WO2019042485A1 - Formes à l'état solide de roxadustat - Google Patents

Formes à l'état solide de roxadustat Download PDF

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Publication number
WO2019042485A1
WO2019042485A1 PCT/CZ2018/000039 CZ2018000039W WO2019042485A1 WO 2019042485 A1 WO2019042485 A1 WO 2019042485A1 CZ 2018000039 W CZ2018000039 W CZ 2018000039W WO 2019042485 A1 WO2019042485 A1 WO 2019042485A1
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Prior art keywords
roxadustat
salt
coformer
crystalline
ray powder
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PCT/CZ2018/000039
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Inventor
Igor CERNA
Filip SEMBERA
Lukas KREJCIK
Ondrej Dammer
Michal Zapadlo
Stefano Lucas GIAFFREDA
Enrico MODENA
Cristina IANNI
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Zentiva KS
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Zentiva KS
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Priority claimed from CZ2017-503A external-priority patent/CZ2017503A3/cs
Priority claimed from CZ2018-277A external-priority patent/CZ2018277A3/cs
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of WO2019042485A1 publication Critical patent/WO2019042485A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the invention relates to solid forms of roxadustat with the systematic name of (4-hydroxy-l- methyl-7-phenoxyisoquinoline-3-carbonyl)glycine of formula I, methods of their preparation and use in a drug form.
  • Roxadustat (CAS no. 808118-40-3) is a hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor, which increases endogenous production of erythropoetin which stimulates production of red blood cells (erythropoiesis).
  • HIF-PH hypoxia inducible factor prolyl hydroxylase
  • roxadustat Preparation of roxadustat and its isolation was first described in the patent application WO 2004/108681 (compound 81).
  • the patent application WO 2014/014835 discloses a preparation method and characterization of crystalline forms of roxadustat free acid (form A-D) and its amorphous form. It further discloses a crystalline sodium salt of roxadustat, amorphous potassium salt, crystalline (hemi) calcium and (hemi) magnesium salt as well as salts of roxadustat with L-arginine, L-lysine, ethanolamine, diethanolarnine, tromethamine, bis- triethylamine, sulphuric and methanesulfonic acid.
  • the invention provides pharmaceutically acceptable salts of roxadustat (I) and a method of their preparation.
  • These solid forms of roxadustat of formula I are prepared by a reaction of roxadustat free acid with suitable coformers (inorganic or organic acids, bases, neutral molecules or possibly salts or ion pairs) in a suitable solvent or mixtures of solvents; or salts of roxadustat are prepared through cation exchange in a suitable solvent or mixtures of solvents, especially through exchange of the cation of the sodium salt of roxadustat.
  • the prepared solid forms have suitable physicochemical characteristics for use in pharmacy and formulation of new drug forms.
  • An object of this invention is a solid form of roxadustat with a coformer wherein the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium, calcium, magnesium, iron, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium acetate and caffeine.
  • the coformer is selected from the group consisting of meglumine, N,N'-dibenzylethylenediamine, tert- butylamine, diethylamine, dicyclohexylamine, ammonia, lithium, potassium, calcium, magnesium, iron, 2-naphtalenesulfonic acid, benzenesulfonic acid, p-tol
  • Another object of this invention is a salt of roxadustat with a coformer in a solid form wherein the coformer is selected from the group consisting of meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • the coformer is selected from the group consisting of meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, ammonia, potassium hydroxide, calcium salt, magnesium salt, iron (III) salt, iron (II) salt, 2- naphtalenesulfonic acid, benzenesulfonic acid and p-to
  • Another object of the invention is a salt of roxadustat with meglumine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with meglumine is further characterized by a differential scanning calorimetric curve with the melting point at 181°C.
  • Another object of the invention is a salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ⁇ , ⁇ '- dibenzylethylenediamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 126°C.
  • Another object of the invention is a salt of roxadustat with N,N-dibenzylemylenediarnine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 7.1; 9.9; 17.1; 19.9; 24.1 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with N,N -dibenzylethylenediamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 115°C.
  • Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with tert-butylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
  • Another object of the invention is a salt of roxadustat with tert-butylamine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with tert-butylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 169°C.
  • Another object of the invention is a salt of roxadustat with diethylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with diethylamine is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 9.9; 16.8; 19.8; 22.5; 24.4 and 29.9 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with dicyclohexylamine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 190°C.
  • Another object of the invention is a salt of roxadustat with dicyclohexylamine in the form of crystalline modification II, the coformer being dicyclohexylamine, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.5; 9.9; 12.4; 18.7; 20.6; 23.8 and 27.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with dicyclohexylamine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 189°C.
  • Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ammonia in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 159°C.
  • Another object of the invention is a salt of roxadustat with ammonia in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 4.9; 11.6; 14.9; 16.7; 18.9 and 22.4 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with ammonia in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 164°C.
  • Another object of the invention is a salt of roxadustat with Hthium in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with lithium in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 125°C.
  • Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.6; 7.8; 10.3; 15.6; 20.7 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with hthium in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 226.1°C.
  • Another object of the invention is a salt of roxadustat with lithium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with lithium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 227°C.
  • Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.6; 5.2; 10.8; 18.1; 20.8 and 24.4 ⁇ 0.2° 2-theta.
  • the potassium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 63°C.
  • Another object of the invention is a potassium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ⁇ 0.2° 2-theta
  • the potassium salt of roxadustat in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 288°C.
  • Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.0; 9.9; 13.0; 19.5 a 24.8 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with potassium in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 308.3°C.
  • Another object of the invention is a salt of roxadustat with potassium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 4.9; 7.3; 11.9; 19.8 and 22.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with potassium in the form of crystalline modification IV is further characterized by a differential scanning calorimetric curve with the melting point at 120.5°C.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ⁇ 0.2° 2-theta.
  • the hemi-calcium salt of roxadustat in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 96°C.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.9; 12.1; 16.6; 20.6 and 25.9 ⁇ 0.2° 2-theta.
  • Another object of the invention is a (hemi) calcium salt of roxadustat in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.5; 9.5; 21.5; 27.0 and 28.8 ⁇ 0.2° 2-theta.
  • Another object of the invention is a salt of roxadustat with calcium in the form of crystalline modification IV, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ⁇ 0.2° 2-theta.
  • Another object of the invention is an amorphous (hemi) calcium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 3.6; 10.2 and 25.8 ⁇ 0.5° 2-theta.
  • the amorphous hemi- calcium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 205°C.
  • Another object of the invention is a (hemi) magnesium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ⁇ 0.2° 2-theta.
  • the hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 85°C.
  • Another object of the invention is an amorphous (hemi) potasssium salt of roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • the amorphous hemi-magnesium salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C.
  • Another object of the invention is an amorphous salt of roxadustat with magnesium, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • the amorphous salt of roxadustat with calcium is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 62°C.
  • Another object of the invention is a semicrystalline iron (III) salt of roxadustat characterized by a diffraction peak in an X-ray powder pattern with the use of CuK ⁇ radiation of 6.5 ⁇ 0.2° 2-theta and amorphous halo with the band maximum of 22.0° ⁇ 1.0° 2-theta.
  • the semicrystalline iron (III) salt of roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is an amorphous (hemi) iron salt of roxadustat, exhibiting a characteristics amorphous halo in an X-ray powder pattern with the use of CuK ⁇ radiation in the range of 4.5 to 21.0 ⁇ 0.5° 2-theta.
  • the amorphous hemi-iron salt of roxadustat is further characterized by a differential scanning calorimetric curve with the glass transition temperature of 60°C.
  • Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 147°C.
  • Another object of the invention is a salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II, exhibiting the following characteristic reflections in an X- ray powder pattern with the use of CuK ⁇ radiation: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with 2-naphtalenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 142°C.
  • Another object of the invention is a salt of roxadustat with benzenesulfonic acid, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ⁇ 0.2° 2-theta.
  • the salt of roxadustat with benzenesulfonic acid is further characterized by a differential scanning calorimetric curve with the melting point at 155°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.7; 11.7; 15.8; 18.4; 21.9 and 26.0 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 150°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification ⁇ , exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ⁇ 0.2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 149°C.
  • Another object of the invention is a salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ⁇ 0,2° 2- theta.
  • the salt of roxadustat with p-toluenesulfonic acid in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 183°C.
  • Another object of the invention is crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ⁇ 0.2° 2-theta.
  • 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is further characterized by a differential scanning calorimetric curve with the melting point at 160°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification I, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ⁇ 0.2° 2- theta, or possibly these characteristic peaks maybe supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ⁇ 0.2° 2-theta.
  • the cocrystal of roxadustat with caffeine in the form of crystalline modification I is further characterized by a differential scanning calorimetric curve with the melting point at 177.2°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification II, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ⁇ 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ⁇ 0.2° 2-theta.
  • the cocrystal od roxadustat .
  • caffeine in the form of crystalline modification II is further characterized by a differential scanning calorimetric curve with the melting point at 178°C.
  • Another object of the invention is a cocrystal of roxadustat with caffeine in the form of crystalline modification III, exhibiting the following characteristic reflections in an X-ray powder pattern with the use of CuK ⁇ radiation: 10.0; 11.8; 16.8; 20.1 and 26.6 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ⁇ 0.2° 2-theta.
  • the cocrystal of roxadustat with caffeine in the form of crystalline modification III is further characterized by a differential scanning calorimetric curve with the melting point at 175.3°C.
  • Another object of the invention is a preparation method of solid forms of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N-dibenzylethylenediamine, tert-butylamine, diemylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2- naphtalenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 3-ethyl-l -methyl- 1H- imidazol-3-ium acetate and caffeine.
  • a coformer is added that is selected from the group consisting of meglumine, N,N-dibenzylethylenediamine, tert-butylamine, diemylamine, dicyclohexylamine, aqueous ammonia,
  • Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein roxadustat free acid is dissolved in a suitable solvent and subsequently, a coformer is added that is selected from the group consisting of meglumine, N,N -dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • Another object of the invention is a preparation method of salts of roxadustat with a coformer according to the present invention wherein a sodium salt of roxadustat is dissolved in a suitable solvent and subsequently a coformer is added that is selected from the group consisting of a calcium salt, magnesium salt, iron (II) salt and iron (III) salt, preferably of calcium chloride, magnesium chloride, iron (II) chloride and iron (III) chloride.
  • a suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, ethers, nitriles, water or their mixture, preferably tetrahydrofuran, methanol, acetone, acetonitrile, water or their mixture.
  • Another object of the invention is the use of solid forms of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
  • Another object of the invention is the use of salts of roxadustat with a coformer according to the present invention for the preparation of a pharmaceutical composition.
  • Another object of the invention is a pharmaceutical composition comprising a solid form of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient.
  • Another object of the invention is a pharmaceutical composition comprising a salt of roxadustat with a coformer according to the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 X-ray powder pattern of the crystalline meglumine salt of roxadustat
  • Figure 5 X-ray powder pattern of the crystalline (hemi) NN-dibenzylethylenediammonium salt of roxadustat - form II
  • Figure 8 DSC record of the crystalline tert-butylammonium salt of roxadustat - form
  • Figure 9 X-ray powder pattern of the crystalline tert-butylammonium salt of roxadustat - form II
  • Figure 10 DSC record of the crystalline tert-butylammonium salt of roxadustat - form II
  • Figure 11 X-ray powder pattern of the crystalline diethylammonium salt of roxadustat
  • Figure 14 DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form
  • Figure 15 X-ray powder pattern of the crystalline dicyclohexylammonium salt of roxadustat - form II
  • Figure 16 DSC record of the crystalline dicyclohexylammonium salt of roxadustat - form II
  • Figure 17 X-ray powder pattern of the crystalline ammonium salt of roxadustat - form I
  • Figure 19 X-ray powder pattern of the crystalline ammonium salt of roxadustat - form II
  • Figure 20 DSC record of the crystalline ammonium salt of roxadustat - form II
  • Figure 25 X-ray powder pattern of the crystalline lithium salt of roxadustat - form HI
  • Figure 31 X-ray powder pattern of the crystalline potassium salt of roxadustat - form III
  • Figure 32 DSC record of the crystalline potassium salt of roxadustat - form III
  • Figure 35 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form
  • Figure 36 DSC record of the crystalline (hemi-)calcium salt of roxadustat - form I
  • Figure 37 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form II
  • Figure 38 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form III
  • Figure 39 X-ray powder pattern of the amorphous (hemi-)calcium salt of roxadustat
  • Figure 40 DSC record of the amorphous (hemi-)calcium salt of roxadustat
  • Figure 41 X-ray powder pattern of the crystalline (hemi-)calcium salt of roxadustat - form IV
  • Figure 42 X-ray powder pattern of the crystalline (hemi-)magnesium salt of roxadustat
  • Figure 44 X-ray powder pattern of the amorphous (hemi-)magnesium salt of roxadustat
  • Figure 45 DSC record of the amorphous (hemi-)magnesium salt of roxadustat
  • Figure 46 X-ray powder pattern of the crystalline iron (III) salt of roxadustat
  • Figure 48 X-ray powder pattern of the amorphous (hemi-)iron (II) salt of roxadustat
  • Figure 54 X-ray powder pattern of crystalline besylate of roxadustat
  • Figure 58 X-ray powder pattern of crystalline tosylate of roxadustat - form II
  • Figure 60 X-ray powder pattern of crystalline tosylate of roxadustat - form III
  • Figure 62 X-ray powder pattern of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat
  • Figure 64 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form I
  • Figure 65 DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form
  • Figure 66 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form II
  • Figure 67 DSC record of a crystalline form of a caffeine cocrystal of roxadustat - form II
  • Figure 68 X-ray powder pattern of a crystalline form of a caffeine cocrystal of roxadustat - form III
  • roxadustat is structurally a very interesting molecule.
  • pKa it is a relatively strong acid, ready to form salts with inorganic as well as organic bases (II), but basic regions are also present, especially the isoquinoline nitrogen, which may be the source of interactions between roxadustat and a suitable acid (III).
  • the molecule comprises several donor and acceptor groups of electrons prone to form hydrogen bridges as well as an isoquinoline heterocycle and a phenoxy group suitable for aromatic interactions of the ⁇ - ⁇ stacking type with a suitable coformer.
  • the present invention provides multiple solid-phase crystalline salts of roxadustat and three solid-state amorphous salts. Within the invention, crystalline forms of salts of roxadustat are preferred.
  • the invention provides solid crystalline forms of roxadustat with meglumine, N ⁇ -dibenzylemylenediamine, tert-butylamine, diethylamine, dicyclohexylamine and ammonia, further a crystalline potassium salt, crystalline and amorphous forms of a calcium and potassium salt of roxadustat, iron (II) and iron (III) salts of roxadustat and salts of roxadustat with 2-naphtalenesulfonic acid, benzenesulfonic acid, />-toluenesulfonic acid, 3- ethyl-l-methyl-lH-imidazol-3-ium and caffeine in various molar ratios.
  • the molar ratios of 1:1, 2:1, 3:1 and 1:1,5 are preferred. Solid forms of roxadustat with these coformers can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form.
  • solid forms can be both anhydrous or non-solvated and in the form of hydrates/solvates of the respective solvents.
  • the prepared solid forms of roxadustat can have various internal arrangements (polymorphism) with different physicochemical characteristics depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.
  • Preparation of the solid forms of roxadustat of formula I according to the present invention is conducted by means of a reaction of roxadustat free acid with meglumine, ⁇ , ⁇ '- dibenzylethylenediamine, tert-butylamine, diethylamine, dicyclohexylamine, aqueous ammonia, lithium hydroxide, potassium hydroxide, 2-naphtalenesulfonic acid, benzenesulfonic acid, aad j>toluenesulfonic acid, 3-ethyl-l-methyl-lH-imidazol-3-ium and caffeine.
  • the forms of the calcium, magnesium iron (III) and iron ( ⁇ ) salt of roxadustat were prepared by cation exchange through a reaction of the sodium salt of roxadustat with calcium chloride, magnesium chloride, iron (III) chloride or iron (II) chloride.
  • calcium acetate, magnesium acetate or iron (II) acetate can alternatively be used for the preparation of the said salts.
  • the reactions can be conducted in a suitable solvent, which may be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic O-C4 alcohols, ketones, ethers, nitriles, water or their mixtures are preferred.
  • the most commonly used solvents are THF, MeOH, acetone, ACN, water or their mixtures.
  • the final product is precipitated or crystallized, or the solution is inoculated, typically at temperatures in the range of -30°C to the boiling point of the solvent.
  • Roxadustat free acid (form A) was prepared in accordance with the procedures disclosed in the patent application WO 2014/014835.
  • Salts of roxadustat according to the present invention especially salts with meglumine, N,N''- dibenzylemylenediamine, p-toluenesulfonic acid, potassium and hemi-calcium salt exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835.
  • Another advantage is increased photostability of the prepared salts of roxadustat compared to hitherto known forms of roxadustat.
  • Solid forms of roxadustat according to the present invention especially salts with meglumine, N,N'-dibenzylemylenediamine, p-toluenesulfonic acid, potassium, hemi-calcium salt and the cocrystal of roxadustat with caffeine exhibit better solubility compared to the thermodynamically most stable form of roxadustat free acid (form A) as well as compared to known salts disclosed in the patent application WO 2014/014835.
  • Another advantage is that the solid forms of roxadustat according to the present invention are suitable for the preparation of roxadustat with high chemical purity.
  • roxadustat was mixed in a suitable solvent or mixture of solvents and in a suitable ratio with a coformer and isolated by filtration of the crystalline product in the form of a salt or cocrystal with meglumine, N,N''- dibenzylethylenediamine, potassium hydroxide, p-toluenesulfonic acid and caffeine, the purity of which was much higher than the purity of the input roxadustat.
  • the examples and results of the purification effect of the conversion of roxadustat to a salt or cocrystal are presented in the table:
  • the crystalline form of the meglumine salt of roxadustat (prepared according to Example 1) is characterized by the reflections presented in Table 1.
  • Table 1 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline form of roxadustat meglumine salt according to the present invention with the use of CuK ⁇ radiation are: 3.3; 11.8; 16.8; 22.8; 25.1 and 27.7 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline (hemi) N,N'-dibenzylethylene diammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 5.0; 10.9; 13.3; 18.1; 19.8; 23.8 and 26,1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline hemi N,N-dibenzylethylene diammonium salt of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 7.1 ; 9.9; 17.1 ; 19.9; 24.1 and 26.5 ⁇ 0.2° 2-theta
  • Differential scanning calorimetry was used to measure the melting point of form II of the crystalline hemi N.N-dibenzylethylenediammonium salt of roxadustat of 115°C.
  • the tert-butylammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 4) is characterized by the reflections presented in Table 4.
  • Table 4 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.5; 12.9; 16.3; 20.1 and 22.7 ⁇ 0.2° 2-theta.
  • Differential scanning calorimetry was used to measure the melting point of the crystalline tert-butylammonium salt of roxadustat of form I of 159°C.
  • the tert-butylammonium salt of roxadustat in the form of crystalline modification II is characterized by the reflections presented in Table 5.
  • Table 5 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline tert-butylammonium salt of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 5.7; 11.1; 18.1; 19.6; 21.7 and 26.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the crystalline diethylammonium salt of roxadustat (prepared according to Example 6) is characterized by the reflections presented in Table 6.
  • Table 6 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peals of the crystalline diethylammonium salt of roxadustat according to the present invention wim the use of CuK ⁇ radiation are: 10.0; 13.3; 15.7; 20.2; 24.0 and 29.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the ammonium salt of roxadustat in the form of crystalline modification I (prepared according to Example 9) is characterized by the reflections presented in Table 9.
  • Table 9 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline ammonium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 6.2; 9.7; 15.9; 18.8; 23.3 and 27.9 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the lithium salt of roxadustat in the form of crystalline modification I (prepared according to Example 11) is characterized by the reflections presented in Table 11.
  • Table 11 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 2.7; 5.5; 10.6; 17.6; 24.0 and 26.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the lithium salt of roxadustat in the form of crystalline modification III is characterized by the reflections presented in Table 13.
  • Table 13 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline lithium salt of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 2.7; 5,4; 8.4; 11.3; 14.8 and 22.4 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • the potassium salt of roxadustat in the form of crystalline modification II (prepared according to Example 15) is characterized by the reflections presented in Table 15.
  • Table 15 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.0; 11.0; 13.8; 18.2; 22.4 and 27.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the potassium salt of roxadustat in the form of crystalline modification III (prepared according to Example 16) is characterized by the reflections presented in Table 16.
  • Table 16 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 5.0; 9.9; 13.0; 19.5 a 24.8 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 7.3; 17.0; 21.3 and 27.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline potassium salt of roxadustat of form IV according to the present invention with the use of CuK ⁇ radiation are: 4.9; 7.3; 11.9; 19.8 and 22.7 ⁇ 0.2° 2- theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 10.8; 15.1; 17.8 and 27.1 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the hemi-calcium salt of roxadustat in the form of crystalline modification I (prepared according to Example 18) is characterized by the reflections presented in Table 18.
  • Table 18 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.0; 11.5; 12.9; 16.6; 20.1; 23.7 and 26.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the hemi-calcium salt of roxadustat in the form of crystalline modification III (prepared according to Example 20) is characterized by the reflections presented in Table 20.
  • Table 20 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 3.5; 9.5; 21.5; 27.0 and 28.8 ⁇ 0.2° 2-theta.
  • the hemi-calcium salt of roxadustat in the form of crystalline modification IV (prepared according to Example 21) is characterized by the reflections presented in Table 21.
  • Table 21 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-calcium salt of roxadustat of form IV according to the present invention with the use of CuK ⁇ radiation are: 3.9; 11.6; 16.4; 19.3; 22.5 and 27.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 15.3; 21.2; 24.1; 24.9 and 30.8 ⁇ 0.2° 2-theta.
  • the amorphous (hemi) calcium salt of roxadustat (prepared according to Example 22) is characterized by the following diffraction peaks with the use of CuK ⁇ radiation: 3.6; 10.2 and 25.8 ⁇ 0.5° 2-theta.
  • DSC Differential scanning calorimetry
  • the crystalline (hemi) magnesium salt of roxadustat (prepared according to Example 23) is characterized by the reflections presented in Table 22.
  • Table 22 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of the crystalline hemi-magnesium salt of roxadustat according to the present invention with the use of CuK ⁇ radiation are: 8.1; 12.0; 14.0; 18.6; 25.5 and 28.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the amorphous (hemi) magnesium salt of roxadustat (prepared according to Example 24) is characterized by the following diffraction peaks with the use of CuK ⁇ radiation: 2.5; 5.2; 7.5; 12.0 and 25.4 ⁇ 0.5° 2-theta.
  • Differential scanning calorimetry (DSC) was used to measure the glass transition temperatute of the amorphous hemi-magnesium salt of roxadustat of 62°C.
  • the semicrystalline iron ( ⁇ ) salt of roxadustat (prepared according to Example 25) is characterized by the reflections presented in Table 23.
  • Table 23 comprises reflections whose relative intensity value is higher than 1%.
  • the semicrystalline form of the iron (III) salt of roxadustat is characterized by a diffraction peak with the use of CuK ⁇ radiation of 6.5 ⁇ 0.2 °2-theta and amorphous halo with the band maximum of 22.0° ⁇ 1.0° 2-theta.
  • DSC Differential scanning calorimetry
  • the amorphous (hemi) iron (II) salt of roxadustat (prepared according to Example 26) is characterized by an amorphous halo in the range of 4.5 to 21.0 ⁇ 0.5° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat napsylate in the form of crystalline modification I (prepared according to Example 27) is characterized by the reflections presented in Table 24.
  • Table 24 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat napsylate of form I according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.1; 18.2; 21.7; 25.2 and 27.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat napsylate in the form of crystalline modification II (prepared according to Example 28) is characterized by the reflections presented in Table 25.
  • Table 25 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat napsylate of form II according to the present invention with the use of CuK ⁇ radiation are: 6.4; 9.9; 13.5; 19.8; 22.0 and 26.5 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Crystalline roxadustat besylate (prepared according to Example 29) is characterized by the reflections presented in Table 26.
  • Table 26 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat besylate according to the present invention with the use of CuK ⁇ radiation are: 6.6; 10.5; 13.4; 20.2; 23.2; 26.1 and 28.3 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat tosylate in the form of crystalline modification II (prepared according to Example 31) is characterized by the reflections presented in Table 28.
  • Table 28 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat tosylate of form II according to the present invention with the use of CuK ⁇ radiation are: 5.8; 9.9; 14.1; 19.8; 22.0 and 26.8 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • Roxadustat tosylate in the form of crystalline modification III (prepared according to Example 32) is characterized by the reflections presented in Table 29.
  • Table 29 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline roxadustat tosylate of form III according to the present invention with the use of CuK ⁇ radiation are: 6.3; 10.9; 12.9; 17.3; 19.3 and 25.4 ⁇ 0,2° 2-theta.
  • DSC Differential scanning calorimetry
  • Crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat (prepared according to Example 33) is characterized by the reflections presented in Table 30.
  • Table 30 comprises reflections whose relative intensity value is higher than 1%.
  • the characteristic diffraction peaks of crystalline 3-ethyl-l-methyl-lH-imidazol-3-ium roxadustat according to the present invention with the use of CuK ⁇ radiation are: 5.1; 11.2; 15.6; 20.8; 23.1 and 25.7 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.8; 14.3; 17.2; 20.0 and 28.6 ⁇ 0.2° 2-theta.
  • Table 30 comprises
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form I according to the present invention with the use of CuK ⁇ radiation are: 8.2; 10.1; 13.1; 16.7; 19.7 and 26.0 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 9.6; 12.1; 17.4; 22.6 and 28.0 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form II according to the present invention with the use of CuK ⁇ radiation are: 7.8; 10.1; 12.8; 15.7; 19.4 and 26.0 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 11.3; 18.4; 23.2 and 27.2 ⁇ 0.2° 2-theta.
  • DSC Differential scanning calorimetry
  • the characteristic diffraction peaks of the crystalline caffeine cocrystal of roxadustat of form III according to the present invention with the use of CuK ⁇ radiation are: 10.0; 11.8; 16.8; 20.1 and 26.6 ⁇ 0.2° 2-theta, or possibly these characteristic peaks may be supplemented with more diffraction peaks: 14.8; 18.0; 21.4 and 24.9 ⁇ 0.2° 2-theta.
  • the prepared solid forms of the salts of roxadustat according to the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules.
  • Such pharmaceutical compositions can comprise at least one excipient from the group of fillers (e.g. lactose), binders (e.g. macrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • a salt or cocrystal of roxadustat can be mixed with the above-mentioned excipients, screened through a sieve and the final mixture can be tabletted or filled into capsules.
  • the tablets can be further coated with conventional layers of e.g. polyvinyl alcohol or polyethylene glycol.
  • 0.02 rad Soller slits, a 10 mm mask and a 1/4° fixed anti- dispersion slit were used.
  • the irradiated area of a sample is 10 mm, programmable divergency slits were used.
  • 0.02 rad Soller slits and a 5.0 mm anti-dispersion slit were used.
  • DSC Differential scanning calorimetry
  • DSC differential scanning calorimetry
  • the charge of the sample in a standard Al pot was 2-3 mg and the heating rate was 10°C/min.
  • the used temperature program consists of 1 stabilization minute at 0°C and then of heating up to 250°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N2 was used at the flow of 20 ml / min.
  • Ultra high performance liquid chromatography UHPLC
  • IR spectra were measured on a Nicolet 6700 FTIR spectrometer (Thermo, USA) using the single-reflection ATR technique (ZnSe). Each spectrum was accumulated with 12 scans with the resolution of 4 cm “1 . The spectra were collected and processed by the Opus 8.2 software (Thermo, USA). Thermogravimetry (TGA)
  • thermogravimetric analysis were measured using a TGA 6 device made by Perking Elmer.
  • the charge of the sample in a corundum pot was 13-20 mg and the heating rate was 10°C/min.
  • the used temperature program consists of 1 stabilization minute at 15°C and then of heating up to 300°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 ml / min.
  • Roxadustat free acid (crystalline form A) was prepared in accordance with the procedure disclosed in the patent application WO 2004/108681, or in accordance with the procedure disclosed in the patent application WO 2014/014835.
  • the sodium salt of roxadustat was prepared in accordance with the procedure disclosed in the patent application WO 2014/014835.
  • Roxadustat 40 mg, form A was dissolved in THF (1 ml) at 50°C.
  • Meglumine 1.1 equivalents in the form of a solution of 25 mg of meglumine in 1 ml of water
  • the solution was stirred for 20 min at 50°C.
  • the solution was subsequently left to cool down freely to 25°C and stirred at this temperature in an open vial.
  • the solid fraction was filtered, washed with water and dried for 0.5 h at the temperature of 45°C in vacuum.
  • the product was isolated in the yield of 86% (53 mg) in the form of white powder.
  • An IR measurement confirmed formation of a salt.
  • the ratio of roxadustat:meglumine 1:1 was determined by means of NMR.
  • the X-ray powder pattern is shown in Fig. 1
  • the DSC record is shown in Fig. 2
  • Tt 181°C
  • Roxadustat (10 mg, form A) was dissolved in THF and the solvent was evaporated in a vacuum drier at 25°C. Then, N,N'-dibenzylethylenediamine was added in the form of a solution in methanol (1 equivalent, 341 ⁇ l of a stock solution at the concentration of 0.0832M) and the solvent was evaporated again in a vacuum drier at the temperature of 25°C. 1 ml of a solvent (acetone or acetonitrile) was added to the prepared mixture and the mixture was stirred up until a solution was obtained. The solution was subsequently left to crystallize for 20 h at 7- 8°C. Then, the solvent was evaporated using a nitrogen stream for 48 h at the temperature of 25°C and subsequently for 22 h at the temperature of 25°C in vacuum. An ER measurement confirmed formation of a salt.
  • the X-ray powder pattern is shown in Fig. 13
  • Roxadustat (1.0 g, form A), which had been dissolved in a mixture of ethanol and tetrahydrofuran in the ratio of 8:3 (total volume 30 ml), was dosed into a flask at the temperature of 80°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 3 ml of water). Then, the solution was left to freely cool down to the room temperature (25°C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity cooled ethanol and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.367 g (34%). An IR measurement confirmed formation of a salt.
  • Roxadustat (1.0 g, form A), which had been dissolved in a mixture of acetone and tetrahydrofuran in the ratio of 8:2 (total volume 27 ml), was dosed into a flask at the temperature of 85°C and subsequently, aqueous LiOH was added (1.5 equivalents, 0.102 g of LiOH dissolved in 5 ml of water). Then, the solution was left to freely cool down to the room temperature (25 °C) and at this temperature it was stirred for another 48 hours. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried freely at the temperature of 25°C. The product was obtained in the form of beige powder in the yield of 0.484 g (47%). An IR measurement confirmed formation of a salt. 13.3% of water were measured by means of TGA.
  • the lithium salt of roxadustat (0.1 g, form II from the previous example) was dried at 60°C in vacuum (200 mbar) for 22 hours.
  • the product was obtained in the form of beige powder in the yield of 0.09 g (90%). 4.2% of water were measured by means of TGA.
  • Roxadustat (1.0 g, form A), which had been dissolved in acetone (66 ml) was dosed into a flask at the temperature of 50°C and subsequently, aqueous KOH was added (approx. 1.5 equivalents, 0.2 g of KOH dissolved in 6 ml of water). The product precipitated immediately after the addition. Then, the suspension was stirred at the temperature of 50°C for 17 h and for another 3 h at the temperature of 25°C. The crystalline product was aspirated on frit, washed with a minimal quantity of acetone and dried at a temperature of 35-40°C for 1 h in vacuum.
  • the product in the form of yellow powder was obtained in the yield of 0.87 g (78%), chemical purity 99.5% (measured with UHPLC).
  • the content of potassium was determined to be 8.6% by titration (10% theoretically).
  • An IR measurement confirmed formation of a salt.
  • Example 11 The mother liquor of Example 11 (containing 3.80 g of the potassium salt of roxadustat) was concentrated on a vacuum evaporator and ethanol was added by dripping to the obtained aqueous solution. The final mixture was concentrated on a rotary vacuum evaporator and the suspension was filtered and washed with ethanol. The product in the form of green powder was obtained in the yield of 3.78 g (99%), chemical purity 99.0% (measured with UHPLC).
  • the X-ray powder pattern is shown in Fig. 33
  • the DSC record is shown in Fig. 34
  • T t 120.5°C.
  • the sodium salt of roxadustat (10 g) was dissolved at 50°C in a methanohwater mixture with the ratio of 1:1 (280 ml).
  • a solution of calcium chloride (CaCl2-2H 2 0, 0.6 equivalents, 2.36 g) in a methanohwater mixture with the ratio of 1:1 (100 ml) was added to this solution by dripping at the temperature of 50°C.
  • the mixture was subsequently slowly cooled down to the laboratory temperature and stirred for 22 h.
  • the product was isolated by filtration and washed with 100 ml of a methanol: water mixture with the ratio of 1 :1 and dried in a vacuum drier at the temperature of 45°C for 20 h.
  • the crystalline product in the form of fine yellowish green powder was obtained in the yield of 6.4 g, chemical purity 99.74% (measured with UHPLC).
  • the X-ray powder pattern is shown in Fig. 38.
  • the X-ray powder pattern is shown in Fig. 40
  • the DSC record is shown in Fig. 41
  • T g 205°C.
  • the X-ray powder pattern is shown in Fig. 46
  • the DSC record is shown in Fig. 47
  • Tt 183°C.
  • the X-ray powder pattern is shown in Fig. 50
  • the DSC record is shown in Fig. 51
  • Tt 147°C.
  • Fig. 52 The X-ray powder pattern of roxadustat napsylate of form II is shown in Fig. 52, the DSC record is shown in Fig. 53; this is a non-solvated form with the melting point of 142°C.
  • the X-ray powder pattern is shown in Fig. 54
  • the DSC record is shown in Fig. 55
  • T t 155°C.
  • Fig. 58 The X-ray powder pattern of roxadustat tosylate of form II is shown in Fig. 58, the DSC record is shown in Fig. 59; this is a non-solvated form with the melting point of 149°C.
  • Fig. 60 The X-ray powder pattern of roxadustat tosylate of form III is shown in Fig. 60, the DSC record is shown in Fig. 61; this is a non-solvated form with the melting point of 183°C.
  • Fig. 62 The X-ray powder pattern of 3 -ethyl- 1 -methyl- lH-imidazol-3-ium roxadustat is shown in Fig. 62, the DSC record is shown in Fig. 63; this is a crystalline form with the melting point of 160°C.
  • Roxadustat 500 g, purity 99.34%) and caffeine (303 mg, 1.1 equiv.) were dosed into a flask and then suspended in acetonitrile (5 ml). The reaction mixture was stirred for 22 hours without the access of light at the room temperature (25°C). Then, the crystals were aspirated on frit, washed with acetonitrile (1 ml) and dried at 45 °C in vacuum (200 mbar) for 18 hours. This way, the amount of 715 mg (92%) of the product was obtained with the purity of 99.64%.
  • Fig. 68 The X-ray powder pattern of the caffeine cocrystal of roxadustat of form III is shown in Fig. 68, the DSC record is shown in Fig. 69; this is a crystalline form with the melting point of 175.3°C.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des formes à l'état solide de roxadustat sous le nom systématique de (4-hydroxy-1-méthyl-7-phénoxyisoquinoline-3-carbonyl)glycine de formule (I), leurs procédés de préparation et d'utilisation sous forme de médicament. Les formes à l'état solide de roxadustat de formule (I), selon l'invention sont préparées par une réaction de l'acide libre de roxadustat avec des co-formateurs appropriés (acides inorganiques ou organiques, bases, molécules neutres, ou sels ou paires d'ions) dans un solvant approprié ou des mélanges de solvants, le co-formateur est choisi dans le groupe constitué de méglumine, N,Ν'-dibenzylethylènediamine, tert-butylamine, diéthylamine, dicyclohexylamine, ammoniac, lithium, hydroxyde de potassium, sel de calcium, sel de magnésium, sel de fer (III), sel de fer (II), acide 2-naphtalènesulfonique, acide benzènesulfonique, acide p-toluènesulfonique, acétate de 3-éthyl-1-méthyl-1H-imidazol-3-ium et la caféine.
PCT/CZ2018/000039 2017-08-30 2018-08-30 Formes à l'état solide de roxadustat Ceased WO2019042485A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CZPV2017-503 2017-08-30
CZ2017-503A CZ2017503A3 (cs) 2017-08-30 2017-08-30 Pevné formy Roxadustatu
CZPV2018-277 2018-06-08
CZ2018-277A CZ2018277A3 (cs) 2018-06-08 2018-06-08 Pevné formy Roxadustatu

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WO2019042485A1 true WO2019042485A1 (fr) 2019-03-07

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CN111205224A (zh) * 2020-04-22 2020-05-29 南京佰麦生物技术有限公司 一种罗沙司他水合物的晶型及其制备方法和应用
WO2021077994A1 (fr) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Forme cristalline d'un inhibiteur de la prolyle hydroxylase du facteur inductible par hypoxie
CN113956200A (zh) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 一种粒径控制的罗沙司他原料药的结晶工艺
WO2022150623A1 (fr) * 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Composés et composition pour traiter l'anémie
WO2024194828A1 (fr) * 2023-03-23 2024-09-26 Ami Lifesciences Private Limited Formes solides de roxadustat avec de l'acide camphosulfonique

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021077994A1 (fr) 2019-10-22 2021-04-29 苏州科睿思制药有限公司 Forme cristalline d'un inhibiteur de la prolyle hydroxylase du facteur inductible par hypoxie
CN113015722A (zh) * 2019-10-22 2021-06-22 苏州科睿思制药有限公司 一种低氧诱导因子脯氨酰羟化酶抑制剂晶型
CN113015722B (zh) * 2019-10-22 2022-02-11 苏州科睿思制药有限公司 一种低氧诱导因子脯氨酰羟化酶抑制剂晶型
CN111205224A (zh) * 2020-04-22 2020-05-29 南京佰麦生物技术有限公司 一种罗沙司他水合物的晶型及其制备方法和应用
WO2022150623A1 (fr) * 2021-01-08 2022-07-14 Akebia Therapeutics, Inc. Composés et composition pour traiter l'anémie
CN113956200A (zh) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 一种粒径控制的罗沙司他原料药的结晶工艺
WO2024194828A1 (fr) * 2023-03-23 2024-09-26 Ami Lifesciences Private Limited Formes solides de roxadustat avec de l'acide camphosulfonique

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