Classifications

• • 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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