WO2018113801A1 - Crystalline forms of2-[1-ethylsulfonyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile with phosphoric acid and a method of their preparation - Google Patents
Crystalline forms of2-[1-ethylsulfonyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile with phosphoric acid and a method of their preparation Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to novel crystalline forms of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-emylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate.
- the invention also relates to a method of their preparation as well as to le compositions.
- Baricitinib of formula II is an inhibitor of JAK1/JAK2 tyrosine kinase and is designated for the treatment of rheumatoid arthritis.
- Further possible indications comprise various autoimmune diseases as e.g. psoriasis, diabetic nephropathy, atopic dermatitis, lupus and more (Drugs Fut
- baricitinib is mentioned in the patent application WO2009114512 of the company Incyte.
- Baricitinib phosphate is disclosed as a white crystalline substance, only characterized by the melting point of 187°C in the patent application. It does not mention or characterize particular crystalline forms of baricitinib phosphate. Further, the salt of baricitinib with trifluoroacetic acid as well as preparation of free baricitinib is described in this application.
- the company Egis Pharmaceuticals disclosed two other crystalline forms of free baricitinib, which were published on November 27, 2015 (IPCOM000244270D).
- the first crystalline form is characterized by the XRPD CuKa diffraction peaks: 4.15; 12.47; 13.98; 14.58; 15.40; 16.28; 16.67; 19.06; 25.18; 25.52.
- the second one of the disclosed forms was prepared by heating of the first form to 120°C and is characterized by the XRPD CuKa diffraction peaks: 4.13; 12.42; 13.97; 14.96; 16.25; 16.49; 18.83; 19.21; 25.05; 25.54.
- the patent application CN105693731 of the company Shanghai Biotech deals with preparation of a novel polymorph of free baricitinib.
- Another patent application CNl 05294699 of the company Shanghai Xunhe pharma discloses a preparation method of baricitinib.
- the patent application CN05541891 of Southeast Univ deals with the preparation of intermediates of the synthesis of baricitinib and their application to baricitinib synthesis.
- the last patent application for the time being, WO2016125080 of the company Sun Pharmaceutical Industries Ltd, discloses a preparation process of baricitinib and its intermediates.
- the present invention provides novel crystalline forms of salts of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate that comply with pharmaceutical requirements.
- the invention also relates to a method of their preparation as well as to their use in pharmaceutically acceptable compositions.
- this invention provides novel crystalline forms of baricitinib phosphate referred to as A, B, C, D, E, F and G.
- this invention provides a preparation method of a crystalline salt of baricitinib with phosphoric acid.
- this invention provides crystalline hemiphosphate of baricitinib.
- this invention provides novel crystalline forms of baricitinib hemiphosphate, referred to as I and II. These novel forms are characterized by an X-ray powder pattern, which is shown below in the section Detailed description of the Invention.
- this invention provides crystalline form A of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.2; 12.8; 16.5; 19.5; 22.4 and 25.8 ⁇ 0.2° 2-theta.
- this invention provides crystalline form B of hereitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.3; 12.7; 15.9; 17.8; 20.7 and 26.6 ⁇ 0.2° 2-theta.
- this invention provides crystalline form C of hereitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.7; 8.6; 14.7; 17.3; 18.5; 20.1 and 27.4 ⁇ 0.2° 2-theta.
- this invention provides crystalline form D of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.6; 8.1; 18.2; 20.6; 22.3; 25.2 and 29.3 ⁇ 0.2° 2-theta.
- this invention provides crystalline form E of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.1; 13.5; 17.5; 19.5; 22.9 and 26.2 ⁇ 0.2° 2-theta.
- this invention provides crystalline form F of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ⁇ 0.2° 2-theta.
- this invention provides crystalline form G of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ⁇ 0.2° 2-theta.
- the invention provides a crystalline form of baricitinib hemiphosphate.
- this invention provides crystalline form I of baricitinib hemiphosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.8; 8.1; 16.9; 19.0 and 22.0 ⁇ 0.2° 2-theta.
- this invention provides crystalline form II of baricitinib hemiphosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 16.2; 18.5; 20.4; 22.9 and 26.0 ⁇ 0.2° 2-theta.
- the invention also provides a preparation method of a crystalline form of baricitinib with phosphoric acid of formula I, baricitinib and/or baricitinib phosphate being dissolved and/or suspended in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water.
- a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water.
- the preparation method is further characterized in that baricitinib is dissolved in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, and phosphoric acid is added after that.
- the preparation method may further comprise the steps of: a) dissolution of baricitinib in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, b) addition of 85% aqueous solution of phosphoric acid, c) stirring of the obtained mixture, d) isolation of the crystalline salt of baricitinib phosphate, optionally comprising the step of drying of the product of step c).
- the invention provides a preparation method, baricitinib phosphate being suspended in a mixture of solvents of ethanol and water and/or acetone and water.
- the preparation method further comprises the steps of: a) suspending of baricitinib phosphate in a mixture of solvents of ethanol and water and/or acetone and water, b) stirring of the suspension, preferably at 50°C and preferably for 2 weeks, c) isolation of the crystalline salt of baricitinib hemiphosphate, optionally comprising the step of drying of the product of step b).
- the invention provides use of the above mentioned inventive forms for the preparation of a pharmaceutical composition comprising the salt of baricitinib with phosphoric acid and at least one pharmaceutically acceptable excipient.
- Fig. 1 XRPD pattern of form A of baricitinib phosphate
- Fig. 2 XRPD pattern of form B of baricitinib phosphate
- Fig. 3 XRPD pattern of form C of baricitinib phosphate
- Fig. 4 XRPD pattern of form D of baricitinib phosphate
- Fig. 5 XRPD pattern of form E of baricitinib phosphate
- Fig. 6 XRPD pattern of form F of baricitinib phosphate
- Fig. 7 XRPD pattern of form G of baricitinib phosphate
- Fig. 8 XRPD pattern of form I of baricitinib hemiphosphate
- Fig. 9 XRPD pattern of form II of baricitinib hemiphosphate
- Fig. 10 XRPD pattern of a form of baricitinib phosphate (according to WO2009114512)
- this invention provides novel crystalline forms of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate that comply with pharmaceutical requirements.
- the invention also relates to a method of their preparation as well as to their use in pharmaceutically acceptable compositions.
- Variations in the crystal structure of the salts of baricitinib can influence the dissolution rate (which may influence the biological availability etc.), preparability (e.g. ease of handling, ability to consistently prepare doses of a known strength) and stability (e.g. thermal stability, durability etc.) of the pharmaceutical treatment agent especially if it is formulated in a solid form for oral administration (e.g. in the tablet form).
- Therapeutic use and production of baricitinib comprises the development of novel solid forms of salts of baricitinib that exhibit higher bioavailability and stability.
- Form A of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 1. Its characteristic diffractions with the use of CuKa radiation are 3.2; 12.8; 16.5; 19.5; 22.4 and 25.8 ⁇ 0.2° 2-theta. More diffraction peaks shown in Table 1.
- Form B of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 2. Its characteristic diffractions with the use of CuKa radiation are 3.3; 12.7; 15.9; 17.8; 20.7 and 26.6 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 2.
- Form C of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 3. Its characteristic diffractions with the use of CuKa radiation are 3.7; 8.6; 14.7; 17.3; 18.5; 20.1 and 27.4 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 3.
- Form D of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 4. Its characteristic diffractions with the use of CuKa radiation are 3.6; 8.1; 18.2; 20.6; 22.3; 25.2 and 29.3 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 4.
- Form E of hereitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 5. Its characteristic diffractions with the use of CuKa radiation are 3.1; 13.5; 17.5; 19.5; 22.9 and 26.2 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 5.
- Form F of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 6. Its characteristic diffractions with the use of CuKa radiation are 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 6.
- Form G of baricitinib phosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 7. Its characteristic diffractions with the use of CuKa radiation are 4.5; 15.2; 18.1 ; 20.9; 23.6 and 26.4 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 7.
- this invention provides a crystalline form of baricitinib hemiphosphate.
- Form I of baricitinib hemiphosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 8. Its characteristic diffractions with the use of CuKa radiation are 3.8; 8.1; 16.9; 19.0 and 22.0 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 8.
- Form II of baricitinib hemiphosphate exhibits a strongly crystalline character.
- the X-ray powder pattern of this salt is shown in Figure 9. Its characteristic diffractions with the use of CuKa radiation are 4.0; 16.2; 18.5; 20.4; 22.9 and 26.0 ⁇ 0.2° 2-theta. More diffraction peaks are shown in Table 9.
- the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
- For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
- the molar ratio of phosphoric acid and baricitinib base was determined by means of 1H a 3I P NMR spectrometry with the use of the internal standard method. NMR spectra were measured using a Bruker Avance 500 device with the frequencies of 500 MHz for ⁇ spectra and 202.4 MHz for 31 P spectra in DMSO-dg. Determination of chemical purity with HPLC:
- Liquid chromatography analyses were performed using an Acquity UPLC device with a TUV detector in an Ascentis Express C8 column, 100 x 3.0 mm, 2.7 mm at 25°C. To separate the analytes, a linear gradient was used with a mobile phase containing 10 mM of KH 2 P0 4 at pH 6.5 (A) and acetonitrile (B):
- the flow was 0.6 ml/min. 1 ml of the sample (0.5 mg/ml prepared in a water acetonitrile - 1/1 mixture) was injected into the system and the analytes were detected at 227 nm.
- Baricitinib (0.50 g; 1.3 mmol) was dissolved in «-propanol (30 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.28 g; 1,8 equivalents; 85% cone, in water) in ethanol (2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form B was obtained as white powder (522 mg; 82.7%). Stoichiometry 1 :1.01; HPLC 99.1%.
- Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85% cone, in water) in methanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2%). Stoichiometry 1:1.14.
- Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.22 g; 2.4 equivalents; 85% cone, in water) in 2- propanol (1.5 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form D was obtained as white powder (371 mg; 97.9%). Stoichiometry 1:1.
- Baricitinib (1.00 g; 2.67 mmol) was dissolved in an ethanol/water mixture (10 ml; mixture ratio 3/1) under reflux conditions. Phosphoric acid (276 ⁇ ; 1,5 equiv) was added dropwise to the solution. The obtained mixture was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off, washed with an ethanol/water mixture (ratio 3/1) and dried at 40°C and 200 mbar for 18h. Baricitinib phosphate of form E was obtained as white powder (971 mg; 77%). Stoichiometry 1:1.01; HPLC 99.8%.
- Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 irdnutes, a solution of phosphoric acid (0.24 g; 2.6 equivalents; 85% cone.) in acetone (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form F was obtained as white powder (397 mg). Stoichiometry 1 :1.36.
- Baricitinib phosphate (100 mg) was suspended in an acetone/water mixture (mixture ratio 98/2). The suspension was stirred at 50°C in a shaker for 2 weeks. The precipitate was filtered off and dried in vacuum. Baricitinib phosphate of form G was obtained as white powder (90 mg; 90%). Stoichiometry 1 :0.92.
- Baricitinib phosphate (200 mg) was suspended in an ethanol/water mixture (mixture ratio 3/1). The suspension was stirred at 50°C in a shaker for 2 weeks. The precipitate was filtered off and dried in vacuum. Baricitinib hemiphosphate of form I was obtained as white powder (185 mg; 93%). Stoichiometry 1:0.6.
- Baricitinib (0.30 g; 0.8 mmol) was dissolved in «-propanol (18 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.22 g; 2,4 equivalents; 85% cone.) in ethanol (1,2 ml) was added by dripping. The obtained suspension was stirred for 1.5 hours at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib hemiphosphate of form II was obtained as white powder (371 mg; 97.9%). Stoichiometry 1 :0.5.
- Baricitinib (8.00 g; 21.5 mmol) was suspended in a mixture of acetonitrile (184 ml) and ethanol (64 ml) and at the temperature of 63°C, a solution of phosphoric acid (3.26 g, 1.3 equivalents; 85% cone.) in ethanol (28.4 ml) was added by dripping during 40 minutes. The reaction mixture was then slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and washed with acetonitrile (25 ml).
- the crystals were stirred up in ethanol (110 ml) and during 25 minutes, a solution of phosphoric acid (1.54 g; 0.6 equivalents; 85% cone.) in ethanol (20 ml) was added by dripping. The reaction mixture was heated up to boiling and stirred at this temperature for 1 hour. After cooling to the laboratory temperature, the crystals were aspirated, washed with ethanol (30 ml) and an ethanol and heptane (12 ml+24 ml) mixture. The crystals were dried at 35°C and 200 mbar for 18 h. Baricitinib phosphate was obtained as white powder (7.40 g; 81.4%) with the melting point of 185.0 - 185.9°C. Stoichiometry 1 :1.13; HPLC 99.9%.
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Abstract
The invention relates to novel crystalline forms of baricitinib with phosphoric acid of the chemical formula of 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1- yl]azetidin-3-yl]acetonitrile phosphate. The invention also relates to a method of their preparation as well as to their use in pharmaceutically acceptable compositions.
Description
Crystalline forms of 2-[l-ethylsuIfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yI)pyrazol-l- yl]azetidin-3-yI]acetonitrile with phosphoric acid and a method of their preparation
Field of the Invention
The invention relates to novel crystalline forms of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-emylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate. The invention also relates to a method of their preparation as well as to le compositions.
(I)
Background Art
Baricitinib of formula II, with the systematic name 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3- d]pvrimidm -yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile is an inhibitor of JAK1/JAK2 tyrosine kinase and is designated for the treatment of rheumatoid arthritis. Further possible indications comprise various autoimmune diseases as e.g. psoriasis, diabetic nephropathy, atopic dermatitis, lupus and more (Drugs Fut
(Π)
For the first time, baricitinib is mentioned in the patent application WO2009114512 of the company Incyte. Baricitinib phosphate is disclosed as a white crystalline substance, only characterized by the melting point of 187°C in the patent application. It does not mention or characterize particular crystalline forms of baricitinib phosphate. Further, the salt of baricitinib with trifluoroacetic acid as well as preparation of free baricitinib is described in this application.
Another patent application of the company Incyte, WO2010039939, discloses the use of baricitinib for the treatment of some eye diseases as the dry eye syndrome (DES).
Several crystalline forms of free baricitinib are disclosed. The patent application of the company Sun Pharmaceutical Industries Ltd., WO2015145286, discloses an amorphous form of baricitinib. In another patent application, WO201S166434, the same company discloses a crystalline form of free baricitinib characterized by the XRPD CuKa diffraction peaks: 2.98; 3.48; 3.52; 4.65; 5.31; 5.43; 5.75; 5.91 and 7.06.
Further, the company Egis Pharmaceuticals disclosed two other crystalline forms of free baricitinib, which were published on November 27, 2015 (IPCOM000244270D). The first crystalline form is characterized by the XRPD CuKa diffraction peaks: 4.15; 12.47; 13.98; 14.58; 15.40; 16.28; 16.67; 19.06; 25.18; 25.52. The second one of the disclosed forms was prepared by heating of the first form to 120°C and is characterized by the XRPD CuKa diffraction peaks: 4.13; 12.42; 13.97; 14.96; 16.25; 16.49; 18.83; 19.21; 25.05; 25.54.
The patent application CN105693731 of the company Shanghai Biotech deals with preparation of a novel polymorph of free baricitinib. Another patent application CNl 05294699 of the company Shanghai Xunhe pharma discloses a preparation method of baricitinib. The patent application CN05541891 of Southeast Univ deals with the preparation of intermediates of the synthesis of baricitinib and their application to baricitinib synthesis. The last patent application for the time being, WO2016125080 of the company Sun Pharmaceutical Industries Ltd, discloses a preparation process of baricitinib and its intermediates.
Particular solid phases of salts of baracitinib with phosphoric acid, properly characterized with suitable analytical methods have not been described in the literature yet. The discovery of new solid phases (polymorphs, solvates and hydrates) of an active pharmaceutical ingredient provides the possibility to select a suitable modification having the desired physicochemical properties and processability to improve the characteristics of the product as it influences its
solubility, chemical stability, purification effect on isolation, mechanical properties as the particle size and so forth, which are important in the preparation of drug forms.
Disclosure of the Invention
The present invention provides novel crystalline forms of salts of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate that comply with pharmaceutical requirements.
These forms are especially advantageous from the point of view of preparation of highly pure baricitinib and exhibit good chemical stability and suitable solubility for the use for the production of pharmaceutical preparations. The invention also relates to a method of their preparation as well as to their use in pharmaceutically acceptable compositions.
In another aspect, this invention provides novel crystalline forms of baricitinib phosphate referred to as A, B, C, D, E, F and G. In still another aspect, this invention provides a preparation method of a crystalline salt of baricitinib with phosphoric acid. In another aspect, this invention provides crystalline hemiphosphate of baricitinib. In still another aspect, this invention provides novel crystalline forms of baricitinib hemiphosphate, referred to as I and II. These novel forms are characterized by an X-ray powder pattern, which is shown below in the section Detailed description of the Invention.
In an aspect, this invention provides crystalline form A of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.2; 12.8; 16.5; 19.5; 22.4 and 25.8 ± 0.2° 2-theta. In another aspect, this invention
provides crystalline form B of bancitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.3; 12.7; 15.9; 17.8; 20.7 and 26.6 ± 0.2° 2-theta. In a further aspect, this invention provides crystalline form C of bancitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.7; 8.6; 14.7; 17.3; 18.5; 20.1 and 27.4 ± 0.2° 2-theta. In still another aspect, this invention provides crystalline form D of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.6; 8.1; 18.2; 20.6; 22.3; 25.2 and 29.3 ± 0.2° 2-theta. In another aspect, this invention provides crystalline form E of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.1; 13.5; 17.5; 19.5; 22.9 and 26.2 ± 0.2° 2-theta. In even another aspect, this invention provides crystalline form F of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ± 0.2° 2-theta. In another aspect, this invention provides crystalline form G of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ± 0.2° 2-theta.
In another aspect, the invention provides a crystalline form of baricitinib hemiphosphate. In still another aspect, this invention provides crystalline form I of baricitinib hemiphosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.8; 8.1; 16.9; 19.0 and 22.0 ± 0.2° 2-theta. In another aspect, this invention provides crystalline form II of baricitinib hemiphosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 16.2; 18.5; 20.4; 22.9 and 26.0 ± 0.2° 2-theta.
In an aspect, the invention also provides a preparation method of a crystalline form of baricitinib with phosphoric acid of formula I, baricitinib and/or baricitinib phosphate being dissolved and/or suspended in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water.
The preparation method is further characterized in that baricitinib is dissolved in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, and phosphoric acid is added after that. The preparation method may further comprise the steps of: a) dissolution of baricitinib in a solvent selected from the group consisting of
methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, b) addition of 85% aqueous solution of phosphoric acid, c) stirring of the obtained mixture, d) isolation of the crystalline salt of baricitinib phosphate, optionally comprising the step of drying of the product of step c). In another aspect, the invention provides a preparation method, baricitinib phosphate being suspended in a mixture of solvents of ethanol and water and/or acetone and water. The preparation method further comprises the steps of: a) suspending of baricitinib phosphate in a mixture of solvents of ethanol and water and/or acetone and water, b) stirring of the suspension, preferably at 50°C and preferably for 2 weeks, c) isolation of the crystalline salt of baricitinib hemiphosphate, optionally comprising the step of drying of the product of step b). In still another aspect, the invention provides use of the above mentioned inventive forms for the preparation of a pharmaceutical composition comprising the salt of baricitinib with phosphoric acid and at least one pharmaceutically acceptable excipient. Brief description of the Drawings
Fig. 1: XRPD pattern of form A of baricitinib phosphate
Fig. 2: XRPD pattern of form B of baricitinib phosphate
Fig. 3: XRPD pattern of form C of baricitinib phosphate
Fig. 4: XRPD pattern of form D of baricitinib phosphate
Fig. 5: XRPD pattern of form E of baricitinib phosphate
Fig. 6: XRPD pattern of form F of baricitinib phosphate
Fig. 7: XRPD pattern of form G of baricitinib phosphate
Fig. 8: XRPD pattern of form I of baricitinib hemiphosphate
Fig. 9: XRPD pattern of form II of baricitinib hemiphosphate
Fig. 10: XRPD pattern of a form of baricitinib phosphate (according to WO2009114512)
Detailed description of the Invention
The description below is provided to make it possible for a person skilled in the art to realize and use various embodiments. The descriptions of individual devices, techniques and applications are only mentioned as examples. Persons with ordinary skills in the art will readily find various modifications described herein in the Examples obvious, and the general principles described herein can be applied to other examples and applications without deviating from the spirit and scope of various embodiments. Therefore, various embodiments
are not restricted to those described and shovm in the Examples, but will fall within the scope defined by the patent claims.
In an aspect, this invention provides novel crystalline forms of baricitinib with phosphoric acid of formula I, with the systematic name of 2-[l-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3-yl]acetonitrile phosphate that comply with pharmaceutical requirements.
(I)
These forms are especially advantageous from the point of view of preparation of highly pure baricitinib and exhibit good chemical stability and suitable solubility for the use for the production of pharmaceutical preparations. The invention also relates to a method of their preparation as well as to their use in pharmaceutically acceptable compositions.
Variations in the crystal structure of the salts of baricitinib can influence the dissolution rate (which may influence the biological availability etc.), preparability (e.g. ease of handling, ability to consistently prepare doses of a known strength) and stability (e.g. thermal stability, durability etc.) of the pharmaceutical treatment agent especially if it is formulated in a solid form for oral administration (e.g. in the tablet form). Therapeutic use and production of baricitinib comprises the development of novel solid forms of salts of baricitinib that exhibit higher bioavailability and stability.
What has been surprisingly found out now is that the above-mentioned crystalline salts of baricitinib phosphate can be easily prepared and have not been described in literature yet and no solid phase analytical data (X-ray diffraction spectroscopy diffractograms with powder samples, X-ray crystallography data etc.) have been published to characterize the crystal phases.
Form A of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 1. Its characteristic diffractions with the use of CuKa
radiation are 3.2; 12.8; 16.5; 19.5; 22.4 and 25.8 ± 0.2° 2-theta. More diffraction peaks shown in Table 1.
Table 1: Diffraction peaks of form A of baricitinib phosphate
Form B of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 2. Its characteristic diffractions with the use of CuKa radiation are 3.3; 12.7; 15.9; 17.8; 20.7 and 26.6 ± 0.2° 2-theta. More diffraction peaks are shown in Table 2.
Table 2: Diffraction peaks of form B of baricitinib phosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
3.27 27.008 84.1
6.41 13.786 21.7
12.74 6.944 50.4
15.94 5.554 100.0
Pos. [°2Θ] d [A] Rel. Int. [%]
16.70 5.304 79.3
17.81 4.975 72.4
18.58 4.771 24.3
20.65 4.298 71.5
22.55 3.940 51.8
23.85 3.728 39.2
26.59 3.350 45.8
27.50 3.241 23.8
29.16 3.060 31.8
Form C of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 3. Its characteristic diffractions with the use of CuKa radiation are 3.7; 8.6; 14.7; 17.3; 18.5; 20.1 and 27.4 ± 0.2° 2-theta. More diffraction peaks are shown in Table 3.
Table 3: Diffraction peaks of form C of baricitinib phosphate
Pos. [°20] d [A] Rel. Int. [%]
3.69 23.940 100.0
7.35 12.024 6.0
7.79 11.342 6.2
8.24 10.728 4.0
8.59 10.280 11.3
11.05 8.001 3.2
13.49 6.559 3.9
14.74 6.004 8.1
15.93 5.558 4.6
16.60 5.338 3.7
17.33 5.112 12.5
17.99 4.928 6.0
18.48 4.798 26.1
19.19 4.622 11.8
Pos. [°2Θ] d [A] Rel. Int. [%]
20.10 4.413 14.0
21.53 4.124 2.5
22.14 4.012 3.3
23.63 3.763 3.5
23.95 3.713 3.8
24.43 3.640 4.5
25.29 3.518 2.7
25.68 3.467 2.1
26.17 3.403 3.8
27.37 3.256 4.2
30.85 2.896 1.9
Form D of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 4. Its characteristic diffractions with the use of CuKa radiation are 3.6; 8.1; 18.2; 20.6; 22.3; 25.2 and 29.3 ± 0.2° 2-theta. More diffraction peaks are shown in Table 4.
Table 4: Diffraction peaks of form D of baricitinib phosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
3.64 24.250 100.0
7.32 12.061 16.6
8.09 10.914 14.9
11.00 8.039 4.0
13.02 6.796 8.2
13.63 6.493 3.5
14.68 6.030 21.9
15.49 5.716 4.9
16.69 5.308 6.4
17.17 5.159 8.8
18.25 4.858 34.1
19.34 4.585 15.6
Pos. [°2Θ] d [A] Rel. Int. [%]
19.98 4.440 12.3
20.62 4.304 27.6
21.34 4.161 11.7
22.25 3.991 28.3
25.25 3.525 22.1
26.89 3.313 9.0
27.83 3.203 3.6
29.32 3.043 9.1
33.86 2.645 4.7
34.87 2.571 4.1
Form E of bancitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 5. Its characteristic diffractions with the use of CuKa radiation are 3.1; 13.5; 17.5; 19.5; 22.9 and 26.2 ± 0.2° 2-theta. More diffraction peaks are shown in Table 5.
Table 5: Diffraction peaks of form E of baricitinib phosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
3.0985 28.49165 100
8.1888 10.78846 12.95
9.4035 9.39747 6.74
10.2949 8.5857 8.32
12.4334 7.11338 15.96
13.5445 6.53221 46.7
14.8443 5.96303 6.68
15.3206 5.7787 26.9
16.4786 5.37514 35.73
17.1405 5.16902 20.85
17.6478 5.02157 37.78
18.213 4.86699 11.25
18.9677 4.67502 20.89
Pos. [°2Θ] d [A] Rel. Int. [%]
19.4899 4.55092 37.03
20.5028 4.3283 32.43
21.878 4.05926 19.3
22.7847 3.89973 26.57
23.437 3.79264 7.59
24.4472 3.63816 8.23
25.0954 3.54564 14.94
26.1896 3.39994 35.89
27.2226 3.27322 10.74
27.5392 3.23631 11.1
28.8066 3.09673 8.32
Form F of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 6. Its characteristic diffractions with the use of CuKa radiation are 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ± 0.2° 2-theta. More diffraction peaks are shown in Table 6.
Table 6: Diffraction peaks of form F of baricitinib phosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
4.49 19.664 100.0
6.39 13.824 11.0
12.44 7.109 7.5
12.98 6.816 14.7
13.38 6.611 20.4
14.24 6.216 10.9
15.20 5.824 37.8
16.00 5.536 11.1
16.14 5.487 11.6
17.82 4.974 25.2
18.11 4.895 37.8
18.43 4.810 14.4
Pos. [°2Θ] d [A] Rel. Int. [%]
19.34 4.587 17.6
19.96 4.444 14.4
20.88 4.251 73.3
21.54 4.121 14.6
22.78 3.901 12.5
23.63 3.763 25.6
25.79 3.452 9.7
26.38 3.376 28.4
27.53 3.237 9.3
27.83 3.203 9.0
29.13 3.063 6.3
Form G of baricitinib phosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 7. Its characteristic diffractions with the use of CuKa radiation are 4.5; 15.2; 18.1 ; 20.9; 23.6 and 26.4 ± 0.2° 2-theta. More diffraction peaks are shown in Table 7.
Table 7: Diffraction peaks of form G of baricitinib phosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
3.74 23.605 100.0
7.72 11.448 8.2
9.55 9.255 6.9
11.40 7.756 4.6
12.62 7.007 3.6
13.30 6.651 7.0
14.35 6.169 10.0
15.20 5.823 22.4
15.63 5.664 36.3
16.70 5.303 7.5
17.29 5.125 9.2
18.72 4.735 55.8
Pos. [°2Θ] d [A] Rel. Int. [%]
19.44 4.564 23.8
20.37 4.357 17.9
20.72 4.283 22.1
21.14 4.198 30.5
22.08 4.022 25.8
23.06 3.853 31.3
24.97 3.563 19.5
26.19 3.400 11.9
27.15 3.282 11.8
28.27 3.155 6.3
28.79 3.098 7.7
30.46 2.933 4.7
In another aspect, this invention provides a crystalline form of baricitinib hemiphosphate. Form I of baricitinib hemiphosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 8. Its characteristic diffractions with the use of CuKa radiation are 3.8; 8.1; 16.9; 19.0 and 22.0 ± 0.2° 2-theta. More diffraction peaks are shown in Table 8.
Table 8: Diffraction peaks of form I of baricitinib hemiphosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
3.76 23.500 98.1
8.10 10.907 100.0
9.34 9.465 6.6
11.25 7.856 7.6
12.62 7.009 5.8
15.14 5.849 8.9
16.94 5.229 66.5
18.43 4.810 31.6
19.01 4.665 79.5
19.83 4.474 27.2
Pos. [°2Θ] d [A] Rel. Int. [%]
21.10 4.207 8.9
22.00 4.036 25.5
23.84 3.729 7.8
24.41 3.644 18.3
24.80 3.587 16.8
25.41 3.503 17.1
Form II of baricitinib hemiphosphate exhibits a strongly crystalline character. The X-ray powder pattern of this salt is shown in Figure 9. Its characteristic diffractions with the use of CuKa radiation are 4.0; 16.2; 18.5; 20.4; 22.9 and 26.0 ± 0.2° 2-theta. More diffraction peaks are shown in Table 9.
Table 9: Diffraction peaks of form II of baricitinib hemiphosphate
Pos. [°2Θ] d [A] Rel. Int. [%]
4.00 22.057 13.4
8.02 11.017 4.8
8.43 10.485 5.5
12.88 6.868 12.2
13.26 6.670 9.0
14.04 6.302 11.3
14.99 5.906 12.5
15.39 5.752 8.5
16.23 5.457 100.0
16.77 5.283 41.1
17.43 5.083 49.5
17.94 4.941 13.8
18.28 4.850 14.3
18.59 4.768 37.4
19.75 4.490 32.9
20.44 4.342 28.5
21.03 4.220 11.9
Pos. [°2Θ] d [A] Rel. Int. [%]
21.53 4.124 15.4
22.90 3.880 32.5
23.81 3.734 22.0
24.27 3.664 9.7
25.15 3.538 18.5
25.46 3.496 13.4
26.01 3.423 25.4
26.37 3.377 15.3
28.15 3.168 13.6
28.45 3.135 16.4
29.11 3.065 9.4
30.12 2.965 6.2
Form of baricitinib phosphate prepared according to the patent application WO2009114512. We repeated this process and measured the X-ray diffraction pattern of this form, which is shown in Figure 10. Its characteristic diffractions with the use of CuKa radiation are 3.7; 8.4; 17.2; 18.6; 19.5 and 25.4 ± 0.2° 2-theta. More diffraction peaks are shown in Table 10. As you can see, this form is different from the forms that are provided by this invention, including the preparation method of these forms. The forms that are provided by this invention are very advantageous especially from the point of view of preparation of highly pure baricitinib or its pharmaceutically acceptable salts and exhibit good chemical stability and suitable solubility for the use for the production of pharmaceutical preparations.
Table 10: Diffraction peaks of baricitinib phosphate according to WO2009114512
Pos. [°2Θ] d [A] Rel. Int. [%]
3.68 23.983 100.0
7.39 11.958 5.6
7.85 11.256 25.3
8.44 10.474 29.5
14.83 5.971 8.0
15.77 5.615 8.8
Pos. [°2Θ] d [A] Rel. Int. [%]
17.23 5.142 43.2
18.01 4.922 18.4
18.56 4.778 42.9
19.46 4.559 24.6
20.49 4.332 5.7
21.81 4.071 5.3
23.99 3.706 9.4
24.80 3.587 6.1
25.41 3.502 19.2
26.20 3.399 6.6
27.07 3.291 5.9
27.74 3.214 5.3
List of analytical methods
Measurement parameters oiXRPDx
The diffractograms were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.02° 2Θ, step dwell time: 200 s, the measurement was carried out on a flat powder sample that was applied on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
Determination of the stoichiometry of baricitinib base and phosphoric acid in the salt by means of NMR:
The molar ratio of phosphoric acid and baricitinib base was determined by means of 1H a 3IP NMR spectrometry with the use of the internal standard method. NMR spectra were measured using a Bruker Avance 500 device with the frequencies of 500 MHz for Ή spectra and 202.4 MHz for 31P spectra in DMSO-dg.
Determination of chemical purity with HPLC:
Liquid chromatography analyses were performed using an Acquity UPLC device with a TUV detector in an Ascentis Express C8 column, 100 x 3.0 mm, 2.7 mm at 25°C. To separate the analytes, a linear gradient was used with a mobile phase containing 10 mM of KH2P04 at pH 6.5 (A) and acetonitrile (B):
The flow was 0.6 ml/min. 1 ml of the sample (0.5 mg/ml prepared in a water acetonitrile - 1/1 mixture) was injected into the system and the analytes were detected at 227 nm.
Examples
The embodiment examples below are only provided to illustrate and to explain the invention and are not in any case intended to restrict the protection scope, which is only delimited by the wording of the patent claims.
Example 1
Preparation of form A of baricitinib phosphate
Baricitinib (0.50 g; 1.3 mmol) was dissolved in methyl ethyl ketone (MEK, 20 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.31 g; 2 equivalents; 85% cone. in water) in ethanol (2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form A was obtained as white powder (585 mg; 92.6%). Stoichiometry 1:1; HPLC 99.9%.
Example 2
Preparation of form B of baricitinib phosphate
Baricitinib (0.50 g; 1.3 mmol) was dissolved in «-propanol (30 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.28 g; 1,8 equivalents; 85% cone, in water) in ethanol (2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form B was obtained as white powder (522 mg; 82.7%). Stoichiometry 1 :1.01; HPLC 99.1%.
Example 3
Preparation of form C of baricitinib phosphate
Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.20 g; 2.1 equivalents; 85% cone, in water) in methanol (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form C was obtained as white powder (376 mg; 99.2%). Stoichiometry 1:1.14.
Example 4
Preparation of form D of baricitinib phosphate
Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.22 g; 2.4 equivalents; 85% cone, in water) in 2- propanol (1.5 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form D was obtained as white powder (371 mg; 97.9%). Stoichiometry 1:1.
Example 5
Preparation of form E of baricitinib phosphate
Baricitinib (1.00 g; 2.67 mmol) was dissolved in an ethanol/water mixture (10 ml; mixture ratio 3/1) under reflux conditions. Phosphoric acid (276 μΐ; 1,5 equiv) was added dropwise to the solution. The obtained mixture was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off, washed with an ethanol/water mixture (ratio 3/1) and dried at 40°C and 200 mbar for 18h. Baricitinib phosphate of form E was obtained as white powder (971 mg; 77%). Stoichiometry 1:1.01; HPLC 99.8%. Example 6
Preparation of form F of baricitinib phosphate
Baricitinib (0.30 g; 0.8 mmol) was dissolved in acetonitrile (7 ml) under boiling and during 30 irdnutes, a solution of phosphoric acid (0.24 g; 2.6 equivalents; 85% cone.) in acetone (1.2 ml) was added by dripping. The obtained suspension was stirred for 1 hour at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib phosphate of form F was obtained as white powder (397 mg). Stoichiometry 1 :1.36.
Example 7
Preparation of form G of baricitinib phosphate
Baricitinib phosphate (100 mg) was suspended in an acetone/water mixture (mixture ratio 98/2). The suspension was stirred at 50°C in a shaker for 2 weeks. The precipitate was filtered off and dried in vacuum. Baricitinib phosphate of form G was obtained as white powder (90 mg; 90%). Stoichiometry 1 :0.92.
Example 8
Preparation of form I of baricitinib hemiphosphate
Baricitinib phosphate (200 mg) was suspended in an ethanol/water mixture (mixture ratio 3/1). The suspension was stirred at 50°C in a shaker for 2 weeks. The precipitate was filtered off and dried in vacuum. Baricitinib hemiphosphate of form I was obtained as white powder (185 mg; 93%). Stoichiometry 1:0.6.
Example 9
Preparation of form II of baricitinib hemiphosphate
Baricitinib (0.30 g; 0.8 mmol) was dissolved in «-propanol (18 ml) under boiling and during 30 minutes, a solution of phosphoric acid (0.22 g; 2,4 equivalents; 85% cone.) in ethanol (1,2 ml) was added by dripping. The obtained suspension was stirred for 1.5 hours at the temperature of 68°C, then it was slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and dried at 35°C and 200 mbar for 18h. Baricitinib hemiphosphate of form II was obtained as white powder (371 mg; 97.9%). Stoichiometry 1 :0.5.
Example 10
Preparation of baricitinib phosphate according to the patent WO2009114512
Baricitinib (8.00 g; 21.5 mmol) was suspended in a mixture of acetonitrile (184 ml) and ethanol (64 ml) and at the temperature of 63°C, a solution of phosphoric acid (3.26 g, 1.3 equivalents; 85% cone.) in ethanol (28.4 ml) was added by dripping during 40 minutes. The reaction mixture was then slowly cooled down to the laboratory temperature and stirred overnight. The precipitate was filtered off and washed with acetonitrile (25 ml). The crystals were stirred up in ethanol (110 ml) and during 25 minutes, a solution of phosphoric acid (1.54 g; 0.6 equivalents; 85% cone.) in ethanol (20 ml) was added by dripping. The reaction mixture was heated up to boiling and stirred at this temperature for 1 hour. After cooling to the laboratory temperature, the crystals were aspirated, washed with ethanol (30 ml) and an ethanol and heptane (12 ml+24 ml) mixture. The crystals were dried at 35°C and 200 mbar for 18 h. Baricitinib phosphate was obtained as white powder (7.40 g; 81.4%) with the melting point of 185.0 - 185.9°C. Stoichiometry 1 :1.13; HPLC 99.9%.
Claims
1. Crystalline form A of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.2; 12.8; 16.5; 19.5; 22.4 and 25.8 ± 0.2° 2-theta.
2. Crystalline form B of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.3; 12.7; 15.9; 17.8; 20.7 and 26.6 ± 0.2° 2-theta.
3. Crystalline form C of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.7; 8.6; 14.7; 17.3; 18.5; 20.1 and 27.4 ± 0.2° 2-theta.
4. Crystalline form D of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.6; 8.1; 18.2; 20.6; 22.3; 25.2 and 29.3 ± 0.2° 2-theta.
5. Crystalline form E of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.1; 13.5; 17.5; 19.5; 22.9 and 26.2 ± 0.2° 2-theta.
6. Crystalline form F of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ± 0.2° 2-theta.
7. Crystalline form G of baricitinib phosphate, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.5; 15.2; 18.1; 20.9; 23.6 and 26.4 ± 0.2° 2-theta.
8. Crystalline form of baricitinib hemiphosphate.
9. Crystalline form I of baricitinib hemiphosphate in accordance with claim 8, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.8; 8.1; 16.9; 19.0 and 22.0 ± 0.2° 2-theta.
10. Crystalline form II of baricitinib hemiphosphate in accordance with claim 8, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 16.2; 18.5; 20.4; 22.9 and 26.0 ± 0.2° 2-theta.
11. A method for preparing a crystalline form of baricitinib with phosphoric acid of formula I,
(I)
characterized in that baricitinib and/or baricitinib phosphate is dissolved and/or suspended in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water.
12. The method of preparing in accordance with claim 11, characterized in that baricitinib is dissolved in a solvent selected from the group consisting of methyl ethyl ketone, propanol, acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, and phosphoric acid is added after that.
13. The method of preparing in accordance with claims 11 and 12, characterized in that it comprises the following steps:
a) dissolution of baricitinib in a solvent selected from the group consisting of methyl ethyl ketone, propanoL acetonitrile or in a mixture of solvents selected from the group consisting of ethanol and water and/or acetone and water, b) adding of an 85% solution of phosphoric acid,
c) stirring of the obtained mixture,
d) isolation of the crystalline salt of baricitinib phosphate, optionally comprising the step of drying of the product of step c).
14. The method for preparing in accordance with claim 11, characterized in that baricitinib phosphate is suspended in a mixture of solvents of ethanol and water and/or acetone and water.
15. The method in accordance with claims 11 and 14, characterized in that it comprises the following steps:
a) suspension of baricitinib phosphate in a mixture of solvents of ethanol and water and/or acetone and water,
b) stirring of the suspension, preferably at 50°C and preferably for 2 weeks, c) isolation of the crystalline salt of baricitinib hemiphosphate, optionally
comprising the step of drying of the product of step b).
16. Use of the crystalline forms in accordance with claims 1 to 10 for the preparation of a pharmaceutical composition comprising a salt of baricitinib with phosphoric acid and at least one pharmaceutically acceptable excipient.
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|---|---|---|---|---|
| WO2019137325A1 (en) * | 2018-01-09 | 2019-07-18 | 广东东阳光药业有限公司 | Novel crystalline form of baricitinib phosphate and preparation method thereof |
| WO2020163431A1 (en) | 2019-02-05 | 2020-08-13 | Teva Pharmaceuticals International Gmbh | Crystalline solid forms of baricitinib |
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| EP3725305A1 (en) | 2019-04-17 | 2020-10-21 | Zentiva K.S. | Pharmaceutical composition containing baricitinib hydrobromide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019137325A1 (en) * | 2018-01-09 | 2019-07-18 | 广东东阳光药业有限公司 | Novel crystalline form of baricitinib phosphate and preparation method thereof |
| WO2020163431A1 (en) | 2019-02-05 | 2020-08-13 | Teva Pharmaceuticals International Gmbh | Crystalline solid forms of baricitinib |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ2016816A3 (en) | 2018-07-04 |
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