CA2806820A1 - N-methylformamide solvate of dasatinib - Google Patents
N-methylformamide solvate of dasatinib Download PDFInfo
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- CA2806820A1 CA2806820A1 CA2806820A CA2806820A CA2806820A1 CA 2806820 A1 CA2806820 A1 CA 2806820A1 CA 2806820 A CA2806820 A CA 2806820A CA 2806820 A CA2806820 A CA 2806820A CA 2806820 A1 CA2806820 A1 CA 2806820A1
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- Prior art keywords
- solvate
- dasatinib
- methylformamide
- crystalline
- methylformamide solvate
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
Abstract
The present invention relates to the N-Methylformamide solvate of dasatinib a process for its preparation. Formula (I)
Description
N-METHYLFORMAMIDE SOLVATE OF DASATINIB
Field of the Invention The present invention relates to a N-Methylformamide solvate of dasatinib and a process for its preparation.
Background of the Invention Dasatinib monohydrate of Formula A, chemically described as N-(2-chloro-6-methylpheny1)-2-R644-(2-hydroxyethyl)-1-piperazinyll-2-methyl-4-pyrimidinyljamino]-5-thiazole carboxamide monohydrate, is a cyclic protein tyrosine kinase inhibitor.
Dasatinib monohydrate, marketed under the brand name Sprycel , is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. Sprycele is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
41, NHS / NHN H20 CI OH
Formula A
U.S. Patent No. 6,596,746 provides a process for the preparation of dasatinib.
U.S. Patent No. 7,491,725 provides for the crystalline monohydrate, butanol solvate form, crystalline ethanol solvates and neat forms of dasatinib. It also provides a process for the preparation of crystalline monohydrate, butanol solvate form, crystalline ethanol solvate and neat form of dasatinib.
U.S. Publication No. 2009/0118297 provides for the anhydrous form, amorphous form, iso-propanol solvate, a n-propanol-dimethylsulfoxide ("DMSO") solvate, a DMSO
solvate, a hemi tetrahydrofuran ("THF") solvate, a 2-methyl-tetrahydrofuran ("2-methyl THF") solvate, a hemi 1,4-dioxane solvate, a pyridine solvate, a toluene solvate, a methyl isobutyl ketone ("MIBK") solvate, a mono acetone solvate, an iso-propanol ("IPA")-DMS0 solvate, a 2-butanol-DMS0 solvate, an IPA-DMF solvate, an IPA solvate, an n-propanol-DMF solvate, an n-propanol solvate, a 2-butanol-DMF solvate, a 2-butanol solvate, an n-butanol-DMSO solvate, a DMF-water solvate, a DMF solvate, a methyl isopropyl ketone ("MIPK") solvate, a dimethoxyethane solvate, a cellosolve solvate, a methylacetate solvate, a methanol solvate, an ethylacetate solvate, a 2-pentanole solvate, a dimethyl carbonate solvate, an isopropylacetate solvate, an ethyleneglycol solvate, a dichloromethane solvate, a methylformate solvate, a tert-butanol solvate, a dimethoxyethane solvate, a methylethylketone ("MEK") solvate, a monochlorobenzene solvate, a propylene glycol monoethyl ether ("PGME") solvate, a glycerol solvate, a cyclopentyl methyl ether solvate, a methyl tert butyl ether ("MTBE") solvate, an amylalcohol solvate, a glycerol formal solvate of dasatinib and processes for their preparation.
WO 2010/062715 discloses an isosorbide dimethyl ether solvate of dasatinib, a N,N'-dimethylethylene urea solvate of dasatinib, and a N,N'-dimethyl-N,N'-propylene urea solvate of dasatinib and processes for their preparation.
WO 2010/067374 discloses a dimethylformamide solvate, dimethyl sulfoxide solvate, toluene solvate, isopropyl acetate solvate, crystalline Form I of dasatinib characterized by their X-ray powder diffractogram and processes for their preparation.
Polymorphism is defined as the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice. Different polymorphs may differ in their physical properties, such as, melting point, solubility, X-ray diffraction patterns, and the like. Although these differences disappear once the compound is dissolved, they can appreciably influence the pharmaceutically relevant properties of the solid form, such as its handling properties, dissolution rate and stability. Such properties can significantly influence the processing, the shelf life, and the 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) powder as well as single crystal, DSC, IR, Solid state NMR, or Raman spectroscopy.
Field of the Invention The present invention relates to a N-Methylformamide solvate of dasatinib and a process for its preparation.
Background of the Invention Dasatinib monohydrate of Formula A, chemically described as N-(2-chloro-6-methylpheny1)-2-R644-(2-hydroxyethyl)-1-piperazinyll-2-methyl-4-pyrimidinyljamino]-5-thiazole carboxamide monohydrate, is a cyclic protein tyrosine kinase inhibitor.
Dasatinib monohydrate, marketed under the brand name Sprycel , is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib. Sprycele is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
41, NHS / NHN H20 CI OH
Formula A
U.S. Patent No. 6,596,746 provides a process for the preparation of dasatinib.
U.S. Patent No. 7,491,725 provides for the crystalline monohydrate, butanol solvate form, crystalline ethanol solvates and neat forms of dasatinib. It also provides a process for the preparation of crystalline monohydrate, butanol solvate form, crystalline ethanol solvate and neat form of dasatinib.
U.S. Publication No. 2009/0118297 provides for the anhydrous form, amorphous form, iso-propanol solvate, a n-propanol-dimethylsulfoxide ("DMSO") solvate, a DMSO
solvate, a hemi tetrahydrofuran ("THF") solvate, a 2-methyl-tetrahydrofuran ("2-methyl THF") solvate, a hemi 1,4-dioxane solvate, a pyridine solvate, a toluene solvate, a methyl isobutyl ketone ("MIBK") solvate, a mono acetone solvate, an iso-propanol ("IPA")-DMS0 solvate, a 2-butanol-DMS0 solvate, an IPA-DMF solvate, an IPA solvate, an n-propanol-DMF solvate, an n-propanol solvate, a 2-butanol-DMF solvate, a 2-butanol solvate, an n-butanol-DMSO solvate, a DMF-water solvate, a DMF solvate, a methyl isopropyl ketone ("MIPK") solvate, a dimethoxyethane solvate, a cellosolve solvate, a methylacetate solvate, a methanol solvate, an ethylacetate solvate, a 2-pentanole solvate, a dimethyl carbonate solvate, an isopropylacetate solvate, an ethyleneglycol solvate, a dichloromethane solvate, a methylformate solvate, a tert-butanol solvate, a dimethoxyethane solvate, a methylethylketone ("MEK") solvate, a monochlorobenzene solvate, a propylene glycol monoethyl ether ("PGME") solvate, a glycerol solvate, a cyclopentyl methyl ether solvate, a methyl tert butyl ether ("MTBE") solvate, an amylalcohol solvate, a glycerol formal solvate of dasatinib and processes for their preparation.
WO 2010/062715 discloses an isosorbide dimethyl ether solvate of dasatinib, a N,N'-dimethylethylene urea solvate of dasatinib, and a N,N'-dimethyl-N,N'-propylene urea solvate of dasatinib and processes for their preparation.
WO 2010/067374 discloses a dimethylformamide solvate, dimethyl sulfoxide solvate, toluene solvate, isopropyl acetate solvate, crystalline Form I of dasatinib characterized by their X-ray powder diffractogram and processes for their preparation.
Polymorphism is defined as the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecule in the crystal lattice. Different polymorphs may differ in their physical properties, such as, melting point, solubility, X-ray diffraction patterns, and the like. Although these differences disappear once the compound is dissolved, they can appreciably influence the pharmaceutically relevant properties of the solid form, such as its handling properties, dissolution rate and stability. Such properties can significantly influence the processing, the shelf life, and the 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) powder as well as single crystal, DSC, IR, Solid state NMR, or Raman spectroscopy.
The solvent medium and/or mode of isolation play a very important role in obtaining one polymorphic form over another.
The discovery of new solid state forms and solvates of a pharmaceutical compound provides a new opportunity to improve the pharmacokinetic properties of a pharmaceutical product. Therefore, there is a need for additional solid state forms of dasatinib.
The present inventors have now surprisingly found a N-Methylformamide solvate of dasatinib. The novel N-Methylformamide solvate of dasatinib of the present invention is suitable for preparing pharmaceutical compositions.
Summary of the Invention In one general aspect, the present invention provides for N-Methylformamide solvate of dasatinib of Formula B.
HNH ...-- CH 3 CH3 jNH CI 1 I
OH
Formula B
In another general aspect, the present invention provides for crystalline N-Methylformamide solvate of dasatinib characterized by an X-Ray Powder Diffractogram (XRPD) substantially as depicted in Figure 1.
In another general aspect, the present invention provides for crystalline N-Methylformamide solvate of dasatinib characterized by an X-ray Powder Diffractogram which includes interplanar distances at approximately 14.21, 7.11, 5.80, 4.74, and 3.65 A.
Embodiments of this aspect may include one or more of the following features.
For example, the crystalline N-Methylformamide solvate of dasatinib may be further characterized by an X-ray Powder Diffractogram which includes interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
The crystalline N-Methylformamide solvate of dasatinib may further be characterized by a DSC thermogram substantially as depicted in Figure 2. For example, the crystalline N-Methylformamide solvate of dasatinib may have characteristic DSC
endothermic peaks at about 160 C and about 287 C.
The crystalline N-Methylformamide solvate of dasatinib may also be further characterized by a TGA substantially as depicted in Figure 3.
In yet another general aspect, the present invention provides for a process for the preparation of N-Methylformamide solvate of dasatinib. The process includes:
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
Embodiments of this aspect may include one or more of the following features.
For example, step a) is carried out at a temperature of 20 C to 50 C and the amount of N-Methylformamide is 3 to 10 times the amount of dasatinib.
In another general aspect, the present invention provides for the use of N-Methylformamide solvate of dasatinib for the preparation of other polymorphic forms or solvates of dasatinib.
In yet another general aspect, the present invention provides for a pharmaceutical composition which includes a therapeutically effective amount of N-Methylformamide solvate of dasatinib and one or more pharmaceutically acceptable excipients.
In another general aspect, the present invention provides for a method for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The method includes administering to a mammal in need thereof a therapeutically effective amount of N-Methylformamide solvate of dasatinib.
Brief Description of the Drawings Figure 1 and Figure la depicts X-Ray Powder Diffractogram (XRPD) of N-Methylformamide solvate of dasatinib and the associated values, respectively.
Figure 2 depicts Differential Scanning Calorimetry (DSC) thermogram of N-Methylformamide solvate of dasatinib.
The discovery of new solid state forms and solvates of a pharmaceutical compound provides a new opportunity to improve the pharmacokinetic properties of a pharmaceutical product. Therefore, there is a need for additional solid state forms of dasatinib.
The present inventors have now surprisingly found a N-Methylformamide solvate of dasatinib. The novel N-Methylformamide solvate of dasatinib of the present invention is suitable for preparing pharmaceutical compositions.
Summary of the Invention In one general aspect, the present invention provides for N-Methylformamide solvate of dasatinib of Formula B.
HNH ...-- CH 3 CH3 jNH CI 1 I
OH
Formula B
In another general aspect, the present invention provides for crystalline N-Methylformamide solvate of dasatinib characterized by an X-Ray Powder Diffractogram (XRPD) substantially as depicted in Figure 1.
In another general aspect, the present invention provides for crystalline N-Methylformamide solvate of dasatinib characterized by an X-ray Powder Diffractogram which includes interplanar distances at approximately 14.21, 7.11, 5.80, 4.74, and 3.65 A.
Embodiments of this aspect may include one or more of the following features.
For example, the crystalline N-Methylformamide solvate of dasatinib may be further characterized by an X-ray Powder Diffractogram which includes interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
The crystalline N-Methylformamide solvate of dasatinib may further be characterized by a DSC thermogram substantially as depicted in Figure 2. For example, the crystalline N-Methylformamide solvate of dasatinib may have characteristic DSC
endothermic peaks at about 160 C and about 287 C.
The crystalline N-Methylformamide solvate of dasatinib may also be further characterized by a TGA substantially as depicted in Figure 3.
In yet another general aspect, the present invention provides for a process for the preparation of N-Methylformamide solvate of dasatinib. The process includes:
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
Embodiments of this aspect may include one or more of the following features.
For example, step a) is carried out at a temperature of 20 C to 50 C and the amount of N-Methylformamide is 3 to 10 times the amount of dasatinib.
In another general aspect, the present invention provides for the use of N-Methylformamide solvate of dasatinib for the preparation of other polymorphic forms or solvates of dasatinib.
In yet another general aspect, the present invention provides for a pharmaceutical composition which includes a therapeutically effective amount of N-Methylformamide solvate of dasatinib and one or more pharmaceutically acceptable excipients.
In another general aspect, the present invention provides for a method for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The method includes administering to a mammal in need thereof a therapeutically effective amount of N-Methylformamide solvate of dasatinib.
Brief Description of the Drawings Figure 1 and Figure la depicts X-Ray Powder Diffractogram (XRPD) of N-Methylformamide solvate of dasatinib and the associated values, respectively.
Figure 2 depicts Differential Scanning Calorimetry (DSC) thermogram of N-Methylformamide solvate of dasatinib.
Figure 3 depicts Thermogravimetric Analysis (TGA) of N-Methylformamide solvate of dasatinib.
The XRPD was determined by using PANalytical X' Pert Pro X-Ray Powder Diffractometer in the range 0 C to 40 C 20 and under tube voltage and current of 45 Kv and 40 mA, respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.
The TGA was recorded on TA (Q500) (Rate of heating = 10 C/minute).
The DSC was recorded on Mettler Toledo (DSC 821) (Rate of heating =
C/minute).
10 Detailed Description of the Invention The present invention provides for the N-Methylformamide solvate of dasatinib of Formula B
CH3 0 11NcH3 H NH õcH3 NHS I NHN
CI OH
Formula B
The present invention may be in the form of crystalline N-Methylformamide solvate of dasatinib.
The crystalline N-Methylformamide solvate of dasatinib has an X-Ray Powder Diffractogram (XRPD) substantially as depicted in Figure 1 of the accompanied drawings. The crystalline N-Methylformamide solvate of dasatinib has an X-ray Powder Diffractogram which shows characteristic peaks expressed as interplanar distance at approximately 14.21, 7.11, 5.80, 4.74, and 3.65 A. The crystalline N-Methylformamide solvate of dasatinib may be further characterized by peaks expressed as interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
The XRPD was determined by using PANalytical X' Pert Pro X-Ray Powder Diffractometer in the range 0 C to 40 C 20 and under tube voltage and current of 45 Kv and 40 mA, respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.
The TGA was recorded on TA (Q500) (Rate of heating = 10 C/minute).
The DSC was recorded on Mettler Toledo (DSC 821) (Rate of heating =
C/minute).
10 Detailed Description of the Invention The present invention provides for the N-Methylformamide solvate of dasatinib of Formula B
CH3 0 11NcH3 H NH õcH3 NHS I NHN
CI OH
Formula B
The present invention may be in the form of crystalline N-Methylformamide solvate of dasatinib.
The crystalline N-Methylformamide solvate of dasatinib has an X-Ray Powder Diffractogram (XRPD) substantially as depicted in Figure 1 of the accompanied drawings. The crystalline N-Methylformamide solvate of dasatinib has an X-ray Powder Diffractogram which shows characteristic peaks expressed as interplanar distance at approximately 14.21, 7.11, 5.80, 4.74, and 3.65 A. The crystalline N-Methylformamide solvate of dasatinib may be further characterized by peaks expressed as interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
The crystalline N-Methylformamide solvate of dasatinib has a DSC
thermogram substantially as depicted in Figure 2 of the accompanied drawings.
The DSC thermogram shows characteristic endothermic peaks at about 160 C and about 287 C.
The crystalline N-Methylformamide solvate of dasatinib has a TGA
substantially as depicted in Figure 3 of the accompanied drawings. The TGA of the crystalline N-Methylformamide solvate of dasatinib shows a weight loss of about 10.6%.
The present invention also provides for a process for the preparation of N-Methylformamide solvate of dasatinib. The process includes:
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
Dasatinib in any previously known crystalline or amorphous form prepared by methods known in the art can be used as the starting material.
Step a) of the process involves adding dasatinib to N-Methylformamide or adding N-Methylformamide to dasatinib in optional order of succession at a suitable temperature of between 20 C to 50 C; preferably under stirring. For example, the addition may be performed at a temperature of between 20 C to 35 C.
N-Methylformamide may be used in an amount of 3 to 10 times the amount of dasatinib.
After the completion of addition, the resultant mixture is heated to a temperature of between about 50 C to 80 C for about 15 minutes to 3 hours. For example, it may be heated at about 60 C to 70 C.
Step b) of the process involves isolating N-Methylformamide solvate of dasatinib through common isolation techniques, such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof For example, step b) involves filtration of the reaction mass obtained in step a) to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The filtrate is maintained at about 10 C to 40 C
for a time period of 2 hours to 24 hours to allow the N-Methylformamide solvate of dasatinib to crystallize.
The isolated crystalline N-Methylformamide solvate of dasatinib may be dried at 40 C to 60 C under vacuum for about 12 hours to 28 hours.
The N-Methylformamide solvate of dasatinib may also be used for the preparation of other polymorphic forms or solvates of dasatinib.
The present invention also provides for a pharmaceutical composition that includes a therapeutically effective amount of N-Methylformamide solvate of dasatinib and one or more pharmaceutically acceptable excipient.
The present invention also provides for a method for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The method includes administering to a mammal in need thereof a therapeutically effective amount of N-Methylformamide solvate of dasatinib.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of N-Methylformamide Solvate of Dasatinib Dasatinib (3.24 g) was charged in a round bottom flask. N-methyl formamide (20 ml) was added to it. The reaction mixture was heated at 70 C for 30 minutes and filtered.
The filtrate was collected in a beaker and kept at a temperature of 20 C to 35 C overnight for crystallization. The solid was filtered and suck dried for 30 minutes.
Solid was unloaded and dried under a vacuum at 55 C to 60 C for 24 hours to obtain the title compound.
Yield: 1.95 g
thermogram substantially as depicted in Figure 2 of the accompanied drawings.
The DSC thermogram shows characteristic endothermic peaks at about 160 C and about 287 C.
The crystalline N-Methylformamide solvate of dasatinib has a TGA
substantially as depicted in Figure 3 of the accompanied drawings. The TGA of the crystalline N-Methylformamide solvate of dasatinib shows a weight loss of about 10.6%.
The present invention also provides for a process for the preparation of N-Methylformamide solvate of dasatinib. The process includes:
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
Dasatinib in any previously known crystalline or amorphous form prepared by methods known in the art can be used as the starting material.
Step a) of the process involves adding dasatinib to N-Methylformamide or adding N-Methylformamide to dasatinib in optional order of succession at a suitable temperature of between 20 C to 50 C; preferably under stirring. For example, the addition may be performed at a temperature of between 20 C to 35 C.
N-Methylformamide may be used in an amount of 3 to 10 times the amount of dasatinib.
After the completion of addition, the resultant mixture is heated to a temperature of between about 50 C to 80 C for about 15 minutes to 3 hours. For example, it may be heated at about 60 C to 70 C.
Step b) of the process involves isolating N-Methylformamide solvate of dasatinib through common isolation techniques, such as one or more of washing, crystallization, precipitation, cooling, filtration, filtration under vacuum, decantation and centrifugation, or a combination thereof For example, step b) involves filtration of the reaction mass obtained in step a) to remove foreign particulate matter or treated with activated charcoal to remove coloring and other related impurities. The filtrate is maintained at about 10 C to 40 C
for a time period of 2 hours to 24 hours to allow the N-Methylformamide solvate of dasatinib to crystallize.
The isolated crystalline N-Methylformamide solvate of dasatinib may be dried at 40 C to 60 C under vacuum for about 12 hours to 28 hours.
The N-Methylformamide solvate of dasatinib may also be used for the preparation of other polymorphic forms or solvates of dasatinib.
The present invention also provides for a pharmaceutical composition that includes a therapeutically effective amount of N-Methylformamide solvate of dasatinib and one or more pharmaceutically acceptable excipient.
The present invention also provides for a method for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib and for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. The method includes administering to a mammal in need thereof a therapeutically effective amount of N-Methylformamide solvate of dasatinib.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of N-Methylformamide Solvate of Dasatinib Dasatinib (3.24 g) was charged in a round bottom flask. N-methyl formamide (20 ml) was added to it. The reaction mixture was heated at 70 C for 30 minutes and filtered.
The filtrate was collected in a beaker and kept at a temperature of 20 C to 35 C overnight for crystallization. The solid was filtered and suck dried for 30 minutes.
Solid was unloaded and dried under a vacuum at 55 C to 60 C for 24 hours to obtain the title compound.
Yield: 1.95 g
Claims (11)
1. N-Methylformamide solvate of dasatinib of Formula B.
2. Crystalline N-Methylformamide solvate of dasatinib characterized by an X-ray Powder Diffractogxam comprising interplanar distance at approximately 14.21, 7.11, 5.80, 4.74, and
3.65 A.
3. The crystalline N-Methylformamide solvate of dasatinib according to claim 2, further characterized by an X-ray Powder Diffractogram comprising interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
3. The crystalline N-Methylformamide solvate of dasatinib according to claim 2, further characterized by an X-ray Powder Diffractogram comprising interplanar distance at approximately 7.45, 4.83, 4.29, 3.82, 3.73 and 3.49 A.
4. The crystalline N-Methylformamide solvate of dasatinib according to claim 2, further characterized by a DSC thermogram substantially as depicted in Figure 2.
5. The crystalline N-Methylformamide solvate of dasatinib according to claim 2, further comprising a DSC having characteristic endothermic peaks at about 160°C
and about 287°C.
and about 287°C.
6. The crystalline N-Methylformamide solvate of dasatinib according to claim 2, further characterized by a TGA substantially as depicted in Figure 3.
7. A process for the preparation of N-Methylfonnamide solvate of dasatinib, the process comprising:
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
a) treating dasatinib with N-Methylformamide; and b) isolating N-Methylformamide solvate of dasatinib.
8. A process according to claim 8, wherein step a) is carried out at a temperature of 20°C to 50°C.
9. A process according to claim 8, wherein the amount of N-Methylformamide is 3 to 10 times the amount of dasatinib.
10. Use of N-Methylformamide solvate of dasatinib prepared according to process of claim 8, for the preparation of other polymorphic forms or solvates of dasatinib.
11. Crystalline N-Methylformamide solvate of dasatinib according to claim 2, characterized by an X-Ray Powder Diffractogram (XRPD) substantially as depicted in Figure 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1807/DEL/2010 | 2010-07-30 | ||
| IN1807DE2010 | 2010-07-30 | ||
| PCT/IB2011/053318 WO2012014149A1 (en) | 2010-07-30 | 2011-07-25 | N-methylformamide solvate of dasatinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2806820A1 true CA2806820A1 (en) | 2012-02-02 |
Family
ID=44545784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2806820A Abandoned CA2806820A1 (en) | 2010-07-30 | 2011-07-25 | N-methylformamide solvate of dasatinib |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2598147A1 (en) |
| AU (1) | AU2011284341A1 (en) |
| CA (1) | CA2806820A1 (en) |
| WO (1) | WO2012014149A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112014031292A2 (en) | 2012-06-15 | 2017-06-27 | Basf Se | multi-component crystalline system, process for obtaining crystalline composition, and pharmaceutical composition |
| WO2017108605A1 (en) | 2015-12-22 | 2017-06-29 | Synthon B.V. | Pharmaceutical composition comprising amorphous dasatinib |
| 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 |
| WO2018078392A1 (en) | 2016-10-29 | 2018-05-03 | Cipla Limited | Polymorphs of dasatinib |
| WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
| US10799459B1 (en) | 2019-05-17 | 2020-10-13 | Xspray Microparticles Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ID30460A (en) | 1999-04-15 | 2001-12-06 | Bristol Myers Squibb Co | INHIBITORS, INHIBITORS, THYROCIN CINASE PROTEIN |
| US7491725B2 (en) | 2004-02-06 | 2009-02-17 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| PL2508523T5 (en) | 2007-10-23 | 2020-08-10 | 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 |
| WO2010067374A2 (en) | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
-
2011
- 2011-07-25 AU AU2011284341A patent/AU2011284341A1/en not_active Abandoned
- 2011-07-25 CA CA2806820A patent/CA2806820A1/en not_active Abandoned
- 2011-07-25 EP EP11751946.2A patent/EP2598147A1/en not_active Withdrawn
- 2011-07-25 WO PCT/IB2011/053318 patent/WO2012014149A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| EP2598147A1 (en) | 2013-06-05 |
| AU2011284341A1 (en) | 2013-02-21 |
| WO2012014149A1 (en) | 2012-02-02 |
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