WO2013065063A1 - Anhydrous form of dasatinib, process for its preparation and its use - Google Patents
Anhydrous form of dasatinib, process for its preparation and its use Download PDFInfo
- Publication number
- WO2013065063A1 WO2013065063A1 PCT/IN2012/000048 IN2012000048W WO2013065063A1 WO 2013065063 A1 WO2013065063 A1 WO 2013065063A1 IN 2012000048 W IN2012000048 W IN 2012000048W WO 2013065063 A1 WO2013065063 A1 WO 2013065063A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dasatinib
- anhydrous form
- reaction mixture
- molar ratio
- preparation
- Prior art date
Links
- 0 *c(cccc1Cl)c1NC(c1cnc(N)[s]1)=O Chemical compound *c(cccc1Cl)c1NC(c1cnc(N)[s]1)=O 0.000 description 1
- FIMUTBLUWQGTIJ-UHFFFAOYSA-N Cc1nc(Cl)cc(Cl)n1 Chemical compound Cc1nc(Cl)cc(Cl)n1 FIMUTBLUWQGTIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 anhydrous form and its preparation for use in the manufacture of pure Dasatinib, in particularly Dasatinib monohydrate.
- BMS-354825 is a drug produced by Bristol Myers Squibb and sold under the trade name Sprycel.
- Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after Imatinib treatment has failed and Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph + ALL). It is also being assessed for use in metastatic melanoma.
- 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, 1R etc. 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.
- XRD X-ray diffraction
- DSC Differential Scanning Calorimetry
- IR Infrared spectrometry
- new polymorphic forms are a continuing goal of formulators.
- the new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physiochemical properties. Some form may turn out to be more efficacious.
- Discovering novel processes to prepare known polymorphic forms is also a primary goal of the pharmaceutical development scientists. New processes can provide novel intermediates or synthetic pathways that result in product with increased chemical and polymorphic purity in addition to providing cost and other advantages. There is thus a need to provide novel synthetic routes and intermediates that can realize these goals.
- Dasatinib Several crystalline forms of Dasatinib are described in the literature; these are designated as HI -7, BU-2, E2-1 , N-6, T1 H1 -7 and TIE2-1. Crystalline Dasatinib monohydrate (H I -7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO 2005077945. In addition US 2006/0004067, which is continuation of US 2005215795 also describe two ethanol solvates (E2-1 ; TIE2-1) and two anhydrous forms (N-6 and T1 H1 -7).
- WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.
- US patent No. 7973045 discloses the anhydrous form of Dasatinib and process for preparation thereof.
- the anhydrous form disclosed therein have typical characteristic XRD peaks at about 7.2, 1 1.9, 14.4, 16.5, 17.3, 19.1 , 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value.
- WO 2010062715 discloses isosorbide dimethyl ether solvate, ⁇ , ⁇ '- dimethylethylene urea solvate and N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib.
- WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.
- WO 2010139979 discloses MDC solvate and process of preparation, for use in the manufacture of pure Dasatinib.
- WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.
- the present invention is a step forward in this direction and provides a novel anhydrous form and process for its preparation, which can be used for the preparation of pure Dasatinib, in particularly Dasatinib monohydrate.
- Dasatinib monohydrate using the novel anhydrous form of the present invention resulted in a highly pure product with a good yield.
- Scheme 1 shows a general process for the preparation of Dasatinib as disclosed in US 2006/0004067.
- Intermediate 3 and N-(2-hydroxyethyl) piperazine are heated together in a solvent system comprising n-butanol as a solvent and diisopropyl ethylamine (DIPEA) as a base.
- DIPEA diisopropyl ethylamine
- a novel anhydrous form of Dasatinib which is characterized by a differential scanning calorimetry (DSC) having one sharp endotherm peak in the range between 276-281 °C.
- DSC differential scanning calorimetry
- the novel anhydrous form of Dasatinib of the present invention is further characterized by a differential scanning calorimetry (DSC) as provided in figure 1 (Fig. l ).
- DSC differential scanning calorimetry
- the novel anhydrous form of Dasatinib is further characterized by its melting point in the range of 274 ⁇ 3°C.
- novel anhydrous form of Dasatinib of the present invention is further characterized by PXRD peaks at 2 ⁇ of 15.5, 17.1, 20.1 , 25.1 and 26.2 ⁇ 0.2 degrees.
- novel anhydrous form of Dasatinib of the present invention is further characterized by a PXRD pattern as provided in Figure 2 (Fig. 2).
- the novel anhydrous form of Dasatinib of the present invention is still further characterized by TGA as provided in Figure 3 (Fig. 3).
- novel anhydrous form of Dasatinib of the present invention is still further characterized by FT-IR as provided in Figure 4 (Fig. 4).
- the process includes:
- the process includes: i) adding N-(2-hydroxyethyl)piperazine in N-(2-chloro-6-methylphenyl)-2-[(6- chloro-2-methyI-4-pyrimidinyl) amino] -5-thiazolecarboxamide of formula III in a suitable molar
- reaction mixture ii) heating the reaction mixture at a temp, to about 60-130 °C, preferably to about
- the process includes:
- reaction mixture ii) heating the reaction mixture at a suitable temperature of about 40-80 °C, preferably 60-80 °C, more preferably at 70-80 °C;
- reaction mixture iv) cooling the reaction mixture at about 0-35 °C, preferably 10-30 °C, more preferably 15-25 °C;
- Figure 1 illustrates the DSC of the novel anhydrous form of Dasatinib according to the present invention.
- Figure 2 illustrates the powder X-ray diffraction pattern of novel anhydrous form of Dasatinib according to the present invention.
- Figure 3 illustrates the TGA of the novel anhydrous form of Dasatinib according to the present invention.
- Figure 4 illustrates the IR of the novel anhydrous form of Dasatinib according to the present invention.
- Figure 5 illustrates the powder X-ray diffraction pattern of Dasatinib monohydrate.
- PXRD powder X-ray diffraction
- DSC Differential scanning calorimetry
- TGA Differential scanning calorimetry
- IR Infrared spectrometry
- anhydrous does not exclude the possibility of the presence of some water on or in the salt (e.g. a crystal of the salt). For example, there may be some water present on the surface of the salt (e.g. salt crystal), or minor amounts within the body of the salt (e.g. salt crystal)
- THF tetrahydrofuran
- DCM dichloromethane
- DMF dimethyl formamide
- DMSO dimethyl Sulfoxide
- DMA dimethyl Sulfoxide
- MEK Methyl ethyl ketone
- MIBK Methyl isobutyl ketone
- the present invention provides a novel anhydrous form of Dasatinib.
- the present invention also provides a process for the preparation of the novel anhydrous form.
- the novel anhydrous form of Dasatinib as per the present invention is characterized by
- the present invention also provides a process for the preparation of Dasatinib monohydrate using the novel anhydrous form of Dasatinib.
- Dasatinib monohydrate as per the present invention is characterized by
- the process includes:
- the suitable solvent used in step (i) may be selected from N,N- dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl-2- pyrrolidinone or suitable mixture thereof.
- the molar ratio of N-(2-hydroxyethyl) piperazine used in step (ii) is at least 5 to 15, preferably the molar ratio is about 8 to 10, more preferably the molar ratio is about 5 to 7.
- the molar ratio of diisopropylethylamine used in step (ii) is at least 2 to 5, preferably the molar ratio is about 3 to 4, more preferably the molar ratio is about 2 to 2.5.
- the process includes:
- N-(2-hydroxyethyl) piperazine in N-(2-chloro-6-methylphenyl)-2-[(6- chIoro-2-methyl-4-pyrimidinyI) amino] -5-thiazolecarboxamide of formula III in a suitable molar ratio is at least 10 to 30, preferably the molar ratio is about 20 to 30, more preferably the molar ratio is about 12 to 15;
- reaction mixture ii) heating the reaction mixture at a temp, to about 60-130 °C, preferably to about
- the suitable solvent or anti-solvent used in step (iii) is selected from acetonitrile, acetone, ME , MIB , water or suitable mixture thereof.
- the process includes: i) mixing anhydrous Dasatinib of the present invention in ethanol and water in a ratio of 50:50, preferably 60:40, more preferably 80:20;
- reaction mixture iv) cooling the reaction mixture to about 0-35 °C, preferably 10-30 °C, more preferably 15-25 °C;
- the novel anhydrous form prepared according to the present invention has a purity of at least 98 %, preferably at least 99 %, more preferably 99.90 %.
- the novel anhydrous form of the present invention is used as an intermediate to obtain highly pure Dasatinib monohydrate, having a purity of at least 99.8 %.
- DSC Differential Scanning Calorimetry
- IR Spectroscopy The IR spectra was performed on 8400S of make Shimadzu by using KBr pellet and recorded from 4000 to 400 cm "1 . About 2 mg of sample was triturated with 300 mg of finely powdered and dried potassium bromide. The mixture was carefully grinded, spread uniformly in a suitable die and submitted it in vacuum to a pressure of about 800 MPa (80 kg/cm 2 ). From the FTIR spectrum a blank FT-IR spectrum of KBr was subtracted. The blank IR spectrum was recorded prior to the measurement of the samples.
- HPLC High Performance Liquid Chromatography Separation Module with PDA detector, Make Waters, Model No 2695.
- the invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention.
- TGA The percent weight has been determined by means of Thermo gravimetric Analysis (TGA) Pyris-1 make Perkin Elmer with Pyris-1 software. At least 4 mg samples were analyzed at a heating rate of 10 °C/min in the temperature range between 50 °C to 300 °C.
- N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring.
- the reaction mixture was heated at 80 °C for 2H.
- Acetonitrile was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min.
- N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring.
- the reaction mixture was heated at 80 °C for 2H.
- Acetone was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min.
- N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazole carboxamide (1 gm, 2.54 mmol) and Dimethyl formamide (6.7 ml) was added under stirring.
- N-(2-hydroxyethyl) piperazine (1.65 gm, 12.67 mmol) and Diisopropyl ethylamine (0.88 ml, 5.06 mmol) were added into the reaction mixture.
- the reaction mixture was heated at 1 10 °C and stirred for I H.
- the above clear reaction mixture was added into hot water dropwise in 45 min under vigorous stirring.
- the suspension was heated at 80 °C.
- N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mole) and Dimethyl sulphoxide (6.7 ml) were added under stirring.
- N-(2-hydroxyethyl) piperazine (1.65 gm, 12.67 mmol) and Diisopropyl ethylamine (0.88 ml, 5.06 mmol) into the reaction mixture.
- the reaction mixture was heated at 1 10 °C and stirred for I H.
- the above clear reaction mixture was added into hot water dropwise in 45 min under vigorous stirring.
- the suspension was heated at 80 °C.
- N, N-(2-chloro-6-methylphenyl)-2-[[6- ⁇ 4-(2- hydroxyethyl)-l -piperazinyl ⁇ -2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide 0.5 gm, 1.02 mmol
- 6.4 ml ethanol and 1.6 ml purified water were added under stirring.
- the reaction mixture was heated at 75 °C to make it clear solution.
- the reaction mixture was cooled to room temperature and stirred for 1 H.
Abstract
The present invention provides a novel anhydrous form of Dasatinib and process for the preparation thereof. The present invention also provides a process for the preparation of Dasatinib monohydrate using novel anhydrous form.
Description
ANHYDROUS FORM OF DASATINIB, PROCESS FOR
ITS PREPARATION AND ITS USE
FIELD OF THE INVENTION
The present invention relates to novel anhydrous form and its preparation for use in the manufacture of pure Dasatinib, in particularly Dasatinib monohydrate.
BACKGROUND OF THE INVENTION: Dasatinib, N-(2-chloro-6-methylphenyl)-2- [(6-[4-
(2-hydroxyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5- thiazolecarboxamide compound having the following chemical structure of Formula (I)
Formula I
Also known as BMS-354825, it is a drug produced by Bristol Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and SRC family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after Imatinib treatment has failed and Philadelphia chromosome- positive acute lymphoblastic leukemia (Ph + ALL). It is also being assessed for use in metastatic melanoma.
A preparation of Dasatinib is described in US patent No. 6596746 (B l ), where the process is done by reacting compound of the following formula III with N-(2- hydroxyethyl) piperazine at 80° C.
Formula III
The compound of Formula (I) and its preparation is described in US Patent No. 6596746, US patent application No. 2005/0176965 Al , and US patent application No. 2006/0004067 Al .
l
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, 1R etc. 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.
The discovery of new polymorphic forms is a continuing goal of formulators. The new polymorphs may be advantageous for dosage form development and enhancing bioavailability owing to the altered physiochemical properties. Some form may turn out to be more efficacious. Discovering novel processes to prepare known polymorphic forms is also a primary goal of the pharmaceutical development scientists. New processes can provide novel intermediates or synthetic pathways that result in product with increased chemical and polymorphic purity in addition to providing cost and other advantages. There is thus a need to provide novel synthetic routes and intermediates that can realize these goals.
Several crystalline forms of Dasatinib are described in the literature; these are designated as HI -7, BU-2, E2-1 , N-6, T1 H1 -7 and TIE2-1. Crystalline Dasatinib monohydrate (H I -7) and butanol solvate (BU-2) along with the processes for their preparation are described in WO 2005077945. In addition US 2006/0004067, which is continuation of US 2005215795 also describe two ethanol solvates (E2-1 ; TIE2-1) and two anhydrous forms (N-6 and T1 H1 -7).
WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.
US patent No. 7973045 discloses the anhydrous form of Dasatinib and process for preparation thereof. The anhydrous form disclosed therein have typical characteristic XRD peaks at about 7.2, 1 1.9, 14.4, 16.5, 17.3, 19.1 , 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value.
WO 2010062715 discloses isosorbide dimethyl ether solvate, Ν,Ν'- dimethylethylene urea solvate and N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib.
WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.
WO 2010139979 discloses MDC solvate and process of preparation, for use in the manufacture of pure Dasatinib.
WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.
The present invention is a step forward in this direction and provides a novel anhydrous form and process for its preparation, which can be used for the preparation of pure Dasatinib, in particularly Dasatinib monohydrate.
The process for preparing Dasatinib monohydrate is described in US 2006/0004067. Further studies by the inventors have shown that the preparation of Dasatinib by using the method, which is disclosed in US 2006/0004067 yields the monohydrate with ~ 90% purity. Therefore the present invention provides a novel anhydrous form which can be used to get Dasatinib monohydrate with high yield and purity.
Preparing API with increased purity is always an aim of the pharmaceutical development team. The inventors of the present invention have found that preparing
Dasatinib monohydrate using the novel anhydrous form of the present invention resulted in a highly pure product with a good yield.
Scheme 1 shows a general process for the preparation of Dasatinib as disclosed in US 2006/0004067. Intermediate 3 and N-(2-hydroxyethyl) piperazine are heated together in a solvent system comprising n-butanol as a solvent and diisopropyl ethylamine (DIPEA) as a base. On cooling of the reaction mixture, Dasatinib precipitates out which is isolated by filtration.
Dasatinib
Scheme 1
SUMMARY OF THE INVENTION
In one general aspect there is provided a novel anhydrous form of Dasatinib, which is characterized by a differential scanning calorimetry (DSC) having one sharp endotherm peak in the range between 276-281 °C.
In another embodiment, the novel anhydrous form of Dasatinib of the present invention is further characterized by a differential scanning calorimetry (DSC) as provided in figure 1 (Fig. l ).
In yet another embodiment, the novel anhydrous form of Dasatinib is further characterized by its melting point in the range of 274 ± 3°C.
In yet another embodiment, the novel anhydrous form of Dasatinib of the present invention is further characterized by PXRD peaks at 2Θ of 15.5, 17.1, 20.1 , 25.1 and 26.2± 0.2 degrees.
In a still further embodiment, the novel anhydrous form of Dasatinib of the present invention is further characterized by a PXRD pattern as provided in Figure 2 (Fig. 2).
In a further embodiment, the novel anhydrous form of Dasatinib of the present invention is still further characterized by TGA as provided in Figure 3 (Fig. 3).
In a further embodiment, the novel anhydrous form of Dasatinib of the present invention is still further characterized by FT-IR as provided in Figure 4 (Fig. 4).
In another general aspect there is provided a process for the preparation of the novel anhydrous form that can be used in the preparation of Dasatinib monohydrate of compound of Formula (1) in a highly pure form.
The process includes:
i) dissolving N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide of formula III in a suitable solvent;
Formula III
ii) adding N-(2-hydroxyethyl)piperazine and diisopropyl ethylamine into above reaction mixture in a suitable molar ratio;
iii) heating the reaction mixture at a temp of about 80-130 °C, preferably to about
100-120 °C and more preferably to about 80-90 °C;
iv) adding water as anti-solvent to the reaction mixture;
v) cooling the mixture to ambient temperature;
vi) isolating the resulting precipitated solid anhydrous Dasatinib;
vii) drying the resulting precipitated solid at 45-90 °C, preferably 60-80 °C, more preferably 50-60 °C
In another general aspect there is provided an alternate process for the preparation of novel anhydrous form that can be used in the preparation of Dasatinib monohydrate of compound of Formula (I) in a highly pure form.
The process includes:
i) adding N-(2-hydroxyethyl)piperazine in N-(2-chloro-6-methylphenyl)-2-[(6- chloro-2-methyI-4-pyrimidinyl) amino] -5-thiazolecarboxamide of formula III in a suitable molar
Formula III
ii) heating the reaction mixture at a temp, to about 60-130 °C, preferably to about
100-120 °C, more preferably to about 70-80 °C;
iii) adding a suitable solvent or anti-solvent to the reaction mixture;
iv) isolating the resulting precipitated solid anhydrous Dasatinib;
v) drying the resulting precipitated solid at 45-90 °C, preferably 60-80 °C and more preferably 50-60 °C.
In other aspect there is provided a process for the preparation of Dasatinib monohydrate in a highly pure form using the novel anhydrous form of the present invention.
The process includes:
i) mixing anhydrous Dasatinib of the present invention in a mixture of ethanol and water in a suitable ratio;
ii) heating the reaction mixture at a suitable temperature of about 40-80 °C, preferably 60-80 °C, more preferably at 70-80 °C;
iii) adding water or suitable alcohol or a mixture of both as anti-solvent;
iv) cooling the reaction mixture at about 0-35 °C, preferably 10-30 °C, more preferably 15-25 °C;
v) stirring the reaction mixture for 30 min to 4H, preferably 30 min. to 2H, more preferably 30 min. to 1 H;
vi) isolating the resulting precipitated solid Dasatinib monohydrate;
vii) drying the resulting precipitated solid at 40-70 °C, preferably 50-60 °C, more preferably 40-50 °C.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 (Fig. 1 ) illustrates the DSC of the novel anhydrous form of Dasatinib according to the present invention.
Figure 2 (Fig. 2) illustrates the powder X-ray diffraction pattern of novel anhydrous form of Dasatinib according to the present invention.
Figure 3 (Fig. 3) illustrates the TGA of the novel anhydrous form of Dasatinib according to the present invention.
Figure 4 (Fig.4) illustrates the IR of the novel anhydrous form of Dasatinib according to the present invention.
Figure 5 (Fig. 5) illustrates the powder X-ray diffraction pattern of Dasatinib monohydrate.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "PXRD" refers to powder X-ray diffraction, the term "DSC" refers to Differential scanning calorimetry, the term "TGA" refers to Thermo gravimetric analysis, the term "IR" refers to Infrared spectrometry.
As used herein, the term "anhydrous" does not exclude the possibility of the presence of some water on or in the salt (e.g. a crystal of the salt). For example, there may be some water present on the surface of the salt (e.g. salt crystal), or minor amounts within the body of the salt (e.g. salt crystal)
As used herein, the term "THF" refers to tetrahydrofuran, the term "DCM" refers to dichloromethane, the term "DMF" refers to dimethyl formamide, the term "DMSO" refers to dimethyl Sulfoxide, the term "DMA" refers to N, N-Dimethyl acetamide, The term "MEK" refers to Methyl ethyl ketone, the term "MIBK" refers to Methyl isobutyl ketone.
The present invention provides a novel anhydrous form of Dasatinib. The present invention also provides a process for the preparation of the novel anhydrous form. The novel anhydrous form of Dasatinib as per the present invention is characterized by
- A DSC having one sharp endotherm peak in the range between 276-281 °C. - A DSC pattern as provided in Fig. 1 of the specification.
- A melting point of 274 ± 3 °C
- A PXRD pattern having characteristic PXRD peaks at 2Θ of 15.5, 17.1 , 20.1 , 25.1 and 26.2 ± 0.2 degrees.
- A PXRD pattern substantially as depicted in Fig. 2 of the specification;
- A TGA pattern as provided in Fig. 3 of the specification;
- An IR pattern as provided in Fig. 4 of the specification.
The present invention also provides a process for the preparation of Dasatinib monohydrate using the novel anhydrous form of Dasatinib. Dasatinib monohydrate as per the present invention is characterized by
- A PXRD pattern substantially as depicted in Fig. 5 of the specification.
In another general aspect there is provided a process for the preparation of novel anhydrous form that can be used in the preparation of Dasatinib monohydrate of Formula (I) in a highly pure form.
The process includes:
i) dissolving N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide of formula III in a suitable solvent;
Formula III
ii) adding N-(2-hydroxyethyl) piperazine and diisopropylethylamine into above reaction mixture in a suitable molar ratio;
iii) heating the reaction mixture at about 80-130 °C, preferably to about 100- 120 °C and more preferably to about 80-90 °C;
iv) adding water as an anti-solvent to the reaction mixture;
v) cooling the mixture at ambient temp;
vi) isolating the resulting precipitated solid anhydrous Dasatinib;
vii) drying the resulting precipitated solid at 45-90 °C, preferably 60-80 °C, more preferably 50-60 °C
Preferably, the suitable solvent used in step (i) may be selected from N,N- dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, N-methyl-2- pyrrolidinone or suitable mixture thereof.
The molar ratio of N-(2-hydroxyethyl) piperazine used in step (ii) is at least 5 to 15, preferably the molar ratio is about 8 to 10, more preferably the molar ratio is about 5 to 7.
The molar ratio of diisopropylethylamine used in step (ii) is at least 2 to 5, preferably the molar ratio is about 3 to 4, more preferably the molar ratio is about 2 to 2.5.
In another general aspect there is provided an alternate process for the preparation of anhydrous form that can be used in the preparation of Dasatinib monohydrate of compound of Formula (I) in a highly pure form.
The process includes:
i) adding N-(2-hydroxyethyl) piperazine in N-(2-chloro-6-methylphenyl)-2-[(6- chIoro-2-methyl-4-pyrimidinyI) amino] -5-thiazolecarboxamide of formula III in a suitable molar ratio is at least 10 to 30, preferably the molar ratio is about 20 to 30, more preferably the molar ratio is about 12 to 15;
Formula III
ii) heating the reaction mixture at a temp, to about 60-130 °C, preferably to about
100-120 °C, more preferably to about 70-80 °C;
iii) adding a suitable solvent or anti-solvent to the reaction mixture;
iv) isolating the resulting precipitated solid anhydrous Dasatinib;
v) drying the resulting precipitated solid anhydrous Dasatinib at about 45-90 °C, preferably 60-80 °C, more preferably 50-60 °C.
Preferably the suitable solvent or anti-solvent used in step (iii) is selected from acetonitrile, acetone, ME , MIB , water or suitable mixture thereof.
In other aspect there is provided a process for the preparation of Dasatinib monohydrate in a highly pure form using the novel anhydrous form of the present invention.
The process includes:
i) mixing anhydrous Dasatinib of the present invention in ethanol and water in a ratio of 50:50, preferably 60:40, more preferably 80:20;
ii) heating the reaction mixture at a temperature of about 70-80 °C;
iii) adding water or ethanol or mixture of both as anti solvent;
iv) cooling the reaction mixture to about 0-35 °C, preferably 10-30 °C, more preferably 15-25 °C;
v) stirring the reaction mixture for 30 min to 4H, preferably 2 to 3H, more preferably 30 min. to 1 H;
vi) isolating the resulting precipitated solid Dasatinib monohydrate;
vii) drying the resulting precipitated solid at 40-70 °C, preferably 50-60 °C, more preferably 40-50 °C.
In one of the embodiments the novel anhydrous form prepared according to the present invention has a purity of at least 98 %, preferably at least 99 %, more preferably 99.90 %.
The novel anhydrous form of the present invention is used as an intermediate to obtain highly pure Dasatinib monohydrate, having a purity of at least 99.8 %.
The present application provides process for the preparation of anhydrous Dasatinib having the following advantages:
1. High yield
2. High Purity
3. Commercially viable process.
Instrument Analysis:
Differential Scanning Calorimetry (DSC): Melting points are determined by means of a DSC thermogram using a Pyris-1 make Perkin Elmer. DSC (Differential Scanning Calorimetry) is the technique of dynamic differential Calorimetry. Using this technique, the melting temperature can be measured by heating the sample until a thermal, i.e. an endothermic or exothermic, reaction is detected by means of ultrasensitive sensors. The DSC cell/sample chamber was purged with lOOml/min of ultra-high purity nitrogen. The instrument was calibrated with high purity Indium. The sample was placed into an open aluminum DSC pan and measured against an empty reference pan. About 2 mg of sample being placed into the bottom of the pan and lightly tapped down to ensure good contact with the pan. The instrument was programmed to heat at a heating rate of 10°C/min in the temperature range between 50°C and 300°C.
Powder X-ray Diffraction: X-ray powder diffraction spectrum was observed on a MF 2100 2KW X-ray Powder diffractometer of make Rigaku having a Copper a-radiation at a voltage of 40kV and 30mA. Approximately 150 mg sample was gently flattened on a quartz plate without further processing (e.g. Grinding and sieving) and scanned from 4° to 40° at 0.010° sampling width and 4.000° per minute.
IR Spectroscopy: The IR spectra was performed on 8400S of make Shimadzu by using KBr pellet and recorded from 4000 to 400 cm"1. About 2 mg of sample was triturated with 300 mg of finely powdered and dried potassium bromide. The mixture was carefully grinded, spread uniformly in a suitable die and submitted it in vacuum to a pressure of about 800 MPa (80 kg/cm2). From the FTIR spectrum a blank FT-IR spectrum of KBr was subtracted. The blank IR spectrum was recorded prior to the measurement of the samples.
HPLC: High Performance Liquid Chromatography Separation Module with PDA detector, Make Waters, Model No 2695.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention.
The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of a person skilled in the art. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.
TGA: The percent weight has been determined by means of Thermo gravimetric Analysis (TGA) Pyris-1 make Perkin Elmer with Pyris-1 software. At least 4 mg samples were analyzed at a heating rate of 10 °C/min in the temperature range between 50 °C to 300 °C.
KF: Moisture content was analyzed by using Karl Fisher Autotitrator 795 KFT Titrino make Metrohm.
MP: Melting points were determined by using Melting point apparatus Mettler Toledo- FP 81 MBC Cell with FP 90 Central processor. At least 10 mg samples were analyzed at a heating rate of 1 °C/min in the temperature range between 35 °C to 300 °C.
Example - 1
In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring. The reaction mixture was heated at 80 °C for 2H. Acetonitrile was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min. Filtered, washed with acetonitrile and dried at 60 °C under vacuum to get 950 mg anhydrous N-(2-chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxy 1)- 1 -piperaziny l]-2- methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide (76.73 % Yield).
HPLC Purity 99.90 %
M/C by KF 0.12 %
DSC 278.17 °C
TGA 2.05 %
XRD as provided in Fig. 2
Example - 2
In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mmol) and N-(2- hydroxyethyl) piperazine (5.3 gm, 40.70 mmol) was added under stirring. The reaction mixture was heated at 80 °C for 2H. Acetone was added into reaction mixture at 80 °C and stirred for 30 min. Cooled the suspension to room temperature and stirred for 30 min. Filtered, washed with acetone and dried at 60 °C under vacuum to get 980 mg anhydrous N-(2-chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxyl)- 1 -piperazinyl]-2- methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide (79.15 % Yield).
HPLC Purity 99.88 %
M/C by KF 0.14 %
DSC 280.5 °C
TGA 1.81 %
XRD Similar to that of Fig. 2
Example - 3
In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazole carboxamide (1 gm, 2.54 mmol) and Dimethyl
formamide (6.7 ml) was added under stirring. N-(2-hydroxyethyl) piperazine (1.65 gm, 12.67 mmol) and Diisopropyl ethylamine (0.88 ml, 5.06 mmol) were added into the reaction mixture. The reaction mixture was heated at 1 10 °C and stirred for I H. The above clear reaction mixture was added into hot water dropwise in 45 min under vigorous stirring. The suspension was heated at 80 °C. The resulting suspension was stirred for 15 min. Cooled the suspension to room temperature and stirred for 15 min. Filtered, washed with water and dried at 60 °C under vacuum to get 1.09 gm N-(2- chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazole carboxamide (88.28 % Yield).
HPLC Purity 99.07 %
M/C by KF 0.16 %
DSC 279.41 °C
TGA 0.26 %
XRD Similar to that of Fig. 2
Example-4
In a reaction vessel, N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4- pyrimidinyl) amino] -5-thiazolecarboxamide (1 gm, 2.54 mole) and Dimethyl sulphoxide (6.7 ml) were added under stirring. Added N-(2-hydroxyethyl) piperazine (1.65 gm, 12.67 mmol) and Diisopropyl ethylamine (0.88 ml, 5.06 mmol) into the reaction mixture. The reaction mixture was heated at 1 10 °C and stirred for I H. The above clear reaction mixture was added into hot water dropwise in 45 min under vigorous stirring. The suspension was heated at 80 °C. Stirred the suspension for 15 min. Cooled the suspension to room temperature and stirred for 15 min. Filtered, washed with water and dried at 55 °C under vacuum to get 1.12 gm anhydrous N-(2- chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxyl)-l-piperazinyl]-2-methyl-4- pyrimidinyl]amino]-5-thiazole carboxamide (90.23% Yield).
HPLC Purity 99.60 %
M/C by KF 0.84 %
DSC 280.36 °C
TGA 0.93 %
XRD Similar to that of Fig. 2
Example - 5
In a reaction vessel, N, N-(2-chloro-6-methylphenyl)-2-[[6-{4-(2- hydroxyethyl)-l -piperazinyl}-2-methyl-4-pyrimidinyl] amino]-5-thiazole carboxamide (0.5 gm, 1.02 mmol) and 6.4 ml ethanol and 1.6 ml purified water were added under stirring. The reaction mixture was heated at 75 °C to make it clear solution. Added 2.5 ml water dropwise in 10 min at 75 °C in the above clear solution and maintained for 30 min. The reaction mixture was cooled to room temperature and stirred for 1 H. Filtered and washed with mixture of ethanol and water and dried under vacuum (9 mbar) for 1 H to get 445 mg N-(2-chloro-6-methylphenyl)-2-[(6-[4-(2-hydroxyl)-l-piperazinyl]-2- methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate (85.58 % Yield). HPLC Purity : 99.80 %
M/C by KF : 3.90 %, which corresponds to the Dasatinib Monohydrate
TGA 3.60 %
XRD as in fig 3, which matches with the reported XRD of the
Dasatinib monohydrate
Claims
1. An anhydrous form of Dasatinib characterized by Differential Scanning Calorimetry (DSC) having one sharp endotherm peak in the range between 276 - 281 °C.
2. An anhydrous form of Dasatinib as claimed in claim 1 characterized by Differential Scanning Calorimetry (DSC) that corresponds to Fig. 1.
3. A novel anhydrous form as claimed in claim 1 is further characterized by melting point in the range of 274 ± 3°C.
4. Anl anhydrous form of Dasatinib as claimed in claim 1 characterized by an X-ray powder diffractogram having peaks at 2Θ of 15.5, 17.1 , 20.1 , 25.1 and 26.2 ± 0.2 degrees.
5. An anhydrous form of Dasatinib as claimed in claim 1 exhibiting PXRD pattern that corresponds to Fig. 2.
6. An anhydrous form of Dasatinib as claimed in claim 1 characterized by TGA that corresponds to Fig. 3.
7. An anhydrous form of Dasatinib as claimed in claim 1 characterized by IR that corresponds to Fig. 4.
8. A process for the preparation of anhydrous form of Dasatinib, comprising;
i) dissolving N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl) amino] -5-thiazole carboxamide of formula III in a suitable solvent.
Formula III
) adding N-(2-hydroxyethyl) piperazine and diisopropyl ethylamine into above reaction mixture in a suitable molar ratio,
i) heating the reaction mixture at about 80-130 °C, preferably to about 100-120 °C and more preferably to about 80-90 °C;
) adding water as an anti-solvent to the reaction mixture & isolating the resulting anhydrous Dasatinib
9. The process as claimed in claim 7 step (i), wherein the suitable solvent is selected from dimethyl sulfoxide, dimethyl formamide, N-methyl-2-pyrrolidone and N,N- dimethyl acetamide.
10. The process as claimed in claim 7 step (ii), wherein the suitable molar ratio of N-(2- hydroxyethy piperazine is 5 to 15, preferably 8 to 10, more preferably 5 to7 molar ratio.
11. The process as claimed in claim 7 step (ii), wherein the suitable molar ratio of diisopropyl ethylamine is 2 to 5, preferably 3 to 4, more preferably 2 to 2.5 molar ratio.
12. A process for the preparation of novel anhydrous form of Dasatinib, comprising; i) reacting N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl) amino] -5-thiazole carboxamide of formula III and N-(2-hydroxyethyl) piperazine in a
Formula III
ii) heating the reaction mixture to about 60-130 °C, preferably to about 100-120
°C, more preferably to about 70-80 °C;
iii) adding a suitable solvent or anti-solvent to the reaction mixture & isolating the resulting anhydrous Dasatinib.
13. The process as claimed in claim 12 step (i), wherein the suitable molar ratio of N- (2-hydroxyethyl) piperazine is 10 to 30, preferably 20 to 30, more preferably 12 to 15 molar ratio.
14. The process as claimed in claim 8 step (iii), wherein the suitable solvent or anti- solvent are selected from acetonitrile, acetone, ME , MIBK, water and suitable mixture thereof.
15. A process for the preparation of Dasatinib monohydrate using novel anhydrous form as claimed in claim 1 , which comprises,
i) mixing anhydrous Dasatinib of the present invention in ethanol and water in a suitable ratio; ii) heating the reaction mixture at about 40-80 °C, preferably 60-80 °C, more preferably at 70-80 °C;
iii) adding water or ethanol or their suitable mixture;
iv) cooling the reaction mixture at about 0-35 °C, preferably 10-30 °C, more preferably 15-25 °C;
v) isolating the resulting precipitated solid Dasatinib monohydrate
16. The process as claimed in claim 15, wherein the suitable ratio of ethanol and water is 50:50, preferably 60:40, more preferably 80:20.
17. The novel anhydrous form of Dasatinib prepared by the process as claimed in claim 7 and claim 1 1 , having purity more than 99.9% by HPLC.
18. The Dasatinib monohydrate form prepared by the process as claimed in claim 14, having purity more than 99.8 % by HPLC.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3100MU2011 | 2011-11-03 | ||
IN3100/MUM/2011 | 2011-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013065063A1 true WO2013065063A1 (en) | 2013-05-10 |
Family
ID=45888452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2012/000048 WO2013065063A1 (en) | 2011-11-03 | 2012-01-20 | Anhydrous form of dasatinib, process for its preparation and its use |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2013065063A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554099A (en) * | 2013-11-04 | 2014-02-05 | 哈药集团技术中心 | Preparation method of Dasatinib |
WO2015049645A3 (en) * | 2013-10-04 | 2015-08-13 | Alembic Pharmaceuticals Limited | An improved process for the preparation of dasatinib |
CN109503568A (en) * | 2018-12-29 | 2019-03-22 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Dasatinib |
WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
US10799459B1 (en) | 2019-05-17 | 2020-10-13 | Xspray Microparticles Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
WO2021176083A1 (en) | 2020-03-06 | 2021-09-10 | Zentiva K.S. | Pharmaceutical compositions comprising dasatinib anhydrous and uses thereof |
RU2777433C2 (en) * | 2019-07-04 | 2022-08-03 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Method for obtaining anhydrous amorphous form of n-(2-chlorine-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6596746B1 (en) | 1999-04-15 | 2003-07-22 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
US20050176965A1 (en) | 2004-02-06 | 2005-08-11 | Bang-Chi Chen | Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors |
WO2005077945A2 (en) | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
US20050215795A1 (en) | 2004-02-06 | 2005-09-29 | Bang-Chi Chen | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
US20060004067A1 (en) | 2004-02-06 | 2006-01-05 | Bang-Chi Chen | 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 |
WO2010067374A2 (en) | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
WO2010139980A1 (en) | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Process for preparing crystalline dasatinib monohydrate |
WO2010139979A2 (en) | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Processes for preparing crystalline forms |
-
2012
- 2012-01-20 WO PCT/IN2012/000048 patent/WO2013065063A1/en active Application Filing
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6596746B1 (en) | 1999-04-15 | 2003-07-22 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
US20050176965A1 (en) | 2004-02-06 | 2005-08-11 | Bang-Chi Chen | Process for preparing 2-aminothiazole-5-carboxamides useful as kinase inhibitors |
WO2005077945A2 (en) | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
US20050215795A1 (en) | 2004-02-06 | 2005-09-29 | Bang-Chi Chen | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
US20060004067A1 (en) | 2004-02-06 | 2006-01-05 | Bang-Chi Chen | 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 |
US7973045B2 (en) | 2007-10-23 | 2011-07-05 | Teva Pharmaceutical Industries Ltd. | Anhydrous form 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 |
WO2010139980A1 (en) | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Process for preparing crystalline dasatinib monohydrate |
WO2010139979A2 (en) | 2009-06-03 | 2010-12-09 | Generics [Uk] Limited | Processes for preparing crystalline forms |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015049645A3 (en) * | 2013-10-04 | 2015-08-13 | Alembic Pharmaceuticals Limited | An improved process for the preparation of dasatinib |
CN103554099A (en) * | 2013-11-04 | 2014-02-05 | 哈药集团技术中心 | Preparation method of Dasatinib |
WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
US11440908B2 (en) | 2018-04-25 | 2022-09-13 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
CN110862387A (en) * | 2018-08-27 | 2020-03-06 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
CN110862387B (en) * | 2018-08-27 | 2023-05-16 | 鲁南制药集团股份有限公司 | Novel dasatinib crystal form and preparation method thereof |
CN109503568A (en) * | 2018-12-29 | 2019-03-22 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Dasatinib |
US10874613B1 (en) | 2019-05-17 | 2020-12-29 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10869837B1 (en) | 2019-05-17 | 2020-12-22 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10874614B1 (en) | 2019-05-17 | 2020-12-29 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10894018B1 (en) | 2019-05-17 | 2021-01-19 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10894017B1 (en) | 2019-05-17 | 2021-01-19 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US11344500B2 (en) | 2019-05-17 | 2022-05-31 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10869836B1 (en) | 2019-05-17 | 2020-12-22 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US10799459B1 (en) | 2019-05-17 | 2020-10-13 | Xspray Microparticles Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
US11833249B2 (en) | 2019-05-17 | 2023-12-05 | Xspray Pharma Ab | Rapidly disintegrating solid oral dosage forms containing dasatinib |
RU2777433C2 (en) * | 2019-07-04 | 2022-08-03 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Method for obtaining anhydrous amorphous form of n-(2-chlorine-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide |
WO2021176083A1 (en) | 2020-03-06 | 2021-09-10 | Zentiva K.S. | Pharmaceutical compositions comprising dasatinib anhydrous and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2508523B2 (en) | Polymorphs of dasatinib and process for preparation thereof | |
US8217061B2 (en) | Polymorphs of sorafenib tosylate and sorafenib hemi-tosylate, and processes for preparation thereof | |
WO2013065063A1 (en) | Anhydrous form of dasatinib, process for its preparation and its use | |
US11149017B2 (en) | Solid state forms of apalutamide | |
KR20180032680A (en) | Crystalline forms of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine | |
WO2010067374A2 (en) | Polymorphs of dasatinib | |
WO2012093402A1 (en) | Processes for the preparation of n-[2-(7-methoxy-1-naphthyl)ethyl]acetamide | |
JP6873053B2 (en) | Method for Producing Protein Deacetylation Inhibitor | |
US10800763B2 (en) | Polymorphic forms of Afatinib free base and Afatinib dimaleate | |
AU2017304887B2 (en) | Polymorphic forms of belinostat and processes for preparation thereof | |
WO2014086326A1 (en) | A method for the preparation and purification of new and known polymorphs and solvates of dasatinib | |
EP2451786A2 (en) | Improved process for the preparation of ambrisentan and novel intermediates thereof | |
WO2012150606A2 (en) | A process for preparing stable polymophic form of erlotinib hydrochloride | |
AU2011284341A1 (en) | N-Methylformamide solvate of dasatinib | |
US20160264565A1 (en) | Crystalline dasatinib process | |
WO2017098391A1 (en) | Process for the preparation of dasatinib | |
US9695147B2 (en) | Process for the preparation of perampanel | |
EP3042893B1 (en) | Novel crystalline arylalkylamine compound and method for producing same | |
EP3322704B1 (en) | Crystalline form of n-[(3-amino-3-oxetanyl)methyl]-2-(2,3-dihydro-1,1-dioxido-1,4-benzothiazepin-4(5h)-yl)-6-methyl-4-quinazolinamine for the treatment of respiratory syncytial virus (rsv) infections | |
TW201829420A (en) | New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
TWI541235B (en) | Process of preparing a quinazoline derivative | |
EP3687987A1 (en) | Crystalline forms of lenalidomide | |
CN111108104A (en) | Polymorphic forms of dasatinib | |
WO2023140809A1 (en) | Novel polymorph of vismodegib and method of preparation | |
WO2014009969A2 (en) | Novel polymorphs of azilsartan |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12710800 Country of ref document: EP Kind code of ref document: A1 |
|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12710800 Country of ref document: EP Kind code of ref document: A1 |