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WO2020075199A1 - Polymorphic forms of vadadustat - Google Patents

Polymorphic forms of vadadustat Download PDF

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Publication number
WO2020075199A1
WO2020075199A1 PCT/IN2019/050759 IN2019050759W WO2020075199A1 WO 2020075199 A1 WO2020075199 A1 WO 2020075199A1 IN 2019050759 W IN2019050759 W IN 2019050759W WO 2020075199 A1 WO2020075199 A1 WO 2020075199A1
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Prior art keywords
vadadustat
crystal
proline
powder
ray diffraction
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PCT/IN2019/050759
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French (fr)
Inventor
Ramakoteswara Rao Jetti
Narasimha Murty PILLI
Srinivasarao PATHURI
Ramamohana Rao Golivi
Sureshbabu JAYACHANDRA
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Mylan Laboratories Ltd
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Mylan Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine

Definitions

  • the present invention relates to processes for the preparation of crystalline Form C of Vadadustat.
  • This invention also relates to Vadadustat co-crystals and processes for the preparation thereof.
  • Vadadustat was first disclosed in U.S Patent No. 7,81 1 ,595.
  • Vadadustat is chemically known as N-[[5- (3-chlorophenyl)-3-hydroxy-2-pyridinyl]carbonyl]glycine, having the following structure:
  • Vadadustat PCT Publication No. WO2015073779 discloses Vadadustat crystalline Form A, Form B and Form C.
  • the inventors of the present disclosure have developed a process for the preparation of crystalline Form C of Vadadustat.
  • This invention also relates to Vadadustat co-crystals and processes for their preparation.
  • a first aspect of the present invention is to provide an improved process for the preparation of crystalline Form C of Vadadustat, comprising the steps of:
  • step (b) cooling the solution to room temperature; c) adding the step (b) solution to an anti-solvent optionally containing a seed of crystalline form C of Vadadustat; and
  • Another aspect of the present invention is to provide a Vadadustat proline co-crystal.
  • Another aspect of the present invention is to provide a Vadadustat L-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 6.27, 18.72 and 25.14 ⁇ 0.2 degrees 2Q.
  • Vadadustat L-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 7.
  • Another aspect of the present invention is to provide a Vadadustat L-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.23, 15.72, 16.15 and 19.22 ⁇ 0.2 degrees 2Q.
  • Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 8.
  • Another aspect of the present invention is to provide a Vadadustat D-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 6.28, 18.73 and 25.13 + 0.2 degrees 2Q.
  • Vadadustat D-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 9.
  • Another aspect of the present invention is to provide a Vadadustat D-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.33, 15.83, 16.27 and 19.33 ⁇ 0.2 degrees 2Q.
  • Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 10.
  • Another aspect of the present invention is to provide a process for the preparation of Vadadustat Proline co-crystal, comprising the steps of:
  • Vadadustat caffeine co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 12.62, 25.1 1 , 25.92 and 26.19 ⁇ 0.2 degrees 2Q.
  • Vadadustat caffeine co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 1 1 .
  • Another aspect of the present invention is to provide a process for the preparation of Vadadustat caffeine co-crystal (1 :1 ) comprising suspending Vadadustat and caffeine in a solvent at room temperature and isolating Vadadustat caffeine co-crystal (1 :1 ).
  • Another aspect of the present invention is to provide a Vadadustat nicotinamide co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.75, 16.78, 17.61 and 18.44 + 0.2 degrees 2Q.
  • Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by the powder X- ray diffraction pattern shown in Figure 12.
  • Another aspect of the present invention is to provide a process for the preparation of Vadadustat nicotinamide co-crystal (1 :1 ) comprising the steps of:
  • step (a) adding the Vadadustat and a ketone solvent to the step (a) solution at 60 ⁇ 5°C temperature; c) cooling the reaction mass to a temperature of 25 ⁇ 5°C; and
  • Another aspect of the present invention is to provide a Vadadustat isonicotinamide co-crystal (2:1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.26, 15.29, 18.20 and 20.15 ⁇ 0.2 degrees 2Q.
  • Vadadustat isonicotinamide co-crystal (2:1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 13.
  • Another aspect of the present invention is to provide a process for the preparation of Vadadustat isonicotinamide co-crystal (2:1 ) comprising the steps of:
  • step (b) adding the Vadadustat and ketone solvent to step (a) suspension at 60 ⁇ 5°C temperature; c) cooling the reaction mass to a temperature of 25 ⁇ 5°C; and
  • Figure. 1 is an X-ray powder diffractogram of amorphous Vadadustat.
  • Figure. 2 is an X-ray powder diffractogram of crystalline form B of Vadadustat.
  • Figure. 3 is an X-ray powder diffractogram of crystalline form C of Vadadustat.
  • Figure. 4 is a differential scanning calorimetry (DSC) analysis of crystalline form C of Vadadustat.
  • Figure. 5 is a thermal gravimetric analysis (TGA) of crystalline form C of Vadadustat.
  • Figure. 6 is an X-ray powder diffractogram of crystalline form of Vadadustat prepared as per reference example.
  • Figure. 7 is an X-ray powder diffractogram of Vadadustat L-Proline co-crystal in the molar ratio of 1 :2.
  • Figure. 8 is an X-ray powder diffractogram of Vadadustat L-Proline co-crystal in the molar ratio of 1 :1 .
  • Figure. 9 is an X-ray powder diffractogram of Vadadustat D-Proline co-crystal in the molar ratio of 1 :2.
  • Figure. 10 is an X-ray powder diffractogram of Vadadustat D-Proline co-crystal in the molar ratio of 1 :1 .
  • FIG. 11 is an X-ray powder diffractogram of Vadadustat Caffeine co-crystal in the molar ratio of 1 :1 .
  • Figure. 12 is an X-ray powder diffractogram of Vadadustat Nicotinamide co-crystal in the molar ratio of 1 :1 .
  • Figure. 13 is an X-ray powder diffractogram of Vadadustat Isonicotinamide co-crystal in the molar ratio of 2:1 .
  • the present invention relates to a process for the preparation of crystalline Form C of Vadadustat.
  • This invention also relates to Vadadustat proline co-crystals and processes for their preparation thereof.
  • the term “about” when modifying a temperature measurement means the recited temperature plus or minus five degrees.
  • the term“about” when modifying an absolute measurement, such as time, mass, or volume means the recited value plus or minus 1 0% of the value.
  • the term“elevated temperature” means a temperature above 25°C and it is depending on the organic solvent ratio, water/organic solvent ratio and the concentration of Vadadustat.
  • parenthetical ratios such as“(1 :2)” and“(1 :1)” following a reference to a co-crystal designate the molar ratio of Vadadustat to the other component of the co-crystal.
  • the PXRD measurements were carried out using PAN analytical X'Pert PRO powder diffractometer equipped with goniometer of Q/Q configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the present invention relates to a process for the preparation of crystalline Form C of Vadadustat.
  • This invention also relates to Vadadustat proline co-crystals and processes for their preparation thereof.
  • the present invention provides a process for the preparation of amorphous Vadadustat comprising the steps of:
  • Vadadustat is dissolved in a mixture of organic solvent and water.
  • the solvent employed may include acetonitrile, acetone, 1 ,4-dioxane and tetrahydrofuran.
  • Vadadustat may be dissolved in a mixture of acetonitrile and water or mixture of 1 ,4-dioxane and water.
  • the organic solvent/water ratio employed is 5:1 to 1 :5.
  • the organic solvent/water ratio is 3:1 or 1 :1 .
  • Vadadustat may be dissolved at an elevated temperature about 50°C to about 65°C.
  • Vadadustat may be dissolved at about 55°C.
  • isolation of the amorphous Vadadustat can be done using any techniques in the art such as, lyophilization, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD and spray-drying.
  • the amorphous Vadadustat is isolated by lyophilization.
  • Vadadustat is dissolved in an organic solvent.
  • the solvent employed may include methanol, ethanol, isopropanol, n-butanol, 2-butanol, n- propanol, 2-propanol, 2-methyl-1 -propanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone.
  • Vadadustat may be dissolved in ethanol or methyl isobutyl ketone.
  • Vadadustat may be dissolved at an elevated temperature of about 55°C to about 70°C. In particular, in some useful embodiments of the present invention, Vadadustat may be dissolved at about 60°C.
  • the solution is then cooled to room temperature.
  • room temperature In particular, in some useful embodiments of the present invention, it is cooled to about 20°C-35°C.
  • isolation of crystalline Form B of Vadadustat can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation and distillation.
  • the crystalline Form B of Vadadustat is isolated by filtration.
  • Another embodiment of the present invention is to provide a process for the preparation of crystalline Form C of Vadadustat, comprising the steps of:
  • step (b) adding the step (b) solution to an anti-solvent optionally containing a seed of crystalline form-C of Vadadustat;
  • Vadadustat is dissolved in an ether solvent.
  • the ether solvent employed may include 1 ,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether and methyl tert-butyl ether.
  • Vadadustat may be dissolved in 2-methyltetrahydrofuran or methyl tert-butyl ether.
  • Vadadustat may be dissolved at an elevated temperature of about 45°C to about 60°C. In particular, in some useful embodiments of the present invention, Vadadustat may be dissolved at about 50°C.
  • Vadadustat clear solution is added to an anti-solvent optionally containing a seed of crystalline form C.
  • the anti-solvent employed for this embodiment may include heptane and hexane.
  • isolation of Vadadustat crystalline Form C can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation and distillation.
  • the crystalline Vadadustat Form C is isolated by filtration.
  • Another embodiment of the present invention relates to Vadadustat proline co-crystals.
  • Vadadustat L-Proline co-crystal (1 :2) is characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 6.27, 18.72 and 25.14 ⁇ 0.2 degrees 2Q.
  • the Vadadustat L-Proline co-crystal (1 :2) may be characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 1 .10, 1 1 .85, 16.27, 17.78, 18.72, 19.26, 19.50, 20.99, 21 .58, 22.40, 22.98, 23.29, 23.92, 24.66, 25.14, 25.47, 25.98, 26.47,
  • Vadadustat L-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 7.
  • Vadadustat L-Proline co-crystal (1 :1 ) is characterized by a powder X-ray diffraction pattern having peaks at 10.23, 15.72, 16.15 and 19.22 ⁇ 0.2 degrees 2Q.
  • Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 5.22, 6.43, 6.77, 8.38, 8.86,
  • Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 8.
  • Vadadustat D-Proline co-crystal (1 :2) that may be characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 6.28, 18.73 and 25.13 + 0.2 degrees 2Q.
  • the Vadadustat D-Proline co-crystal (1 :2) may be characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 1 .1 1 , 1 1 .85, 16.28, 17.78, 18.73, 19.50, 20.96, 21 .57, 22.40, 23.27, 23.89, 24.62, 25.13, 25.42, 25.97, 26.44, 26.80, 27.81 , 28.73, 29.31 , 30.14, 30.54, 31 .73, 32.40, 33.06, 33.55, 34.64, 36.03, 36.97, 38.03, 39.20, 40.25, 42.00, 42.60, 42.92, 44.02 ⁇ 0.2 degrees 2Q.
  • Vadadustat D-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 9.
  • Vadadustat D-Proline co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 10.33, 15.83, 16.27 and 19.33 ⁇ 0.2 degrees 2Q.
  • the Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 5.34, 6.53, 6.88, 8.49, 8.99, 10.33, 10.88, 1 1 .51 , 12.02, 12.99, 15.83, 16.27, 16.93, 17.33, 17.80, 18.17, 19.33, 20.27, 20.57, 21 .05, 21 .91 , 22.45, 22.76, 23.37, 24.05, 25.05, 25.20, 26.12, 27.22, 28.19, 29.49, 30.27, 31 .38, 32.61 , 33.60, 34.99, 36.60, 37.59, 39.95, 41 .35 ⁇ 0.2 degrees 2Q.
  • Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 10.
  • the process may include contacting Vadadustat and proline in an organic solvent at room temperature to form a suspension, heating the suspension to 55°C-70°C, slowly cooling the reaction mixture to room temperature and filtering the reaction mass to get Vadadustat praline co-crystal.
  • the reaction mixture may be heated to about 60°C-65°C.
  • the solvents may be selected from ketones and alcohols.
  • the ketonic solvents include, but are not limited to acetone, methyl isobutyl ketone or methyl ethyl ketone and mixtures thereof.
  • the suitable ketonic solvent is acetone.
  • Alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol or t-butanol.
  • the suitable alcohol solvent is methanol.
  • proline is selected from L-Proline, D-Proline or DL-Proline.
  • isolation of Vadadustat co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, or distillation.
  • the Vadadustat co-crystal is isolated by filtration.
  • the molar ratio of Vadadustat to proline is about 1 to 2.
  • Vadadustat caffeine co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 12.62, 25.1 1 , 25.92 and 26.19 ⁇ 0.2 degrees 2Q.
  • the Vadadustat caffeine co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 8.27, 12.62, 12.89, 14.42, 15.13, 17.18, 19.85, 20.40, 22.16, 22.49, 22.99, 23.83, 24.78, 25.1 1 , 25.92, 26.19, 26.75, 27.63, 27.97, 28.58, 29.10, 30.13, 30.65 ⁇ 0.2 degrees 2Q.
  • Vadadustat caffeine co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 1 1 .
  • Another embodiment of the present invention is a process for the preparation of Vadadustat caffeine co-crystal (1 :1 ) comprising: suspending Vadadustat and caffeine in a solvent at room temperature and isolating Vadadustat caffeine co-crystals (1 :1 ).
  • Vadadustat and caffeine may be suspended in a solvent at room temperature.
  • the solvents may be selected from acetonitrile, tetrahydrofuran and acetone.
  • the solvent is acetonitrile.
  • isolation of Vadadustat caffeine co crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation.
  • the Vadadustat caffeine co-crystal is isolated by filtration.
  • Vadadustat nicotinamide co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 14.75, 16.78, 17.61 and 18.44 ⁇ 0.2 degrees 2Q.
  • the Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 7.39, 14.75, 16.78, 17.61 , 18.44, 23.16, 23.91 , 26.51 , 27.06, 28.40 ⁇ 0.2 degrees 2Q.
  • Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 12.
  • Another embodiment of the present invention is a process for the preparation of Vadadustat nicotinamide co-crystal (1 :1 ) comprising the steps of:
  • step (a) adding the Vadadustat and a ketone solvent to step (a) solution at 60 ⁇ 5°C temperature; c) cooling the reaction mass to a temperature of 25 ⁇ 5°C; and
  • Suitable alcohol solvents include methanol, ethanol and isopropanol.
  • the alcohol solvent is ethanol.
  • Suitable ketone solvents include acetone, methyl ethyl ketone and Methyl iso butyl ketone.
  • the ketone solvent is methyl ethyl ketone.
  • Vadadustat nicotinamide co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation.
  • the Vadadustat nicotinamide co-crystal is isolated by filtration.
  • Vadadustat isonicotinamide co-crystal (2:1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 14.26, 15.29, 18.20 and 20.15 ⁇ 0.2 degrees 2Q.
  • Vadadustat Isonicotinamide co crystal (2:1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 7.71 , 14.26, 15.29, 15.79, 18.20, 20.15, 25.86, 29.21 , 29.54, 30.45 ⁇ 0.2 degrees 20.
  • Vadadustat Isonicotinamide co-crystal (2:1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 13.
  • Another embodiment of the present invention is t a process for the preparation of Vadadustat isonicotinamide co-crystal (2:1 ) comprising the steps of:
  • step (a) adding the Vadadustat and a ketone solvent to step (a) suspension at 60+5°C temperature; c) cooling the reaction mass to a temperature of 25 ⁇ 5°C; and
  • Suitable alcohol solvents include methanol, ethanol and isopropanol. Preferably the alcohol solvent is ethanol.
  • Suitable ketone solvents include acetone, methyl ethyl ketone and methyl iso butyl ketone. Preferably the ketone solvent is methyl ethyl ketone.
  • Vadadustat isonicotinamide co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation.
  • the Vadadustat nicotinamide co-crystal is isolated by filtration.
  • Vadadustat form C was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD and HPLC. The Vadadustat form C was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
  • the physical stability of 1 :1 co-crystal of Vadadustat L-Proline was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD. The 1 :1 co-crystal of Vadadustat L-Proline was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
  • the physical stability of 1 :1 co-crystal of Vadadustat D-Proline was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD. The 1 :1 co-crystal of Vadadustat D-Proline was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
  • the physical stability of 1 :2 co-crystal of Vadadustat L-Proline was determined by storing at 25°C/60% relative humidity (RH) conditions for two months as mentioned below in Table 2. The samples were then analyzed by PXRD. The 1 :2 co-crystal of Vadadustat L-Proline was found to be physically stable at 25°C/60% relative humidity (RH) up to two months.
  • the physical stability of 1 :2 co-crystal of Vadadustat D-Proline was determined by storing at 25°C/60% relative humidity (RH) conditions for two months as mentioned below in Table 2. The samples then were analyzed by PXRD. The 1 :2 co-crystal of Vadadustat D- Proline was found to be physically stable at 25°C/60% relative humidity (RH) up to two months. Table 1
  • Example 4 discloses a process for preparation of Vadadustat.
  • the US ‘366 patent process involves hydrolysis of Vadadustat methyl ester (obtained as per Example 3 and 4 of US’366) with sodium hydroxide, followed by acidifying the reaction mass with hydrochloric acid resulting in crude Vadadustat, which, upon slurrying in hot water, resulted in pure Vadadustat as an off- white solid.
  • the US ‘366 patent does not disclose any polymorphic information on the resulting Vadadustat.
  • Vadadustat crude (13g) obtained as per example 4 of U.S. Patent No. 9,145,366 B2 was suspended in deionized water (1 05mL) at 25 ⁇ 2°C. The suspension was heated to 70 ⁇ 2°C and maintained for 16 hours at 70 ⁇ 2°C. The reaction mass was then cooled to 25 ⁇ 2°C and stirred for 2 hours at 25 ⁇ 2°C. The reaction mass was then filtered, washed with deionized water (13mL) and dried under vacuum at 50°C for 15 hours. The powder X-ray diffractogram of pure Vadadustat obtained according to US 9145366B2 is shown in Figure 4.
  • Vadadustat (200mg) was dissolved in a mixture of acetonitrile (6mL) and water (2mL) at 55 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Vadadustat.
  • Vadadustat (200mg) was dissolved in a mixture of 1 ,4-dioxane (2mL) and water (2mL) at 55 ⁇ 5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Vadadustat.
  • Vadadustat (200mg) was dissolved in ethanol (2mL) at 60 ⁇ 2°C and maintained for 1 h at 60 ⁇ 2°C. The clear solution was cooled to 25 ⁇ 2°C and maintained under stirring for 1 6 hours at 25 ⁇ 2°C. The reaction mass was filtered, and the solid obtained was identified as crystalline Vadadustat Form B.
  • Vadadustat (50mg) was dissolved in methyl isobutyl ketone (MIBK) (1 mL) at 60 ⁇ 2°C and maintained for 1 hour at 60 ⁇ 2°C. The reaction mass was cooled to 25 ⁇ 2°C and maintained under stirring for 16 hours at 25 ⁇ 2°C. The reaction mass was filtered, and the solid obtained was identified as crystalline Vadadustat Form B.
  • MIBK methyl isobutyl ketone
  • Example 7 Process for the preparation of Vadadustat L-Proline co-crystal (1 :2)
  • Vadadustat (1 .0g), L-Proline (0.38g) and acetone (20mL) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 15-30 minutes at 60-65°C.
  • the reaction mass was slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the product obtained was filtered and dried under vacuum for 4 hours at 35°C.
  • the solid obtained was identified as 1 :2 co crystal of Vadadustat L-Proline. Yield: 0.78g
  • Example 8 Process for the preparation of Vadadustat L-Proline co-crystal (1 :2)
  • Vadadustat (4.0g), L-Proline (2.85g) and acetone (60mL) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 60 minutes at 60-65°C.
  • the reaction mass was slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the product obtained was filtered, washed with acetone (8 mL) and dried under vacuum for 16 hours at 40°C.
  • the solid obtained was identified as 1 :2 co-crystal of Vadadustat L-Proline. Yield: 6.1 g
  • Example 9 Process for the preparation of Vadadustat D-Proline co-crystal (1 :2)
  • Vadadustat (0.5g), D-Proline (0.36g) and acetone (8mL) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C.
  • the reaction mass was slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the product obtained was filtered, washed with acetone (2 mL) and dried under vacuum for 16 hours at 40°C.
  • the solid obtained was identified as 1 :2 co-crystal of Vadadustat D-Proline. Yield: 0.76g
  • Example 10 Process for the preparation of Vadadustat L-Proline co-crystal (1 :1)
  • Vadadustat (0.5g), L-Proline (0.36g) and methanol (8mL) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C.
  • the reaction mass was slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the product obtained was filtered and dried under vacuum for 16 hours at 40°C.
  • the solid obtained was identified as 1 :1 co crystal of Vadadustat L-Proline. Yield: 0.47g
  • Example 11 Process for the preparation of Vadadustat D-Proline co-crystal (1 :1)
  • Vadadustat (1 .0g), D-Proline (0.71 g) and methanol (16mL) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C.
  • the reaction mass was slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the product obtained was filtered, washed with prechilled methanol (1 mL) and dried under vacuum for 16 hours at 40°C.
  • the solid obtained was identified as 1 :1 co-crystal of Vadadustat D-Proline. Yield: 0.86g.
  • Example 12 Process for the preparation of Vadadustat caffeine co-crystal (1 :1)
  • Vadadustat (0.5g), caffeine (0.35g) and acetonitrile (5mL) were charged in a RBF at 25 ⁇ 5°C. The reaction mass was maintained under stirring at 25 ⁇ 5°C for 16 hours. The product obtained was filtered and dried under vacuum for 3 hours at 40°C. The solid obtained was identified as 1 :1 co-crystal of Vadadustat Caffeine. Yield: 0.55g.
  • Example 13 Process for the preparation of Vadadustat nicotinamide co-crystal (1 :1)
  • Ethanol (1 5mL) and nicotinamide (0.2g) were charged in a RBF at 25 ⁇ 5°C and the contents were heated to 60-65°C and stirred for 30 min at 60-65°C.
  • Methyl ethyl ketone (15mL) and Vadadustat (0.5g) were charged into the reaction mass at 60-65°C.
  • the reaction mass was stirred for 30 minutes at 60- 65°C.
  • the mass was then slowly cooled to 25 ⁇ 5°C and maintained under stirring at 25 ⁇ 5°C for 16 hours.
  • the reaction mass was cooled to 0-5°C and stirred for 2-3 hours.
  • Example 14 Process for the preparation of Vadadustat isonicotinamide co-crystal (2:1)

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Abstract

Described is a process for the preparation of crystalline Form C of Vadadustat. Also described are Vadadustat co-crystals and processes for the preparation thereof.

Description

POLYMORPHIC FORMS OF VADADUSTAT
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. IN201 9410081 54 filed on March 1 , 2019; and Indian provisional patent application No. IN201841038858 filed on October 12, 2018, the entire contents of each of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to processes for the preparation of crystalline Form C of Vadadustat. This invention also relates to Vadadustat co-crystals and processes for the preparation thereof.
BACKGROUND OF THE INVENTION Vadadustat was first disclosed in U.S Patent No. 7,81 1 ,595. Vadadustat is chemically known as N-[[5- (3-chlorophenyl)-3-hydroxy-2-pyridinyl]carbonyl]glycine, having the following structure:
Figure imgf000002_0001
Vadadustat PCT Publication No. WO2015073779 discloses Vadadustat crystalline Form A, Form B and Form C.
The inventors of the present disclosure have developed a process for the preparation of crystalline Form C of Vadadustat. This invention also relates to Vadadustat co-crystals and processes for their preparation.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide an improved process for the preparation of crystalline Form C of Vadadustat, comprising the steps of:
a) dissolving Vadadustat in an ether solvent at elevated temperature;
b) cooling the solution to room temperature; c) adding the step (b) solution to an anti-solvent optionally containing a seed of crystalline form C of Vadadustat; and
d) isolating the crystalline Form C of Vadadustat.
Another aspect of the present invention is to provide a Vadadustat proline co-crystal.
Another aspect of the present invention is to provide a Vadadustat L-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 6.27, 18.72 and 25.14 ± 0.2 degrees 2Q.
In a specific aspect, Vadadustat L-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 7.
Another aspect of the present invention is to provide a Vadadustat L-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.23, 15.72, 16.15 and 19.22 ± 0.2 degrees 2Q.
In a specific aspect, Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 8.
Another aspect of the present invention is to provide a Vadadustat D-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 6.28, 18.73 and 25.13 + 0.2 degrees 2Q.
In a specific aspect, Vadadustat D-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 9.
Another aspect of the present invention is to provide a Vadadustat D-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.33, 15.83, 16.27 and 19.33 ± 0.2 degrees 2Q.
In a specific aspect, Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 10.
Another aspect of the present invention is to provide a process for the preparation of Vadadustat Proline co-crystal, comprising the steps of:
a) mixing Vadadustat with proline in a solvent to form a suspension ;
b) heating the suspension to 55-70°C;
c) slowly cooling the suspension to room temperature; and
d) isolating Vadadustat proline co-crystal from the suspension. Another aspect of the present invention is to provide a Vadadustat caffeine co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 12.62, 25.1 1 , 25.92 and 26.19 ± 0.2 degrees 2Q.
In a specific aspect, Vadadustat caffeine co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 1 1 .
Another aspect of the present invention is to provide a process for the preparation of Vadadustat caffeine co-crystal (1 :1 ) comprising suspending Vadadustat and caffeine in a solvent at room temperature and isolating Vadadustat caffeine co-crystal (1 :1 ).
Another aspect of the present invention is to provide a Vadadustat nicotinamide co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.75, 16.78, 17.61 and 18.44 + 0.2 degrees 2Q.
In a specific aspect, Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by the powder X- ray diffraction pattern shown in Figure 12.
Another aspect of the present invention is to provide a process for the preparation of Vadadustat nicotinamide co-crystal (1 :1 ) comprising the steps of:
a) dissolving nicotinamide in alcohol solvent at a temperature of 60±5°C;
b) adding the Vadadustat and a ketone solvent to the step (a) solution at 60±5°C temperature; c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat nicotinamide co-crystal.
Another aspect of the present invention is to provide a Vadadustat isonicotinamide co-crystal (2:1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.26, 15.29, 18.20 and 20.15 ± 0.2 degrees 2Q.
In a specific aspect, Vadadustat isonicotinamide co-crystal (2:1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 13.
Another aspect of the present invention is to provide a process for the preparation of Vadadustat isonicotinamide co-crystal (2:1 ) comprising the steps of:
a) suspending isonicotinamide in alcohol solvent at a temperature of 60±5°C;
b) adding the Vadadustat and ketone solvent to step (a) suspension at 60±5°C temperature; c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat isonicotinamide co-crystal. BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present invention together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure, which are shown in the accompanying drawing figures wherein :
Figure. 1 is an X-ray powder diffractogram of amorphous Vadadustat.
Figure. 2 is an X-ray powder diffractogram of crystalline form B of Vadadustat.
Figure. 3 is an X-ray powder diffractogram of crystalline form C of Vadadustat.
Figure. 4 is a differential scanning calorimetry (DSC) analysis of crystalline form C of Vadadustat. Figure. 5 is a thermal gravimetric analysis (TGA) of crystalline form C of Vadadustat.
Figure. 6 is an X-ray powder diffractogram of crystalline form of Vadadustat prepared as per reference example.
Figure. 7 is an X-ray powder diffractogram of Vadadustat L-Proline co-crystal in the molar ratio of 1 :2. Figure. 8 is an X-ray powder diffractogram of Vadadustat L-Proline co-crystal in the molar ratio of 1 :1 . Figure. 9 is an X-ray powder diffractogram of Vadadustat D-Proline co-crystal in the molar ratio of 1 :2. Figure. 10 is an X-ray powder diffractogram of Vadadustat D-Proline co-crystal in the molar ratio of 1 :1 . Figure. 11 is an X-ray powder diffractogram of Vadadustat Caffeine co-crystal in the molar ratio of 1 :1 . Figure. 12 is an X-ray powder diffractogram of Vadadustat Nicotinamide co-crystal in the molar ratio of 1 :1 .
Figure. 13 is an X-ray powder diffractogram of Vadadustat Isonicotinamide co-crystal in the molar ratio of 2:1 .
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of crystalline Form C of Vadadustat. This invention also relates to Vadadustat proline co-crystals and processes for their preparation thereof.
Within the context of the present disclosure, the term “about” when modifying a temperature measurement means the recited temperature plus or minus five degrees. Within the context of the present disclosure, the term“about” when modifying an absolute measurement, such as time, mass, or volume, means the recited value plus or minus 1 0% of the value.
Wthin the context of the present disclosure, the term“elevated temperature” means a temperature above 25°C and it is depending on the organic solvent ratio, water/organic solvent ratio and the concentration of Vadadustat.
As used herein, parenthetical ratios such as“(1 :2)” and“(1 :1)” following a reference to a co-crystal designate the molar ratio of Vadadustat to the other component of the co-crystal. The PXRD measurements were carried out using PAN analytical X'Pert PRO powder diffractometer equipped with goniometer of Q/Q configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
The present invention relates to a process for the preparation of crystalline Form C of Vadadustat. This invention also relates to Vadadustat proline co-crystals and processes for their preparation thereof.
In an embodiment, the present invention provides a process for the preparation of amorphous Vadadustat comprising the steps of:
a) dissolving Vadadustat in a mixture of organic solvent and water at elevated temperature ; b) cooling the solution to room temperature; and
c) isolating the amorphous Vadadustat.
Within the context of this embodiment of the present invention, Vadadustat is dissolved in a mixture of organic solvent and water. The solvent employed may include acetonitrile, acetone, 1 ,4-dioxane and tetrahydrofuran. In particular, useful embodiments of the present invention, Vadadustat may be dissolved in a mixture of acetonitrile and water or mixture of 1 ,4-dioxane and water.
Within the context of this embodiment of the present invention, the organic solvent/water ratio employed is 5:1 to 1 :5. In particular, useful embodiments, the organic solvent/water ratio is 3:1 or 1 :1 .
Within the context of this embodiment, Vadadustat may be dissolved at an elevated temperature about 50°C to about 65°C. In particular, useful embodiments, of the present invention, Vadadustat may be dissolved at about 55°C.
Within the context of this embodiment of the present invention, isolation of the amorphous Vadadustat can be done using any techniques in the art such as, lyophilization, decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation, ATFD and spray-drying. In particular, useful embodiments of the present invention, the amorphous Vadadustat is isolated by lyophilization.
Another embodiment of the present invention is to provide a process for the preparation of crystalline Form B of Vadadustat comprising the steps of:
a) dissolving Vadadustat in an organic solvent at elevated temperature;
b) cooling the solution to room temperature; and
c) isolating the crystalline Form B of Vadadustat.
Within the context of this embodiment of the present invention, Vadadustat is dissolved in an organic solvent. The solvent employed may include methanol, ethanol, isopropanol, n-butanol, 2-butanol, n- propanol, 2-propanol, 2-methyl-1 -propanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and acetone. In particular, useful embodiments of the present invention, Vadadustat may be dissolved in ethanol or methyl isobutyl ketone.
Within the context of this embodiment, Vadadustat may be dissolved at an elevated temperature of about 55°C to about 70°C. In particular, in some useful embodiments of the present invention, Vadadustat may be dissolved at about 60°C.
Within the context of this embodiment of the present invention, the solution is then cooled to room temperature. In particular, in some useful embodiments of the present invention, it is cooled to about 20°C-35°C.
Within the context of this embodiment of the present invention, isolation of crystalline Form B of Vadadustat can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation and distillation. In particular, useful embodiments of the present invention, the crystalline Form B of Vadadustat is isolated by filtration.
Another embodiment of the present invention is to provide a process for the preparation of crystalline Form C of Vadadustat, comprising the steps of:
a) dissolving Vadadustat in an ether solvent at elevated temperature;
b) cooling the solution to room temperature;
c) adding the step (b) solution to an anti-solvent optionally containing a seed of crystalline form-C of Vadadustat; and
d) isolating the crystalline Form C of Vadadustat.
Within the context of this embodiment of the present invention, Vadadustat is dissolved in an ether solvent. The ether solvent employed may include 1 ,4-dioxane, tetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether and methyl tert-butyl ether. In particular, useful embodiments of the present invention, Vadadustat may be dissolved in 2-methyltetrahydrofuran or methyl tert-butyl ether.
Within the context of this embodiment, Vadadustat may be dissolved at an elevated temperature of about 45°C to about 60°C. In particular, in some useful embodiments of the present invention, Vadadustat may be dissolved at about 50°C.
Within the context of this embodiment, Vadadustat clear solution is added to an anti-solvent optionally containing a seed of crystalline form C. The anti-solvent employed for this embodiment may include heptane and hexane.
Within the context of this embodiment of the present invention, isolation of Vadadustat crystalline Form C can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation and distillation. In particular, useful embodiments of the present invention, the crystalline Vadadustat Form C is isolated by filtration.
Another embodiment of the present invention relates to Vadadustat proline co-crystals.
Another embodiment of the present invention, is a Vadadustat L-Proline co-crystal (1 :2) that may be characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 6.27, 18.72 and 25.14 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat L-Proline co-crystal (1 :2) may be characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 1 .10, 1 1 .85, 16.27, 17.78, 18.72, 19.26, 19.50, 20.99, 21 .58, 22.40, 22.98, 23.29, 23.92, 24.66, 25.14, 25.47, 25.98, 26.47,
26.84, 27.82, 28.77, 29.32, 29.73, 30.16, 30.56, 31 .77, 32.44, 33.07, 33.61 , 33.88, 34.64, 35.55, 36.08,
37.05, 37.54, 38.05, 39.25, 40.26, 41 .98, 42.89, 44.03, 46.09, 46.72, 47.41 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat L-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 7.
Another embodiment of the present invention, is a Vadadustat L-Proline co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 10.23, 15.72, 16.15 and 19.22 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 5.22, 6.43, 6.77, 8.38, 8.86,
10.23. 10.46, 10.75, 1 1 .39, 1 1 .91 , 12.88, 15.72, 16.15, 16.80, 17.23, 17.80, 18.03, 18.69, 19.22, 20.16,
20.46, 20.97, 21 .80, 22.35, 22.64, 23.24, 23.97, 24.27, 24.65, 25.1 1 , 25.96, 26.39, 27.09, 27.83, 28.13,
29.38, 30.25, 31 .26, 32.53, 33.50, 33.67, 34.91 , 36.36, 37.49, 38.43, 38.98, 39.94, 40.69, 41 .32, 41 .86,
43.20, 44.40, 45.08, 46.26, 46.75, 46.75, 48.27 49.17 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat L-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 8.
Another embodiment of the present invention is a Vadadustat D-Proline co-crystal (1 :2) that may be characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 6.28, 18.73 and 25.13 + 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat D-Proline co-crystal (1 :2) may be characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 1 .1 1 , 1 1 .85, 16.28, 17.78, 18.73, 19.50, 20.96, 21 .57, 22.40, 23.27, 23.89, 24.62, 25.13, 25.42, 25.97, 26.44, 26.80, 27.81 , 28.73, 29.31 , 30.14, 30.54, 31 .73, 32.40, 33.06, 33.55, 34.64, 36.03, 36.97, 38.03, 39.20, 40.25, 42.00, 42.60, 42.92, 44.02 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat D-Proline co-crystal (1 :2) may be characterized by the powder X-ray diffraction pattern shown in Figure 9.
Another embodiment of the present invention is a Vadadustat D-Proline co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 10.33, 15.83, 16.27 and 19.33 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 5.34, 6.53, 6.88, 8.49, 8.99, 10.33, 10.88, 1 1 .51 , 12.02, 12.99, 15.83, 16.27, 16.93, 17.33, 17.80, 18.17, 19.33, 20.27, 20.57, 21 .05, 21 .91 , 22.45, 22.76, 23.37, 24.05, 25.05, 25.20, 26.12, 27.22, 28.19, 29.49, 30.27, 31 .38, 32.61 , 33.60, 34.99, 36.60, 37.59, 39.95, 41 .35 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat D-Proline co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 10.
Another embodiment of the present invention is t a process for the preparation of Vadadustat Proline co-crystal comprising the steps of:
a) mixing Vadadustat with proline in a solvent to form a suspension;
b) heating the suspension to 55-70°C;
c) slowly cooling the suspension to room temperature; and
d) isolating Vadadustat proline co-crystal.
Within the context of the present disclosure, the process may include contacting Vadadustat and proline in an organic solvent at room temperature to form a suspension, heating the suspension to 55°C-70°C, slowly cooling the reaction mixture to room temperature and filtering the reaction mass to get Vadadustat praline co-crystal. In particularly useful embodiments, the reaction mixture may be heated to about 60°C-65°C. The solvents may be selected from ketones and alcohols. The ketonic solvents include, but are not limited to acetone, methyl isobutyl ketone or methyl ethyl ketone and mixtures thereof. Preferably the suitable ketonic solvent is acetone. Alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol or t-butanol. Preferably the suitable alcohol solvent is methanol.
Within the context of the present disclosure, proline is selected from L-Proline, D-Proline or DL-Proline.
Within the context of this embodiment of the present invention, isolation of Vadadustat co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, or distillation. In particularly useful embodiments of the present invention, the Vadadustat co-crystal is isolated by filtration.
Another embodiment of the present invention, the molar ratio of Vadadustat to proline is about 1 to 2.
Another embodiment of the present invention is a Vadadustat caffeine co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 12.62, 25.1 1 , 25.92 and 26.19 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat caffeine co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 8.27, 12.62, 12.89, 14.42, 15.13, 17.18, 19.85, 20.40, 22.16, 22.49, 22.99, 23.83, 24.78, 25.1 1 , 25.92, 26.19, 26.75, 27.63, 27.97, 28.58, 29.10, 30.13, 30.65 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat caffeine co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 1 1 .
Another embodiment of the present invention is a process for the preparation of Vadadustat caffeine co-crystal (1 :1 ) comprising: suspending Vadadustat and caffeine in a solvent at room temperature and isolating Vadadustat caffeine co-crystals (1 :1 ).
Within the context of this embodiment of the present invention, Vadadustat and caffeine may be suspended in a solvent at room temperature. The solvents may be selected from acetonitrile, tetrahydrofuran and acetone. Preferably the solvent is acetonitrile.
Within the context of this embodiment of the present invention, isolation of Vadadustat caffeine co crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation. In particular, useful embodiments of the present invention, the Vadadustat caffeine co-crystal is isolated by filtration.
Another embodiment of the present invention is a Vadadustat nicotinamide co-crystal (1 :1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 14.75, 16.78, 17.61 and 18.44 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 7.39, 14.75, 16.78, 17.61 , 18.44, 23.16, 23.91 , 26.51 , 27.06, 28.40 ± 0.2 degrees 2Q.
In another embodiment, the Vadadustat nicotinamide co-crystal (1 :1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 12. Another embodiment of the present invention is a process for the preparation of Vadadustat nicotinamide co-crystal (1 :1 ) comprising the steps of:
a) dissolving nicotinamide in alcohol solvent at a temperature of 60±5°C;
b) adding the Vadadustat and a ketone solvent to step (a) solution at 60±5°C temperature; c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat nicotinamide co-crystal.
Suitable alcohol solvents include methanol, ethanol and isopropanol. Preferably the alcohol solvent is ethanol.
Suitable ketone solvents include acetone, methyl ethyl ketone and Methyl iso butyl ketone. Preferably the ketone solvent is methyl ethyl ketone.
Isolation of Vadadustat nicotinamide co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation. In particular useful embodiments of the present invention the Vadadustat nicotinamide co-crystal is isolated by filtration.
Another embodiment of the present invention is a Vadadustat isonicotinamide co-crystal (2:1 ) that may be characterized by a powder X-ray diffraction pattern having peaks at 14.26, 15.29, 18.20 and 20.15 ± 0.2 degrees 2Q.
Within the context of this embodiment of the present invention, the Vadadustat Isonicotinamide co crystal (2:1 ) may be characterized by a powder X-ray diffraction pattern having peaks at 7.71 , 14.26, 15.29, 15.79, 18.20, 20.15, 25.86, 29.21 , 29.54, 30.45± 0.2 degrees 20.
In another embodiment, the Vadadustat Isonicotinamide co-crystal (2:1 ) may be characterized by the powder X-ray diffraction pattern shown in Figure 13.
Another embodiment of the present invention is t a process for the preparation of Vadadustat isonicotinamide co-crystal (2:1 ) comprising the steps of:
a) suspending isonicotinamide in alcohol solvent at a temperature of 60±5°C;
b) adding the Vadadustat and a ketone solvent to step (a) suspension at 60+5°C temperature; c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat isonicotinamide co-crystal.
Suitable alcohol solvents include methanol, ethanol and isopropanol. Preferably the alcohol solvent is ethanol. Suitable ketone solvents include acetone, methyl ethyl ketone and methyl iso butyl ketone. Preferably the ketone solvent is methyl ethyl ketone.
Isolation of Vadadustat isonicotinamide co-crystal can be done using any techniques in the art such as decantation, filtration by gravity or suction, centrifugation, slow evaporation, distillation. In particular, in some useful embodiments of the present invention, the Vadadustat nicotinamide co-crystal is isolated by filtration.
Indicative stability:
In one embodiment, the physical and chemical stability of Vadadustat form C was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD and HPLC. The Vadadustat form C was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
In yet another embodiment, the physical stability of 1 :1 co-crystal of Vadadustat L-Proline was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD. The 1 :1 co-crystal of Vadadustat L-Proline was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
In yet another embodiment, the physical stability of 1 :1 co-crystal of Vadadustat D-Proline was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for three months as mentioned below in Table 1 . The samples were then analyzed by PXRD. The 1 :1 co-crystal of Vadadustat D-Proline was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to three months.
In yet another embodiment, the physical stability of 1 :2 co-crystal of Vadadustat L-Proline was determined by storing at 25°C/60% relative humidity (RH) conditions for two months as mentioned below in Table 2. The samples were then analyzed by PXRD. The 1 :2 co-crystal of Vadadustat L-Proline was found to be physically stable at 25°C/60% relative humidity (RH) up to two months.
In yet another embodiment, the physical stability of 1 :2 co-crystal of Vadadustat D-Proline was determined by storing at 25°C/60% relative humidity (RH) conditions for two months as mentioned below in Table 2. The samples then were analyzed by PXRD. The 1 :2 co-crystal of Vadadustat D- Proline was found to be physically stable at 25°C/60% relative humidity (RH) up to two months. Table 1
Figure imgf000013_0001
Table 2
Figure imgf000013_0002
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
EXAMPLES U.S. Patent No. 9,145,366 B2, Example 4 discloses a process for preparation of Vadadustat. The US ‘366 patent process involves hydrolysis of Vadadustat methyl ester (obtained as per Example 3 and 4 of US’366) with sodium hydroxide, followed by acidifying the reaction mass with hydrochloric acid resulting in crude Vadadustat, which, upon slurrying in hot water, resulted in pure Vadadustat as an off- white solid. The US ‘366 patent does not disclose any polymorphic information on the resulting Vadadustat.
Comparative Example 1 : Repetition of process according to Example 4 of US 9145366
Vadadustat crude (13g) obtained as per example 4 of U.S. Patent No. 9,145,366 B2 was suspended in deionized water (1 05mL) at 25±2°C. The suspension was heated to 70±2°C and maintained for 16 hours at 70±2°C. The reaction mass was then cooled to 25±2°C and stirred for 2 hours at 25±2°C. The reaction mass was then filtered, washed with deionized water (13mL) and dried under vacuum at 50°C for 15 hours. The powder X-ray diffractogram of pure Vadadustat obtained according to US 9145366B2 is shown in Figure 4.
Working Examples
Example 1 : Preparation of Amorphous form of Vadadustat
Vadadustat (200mg) was dissolved in a mixture of acetonitrile (6mL) and water (2mL) at 55±5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Vadadustat.
Example 2: Preparation of Amorphous form of Vadadustat
Vadadustat (200mg) was dissolved in a mixture of 1 ,4-dioxane (2mL) and water (2mL) at 55±5°C. The resulting clear solution was filtered to remove any undissolved particulate and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield amorphous form of Vadadustat.
Example 3: Preparation of crystalline Form B of Vadadustat
Vadadustat (200mg) was dissolved in ethanol (2mL) at 60±2°C and maintained for 1 h at 60±2°C. The clear solution was cooled to 25±2°C and maintained under stirring for 1 6 hours at 25±2°C. The reaction mass was filtered, and the solid obtained was identified as crystalline Vadadustat Form B.
Example 4: Preparation of crystalline Form B of Vadadustat
Vadadustat (50mg) was dissolved in methyl isobutyl ketone (MIBK) (1 mL) at 60±2°C and maintained for 1 hour at 60±2°C. The reaction mass was cooled to 25±2°C and maintained under stirring for 16 hours at 25±2°C. The reaction mass was filtered, and the solid obtained was identified as crystalline Vadadustat Form B.
Example 5: Preparation of crystalline Form C of Vadadustat
Vadadustat (0.5g) and methyl tert-butyl ether (MTBE) (20 mL) were charged in a round-bottom flask (RBF) at 25+5°C and heated to 50+5°C, The reaction mass was stirred for 30 minutes, and the obtained clear solution was filtered through hyflo to remove any undissolved particles. The clear solution was then added to heptane (1 OmL) at 25±5°C and stirred for 15 hours. The solid was filtered and suck dried under vacuum at 25±5°C for 30 min. The product obtained was confirmed as Vadadustat Form C. Yield= 0.3g
Example 6: Preparation of crystalline Form C of Vadadustat
Vadadustat (1 Og) and methyl tert-butyl ether (MTBE) (350 ml_) were charged in a RBF at 25±5°C and heated to 50±5°C, The reaction mass was stirred for 30 minutes and the obtained clear solution was filtered through hyflo to remove any undissolved particles. The clear solution was then added to heptane (200mL) containing Vadadustat Form C seed (20mg) at 25±5°C and stirred for 15 hours. The solid was filtered and suck dried under vacuum at 25±5°C for 30 minutes. The product obtained was conformed as Vadadustat Form C. Yield= 7.9g
Example 7: Process for the preparation of Vadadustat L-Proline co-crystal (1 :2)
Vadadustat (1 .0g), L-Proline (0.38g) and acetone (20mL) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 15-30 minutes at 60-65°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered and dried under vacuum for 4 hours at 35°C. The solid obtained was identified as 1 :2 co crystal of Vadadustat L-Proline. Yield: 0.78g
Example 8: Process for the preparation of Vadadustat L-Proline co-crystal (1 :2)
Vadadustat (4.0g), L-Proline (2.85g) and acetone (60mL) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 60 minutes at 60-65°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered, washed with acetone (8 mL) and dried under vacuum for 16 hours at 40°C. The solid obtained was identified as 1 :2 co-crystal of Vadadustat L-Proline. Yield: 6.1 g
Example 9: Process for the preparation of Vadadustat D-Proline co-crystal (1 :2)
Vadadustat (0.5g), D-Proline (0.36g) and acetone (8mL) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered, washed with acetone (2 mL) and dried under vacuum for 16 hours at 40°C. The solid obtained was identified as 1 :2 co-crystal of Vadadustat D-Proline. Yield: 0.76g
Example 10: Process for the preparation of Vadadustat L-Proline co-crystal (1 :1)
Vadadustat (0.5g), L-Proline (0.36g) and methanol (8mL) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered and dried under vacuum for 16 hours at 40°C. The solid obtained was identified as 1 :1 co crystal of Vadadustat L-Proline. Yield: 0.47g Example 11 : Process for the preparation of Vadadustat D-Proline co-crystal (1 :1)
Vadadustat (1 .0g), D-Proline (0.71 g) and methanol (16mL) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 30-40 minutes at 60-65°C. The reaction mass was slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered, washed with prechilled methanol (1 mL) and dried under vacuum for 16 hours at 40°C. The solid obtained was identified as 1 :1 co-crystal of Vadadustat D-Proline. Yield: 0.86g.
Example 12: Process for the preparation of Vadadustat caffeine co-crystal (1 :1)
Vadadustat (0.5g), caffeine (0.35g) and acetonitrile (5mL) were charged in a RBF at 25±5°C. The reaction mass was maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered and dried under vacuum for 3 hours at 40°C. The solid obtained was identified as 1 :1 co-crystal of Vadadustat Caffeine. Yield: 0.55g.
Example 13: Process for the preparation of Vadadustat nicotinamide co-crystal (1 :1)
Ethanol (1 5mL) and nicotinamide (0.2g) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 30 min at 60-65°C. Methyl ethyl ketone (15mL) and Vadadustat (0.5g) were charged into the reaction mass at 60-65°C. The reaction mass was stirred for 30 minutes at 60- 65°C. The mass was then slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The reaction mass was cooled to 0-5°C and stirred for 2-3 hours. The product obtained was filtered, washed with methyl ethyl ketone (2 mL) and dried under vacuum for 3 hours at 40°C. The solid obtained was identified as 1 :1 co-crystal of Vadadustat Nicotinamide. Yield: 0.45 g.
Example 14: Process for the preparation of Vadadustat isonicotinamide co-crystal (2:1)
Ethanol (3mL) and isonicotinamide (0.2g) were charged in a RBF at 25±5°C and the contents were heated to 60-65°C and stirred for 30 minutes at 60-65°C. Methyl ethyl ketone (30mL) and Vadadustat (0.5g) were charged into the reaction mass at 60-65°C. The reaction mass was stirred for 30 minutes at 60-65°C. The mass was then slowly cooled to 25±5°C and maintained under stirring at 25±5°C for 16 hours. The product obtained was filtered, washed with methyl ethyl ketone (1 mL) and dried under vacuum for 2 hours at 40°C. The solid obtained was identified as 2:1 co-crystal of Vadadustat Isonicotinamide. Yield: 0.6 g.

Claims

We claim:
1 . A process for the preparation of crystalline Form C of Vadadustat, comprising the steps of: a) dissolving Vadadustat in an ether solvent at elevated temperature to form a solution; b) cooling the solution to room temperature;
c) adding the step (b) solution to an anti-solvent optionally containing a seed of crystalline form C of Vadadustat; and
d) isolating the crystalline Form C of Vadadustat.
2. The process according to claim 1 , wherein the ether solvent is selected from the group consisting of tetrahydrofuran and methyl tert-butyl ether and the anti-solvent is heptane.
3. The process according to claim 1 , wherein the elevated temperature is about 45°C to about 60°C.
4. The process according to claim 1 , wherein the crystalline Form C is isolated by filtration and distillation.
5. A Vadadustat L-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.12, 16.27, 18.72 and 25.14 ± 0.2 degrees 2Q.
6. The Vadadustat L-Proline co-crystal (1 :2) of claim 5, further characterized by a powder X-ray diffraction pattern having peaks at 8.12, 1 1 .85, 16.27, 17.78, 18.72, 24.66 and 25.14 ± 0.2 degrees 2Q.
7. The Vadadustat L-Proline co-crystal (1 :2) of claim 5, further characterized by a PXRD pattern as shown in Figure 7.
8. A Vadadustat L-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.23, 15.72, 16.15 and 19.22 ± 0.2 degrees 2Q.
9. The Vadadustat L-Proline co-crystal (1 :1 ) of claim 8, further characterized by a powder X-ray diffraction pattern having peaks at 7.79, 10.23, 10.46, 15.72, 16.15 and 19.22 ± 0.2 degrees 20.
10. The Vadadustat L-Proline co-crystal (1 :1 ) of claim 8, further characterized by a PXRD pattern as shown in Figure 8.
1 1 . A Vadadustat D-Proline co-crystal (1 :2) characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 16.28, 18.73 and 25.13 ± 0.2 degrees 20.
12. The Vadadustat D-Proline co-crystal (1 :2) of claim 1 1 , further characterized by a powder X-ray diffraction pattern having peaks at 8.1 1 , 1 1 .85, 16.28, 17.78, 18.73, 24.62 and 25.13 ± 0.2 degrees 20.
13. The Vadadustat D-Proline co-crystal (1 :2) of claim 1 1 , further characterized by a PXRD pattern as shown in Figure 9.
14. A Vadadustat D-Proline co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 10.33, 15.83, 16.27 and 19.33 ± 0.2 degrees 20.
15. The Vadadustat D-Proline co-crystal (1 :1 ) of claim 14, further characterized by a powder X-ray diffraction pattern having peaks at 5.34, 12.99, 10.33, 15.83, 16.27, 1 9.33, 29.49 and 31 .38 + 0.2 degrees 20.
16. The Vadadustat D-Proline co-crystal (1 :1 ) of claim 14, further characterized by a PXRD pattern as shown in Figure 10.
17. A process for the preparation of Vadadustat Proline co-crystal comprising the steps of:
a) mixing Vadadustat with proline in a solvent to form a suspension ;
b) heating the suspension to 55-70°C;
c) slowly cooling the suspension to room temperature; and
d) isolating Vadadustat Proline co-crystal from the suspension.
18. The process according to claim 17, wherein the proline is selected from the group consisting of L-Proline, D-Proline and DL-Proline.
19. The process according to claim 17, wherein the solvent is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, isopropanol, n- propanol and t-butanol.
20. The process according to claim 17, wherein the Vadadustat Proline co-crystal is isolated by filtration and distillation.
21 . A Vadadustat caffeine co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 12.62, 25.11 , 25.92 and 26.19± 0.2 degrees 2Q.
22. The Vadadustat caffeine co-crystal (1 :1 ) of claim 21 , further characterized by a powder X-ray diffraction pattern having peaks at 8.27, 12.62, 12.89, 14.42, 24.78, 25.1 1 , 25.92, 26.19 and 26.75 ± 0.2 degrees 2Q.
23. The Vadadustat caffeine co-crystal (1 :1 ) of claim 21 , further characterized by a PXRD pattern as shown in Figure 1 1 .
24. A process for the preparation of Vadadustat caffeine co-crystal (1 :1 ) comprising: suspending Vadadustat and caffeine in a solvent at room temperature to form a suspension and isolating Vadadustat caffeine co-crystal (1 :1 ) from the suspension.
25. The process according to claim 24, wherein the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran and acetone.
26. A Vadadustat nicotinamide co-crystal (1 :1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.75, 16.78, 17.61 and 18.44± 0.2 degrees 2Q.
27. The Vadadustat nicotinamide co-crystal (1 :1 ) of claim 26, further characterized by a powder X- ray diffraction pattern having peaks at 7.39, 14.75, 16.78, 17.61 , 1 8.44, 23.16, 23.91 , 26.51 , 27.06, 28.40 ± 0.2° degrees 2Q.
28. The Vadadustat nicotinamide co-crystal (1 :1 ) of claim 26, further characterized by a PXRD pattern as shown in Figure 12.
29. A Vadadustat isonicotinamide co-crystal (2:1 ) characterized by a powder X-ray diffraction pattern having peaks at 14.26, 15.29, 18.20 and 20.15 ± 0.2 degrees 2Q.
30. The Vadadustat Isonicotinamide co-crystal (2:1 ) of claim 29, further characterized by a powder X-ray diffraction pattern having peaks at 7.71 , 14.26, 15.29, 15.79, 18.20, 20.15, 25.86, 29.21 , 29.54, 30.45± 0.2 degrees 20.
31 . The Vadadustat Isonicotinamide co-crystal (2:1 ) of claim 29, further characterized by a PXRD pattern as shown in Figure 13.
32. A process for the preparation of Vadadustat nicotinamide co-crystal (1 :1 ) comprising the steps of:
a) dissolving nicotinamide in an alcohol solvent at a temperature of 60±5°C to form a solution;
b) adding Vadadustat and a ketone solvent to the step (a) solution at 60±5°C temperature to produce a reaction mass;
c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat nicotinamide co-crystal from the reaction mass.
33. A process for the preparation of Vadadustat isonicotinamide co-crystal (2:1 ) comprising the steps of:
a) suspending isonicotinamide in an alcohol solvent at a temperature of 60+5°C to form a suspension ;
b) adding Vadadustat and a ketone solvent to the step (a) suspension at 60±5°C temperature to produce a reaction mass;
c) cooling the reaction mass to a temperature of 25±5°C; and
d) isolating the Vadadustat isonicotinamide co-crystal from the reaction mass.
34. The process according to claim 32 or 33, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, and isopropanol and the ketone solvent is selected from the group consisting of acetone, methyl ethyl ketone and methyl iso butyl ketone.
35. The process according to any one of claims 24, 32 and 33, wherein the Vadadustat caffeine co-crystal (1 :1 ) or the Vadadustat nicotinamide co-crystal (1 :1 ) or the Vadadustat isonicotinamide co-crystal (2:1 ) is isolated by filtration and distillation.
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CN115996720A (en) * 2020-09-04 2023-04-21 广东东阳光药业有限公司 Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor and preparation method thereof

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