WO2010062715A2 (en) * | 2008-11-03 | 2010-06-03 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
-
2008
- 2008-12-08 WO PCT/IN2008/000822 patent/WO2010067374A2/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
WO2010062715A2 (en) * | 2008-11-03 | 2010-06-03 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
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