WO2024256830A1 - Polymorphes de daprodustat et leurs procédés de préparation - Google Patents

Polymorphes de daprodustat et leurs procédés de préparation Download PDF

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Publication number
WO2024256830A1
WO2024256830A1 PCT/GB2024/051521 GB2024051521W WO2024256830A1 WO 2024256830 A1 WO2024256830 A1 WO 2024256830A1 GB 2024051521 W GB2024051521 W GB 2024051521W WO 2024256830 A1 WO2024256830 A1 WO 2024256830A1
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Prior art keywords
daprodustat
crystalline form
solvent
temperature
solid
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Inventor
Arijit Das
Ramanaiah CHENNURU
Pullareddy LAKKIREDDY
Anjaneyaraju Indukuri
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Cipla Ltd
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Cipla Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

  • Daprodustat is chemically known as 2-[(1,3-dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5- carbonyl)amino]acetic acid (compound of formula I), which is an small-molecule hypoxia- inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor.
  • HIF hypoxia- inducible factor
  • PLD prolyl hydroxylase
  • Daprodustat is a potent inhibitor of PHD1, PHD2 and PHD3and leads to stabilization of cellular HIF1 ⁇ and HIF2 ⁇ and the induction of erythropoiesis.
  • Daprodustat was fully approved by the FDA as the first oral treatment for anemia caused by chronic kidney disease in patients on dialysis.
  • Daprodustat was first disclosed in the US Patent No.8,324,208 as antagonists of HIF prolyl hydroxylases useful for treatment of anemia.
  • the PCT publication WO 2019/052133 relates to crystalline forms of CS1 and CS9 of 2-[(1,3- dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5- carbonyl)amino]acetic acid.
  • the dissolution property of tablets prepared from the crystalline forms of CS1 and CS9 is not good due to poor solubility of the crystal forms.
  • the PCT publication WO 2020/102302 relates to crystalline Form 3 and Form 4 of 2-[(1,3- dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid.
  • the PCT publication WO 2021/031102 relates to crystalline Form M and K of 2-[(1,3- dicyclohexyl-2,4,6-trioxo-1,3-diazinane-5-carbonyl)amino]acetic acid. Characteristics such as high purity and high solubility, good dissolution make a compound polymorphic form more suitable for use in pharmaceutical formulations.
  • the present invention provides novel polymorphic forms of Daprodustat, which are physically and chemically stable at storage conditions and has sufficient solubility and bioavailability with high purity, and processes for preparation thereof, and pharmaceutical compositions and uses thereof. Accordingly, the present invention provides a crystalline Form C1 of Daprodustat as described herein. It is, in particular, characterized by at least one of: (a) an X-ray powder diffraction pattern (PXRD) peaks, (b) Differential scanning calorimetry (DSC) data, and (c) Thermogravimetric analysis (TGA) data as shown in Figure 1(a-c) respectively.
  • PXRD X-ray powder diffraction pattern
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • the crystalline Form C1 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks at 4.9, 6.9, 10.9, 21.9, 23.2 and 25.0 ⁇ 0.2 °2 ⁇ . Accordingly, the present invention further provides a crystalline Form C2 of Daprodustat as described herein. It is, in particular, characterized by at least one of: (a) an X-ray powder diffraction pattern (PXRD) peaks, b) Differential scanning calorimetry (DSC) data, and (c) Thermogravimetric analysis (TGA) data as shown in Figure 2(a-c) respectively.
  • PXRD X-ray powder diffraction pattern
  • DSC Differential scanning calorimetry
  • TGA Thermogravimetric analysis
  • the crystalline Form C2 of Daprodustat may be further characterized by an X-ray powder diffraction pattern having peaks at 4.9, 7.6, 8.0, 10.9, 13.8, 15.4, 23.2 and 24.9 ⁇ 0.2°2 ⁇ . Accordingly, the present invention further provides a co-crystalline Form C3 of Daprodustat and L-proline characterized by an X-ray powder diffraction pattern (PXRD) peaks as shown in Figure 3.
  • the co-crystal Form C3 of Daprodustat comprising Daprodustat and L-Proline may be further characterized by an X-ray powder diffraction pattern having peaks at 3.3, 6.0, 6.8, 7.7, 9.4, 10.8, 16.3 and 17.0 ⁇ 0.2°2 ⁇ .
  • the present invention further provides a crystalline Form C4 of Daprodustat as described herein. It is, in particular, characterized by an X-ray powder diffraction pattern (PXRD) peaks as shown in Figure 4, DSC data as shown in Figure 5 and TGA data as shown in Figure 6.
  • the crystalline Form C4 of Daprodustat may be further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 6.4, 7.5, 8.2, 17.9 and 19.9 ⁇ 0.2° 2 ⁇ .
  • the present invention further provides a co-crystalline Form C5 of Daprodustat and maltol as described herein.
  • Daprodustat and maltol may be further characterized by an X-ray powder diffraction pattern having peaks at 6.6, 7.4, 12.4, 14.8, 18.7 and 27.7 ⁇ 0.2° 2 ⁇ . Accordingly, the present invention further provides processes for preparing the novel polymorphs of Daprodustat.
  • the present invention further provides a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat and one or more pharmaceutically acceptable excipient.
  • the pharmaceutical composition may comprise the crystalline Form C2 of Daprodustat and a pharmaceutically acceptable excipient.
  • the present invention further provides at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, for use as a medicament.
  • the present invention provides crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising crystalline Form C2 of Daprodustat for use as a medicament.
  • the present invention further provides at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, for use in the treatment of anemia.
  • the present invention provides crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising crystalline Form C2 of Daprodustat for use the treatment of anemia.
  • the anemia may be anemia secondary to chronic kidney disease. Accordingly, the present invention further provides a method of treating anaemia, comprising administering a therapeutically effective amount of at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, to a subject in need of the treatment. In particular, the present invention provides a method of treating anaemia, comprising administering a therapeutically effective amount of the crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising crystalline Form C2 of Daprodustat, to a subject in need of the treatment.
  • the anemia may be anemia secondary to chronic kidney disease.
  • Figure 1 shows (a) an X-ray powder diffraction pattern (PXRD) of crystalline Form C1 of Daprodustat; (b) DSC curve of crystalline Form C1 of Daprodustat; and (c) TGA curve of crystalline Form C1 of Daprodustat.
  • Figure 2 shows (a) an X-ray powder diffraction pattern (PXRD) of crystalline Form C2 of Daprodustat; (b) DSC curve of crystalline Form C2 of Daprodustat; and (c) TGA curve of crystalline Form C2 of Daprodustat.
  • Figure 3 shows an X-ray powder diffraction pattern (PXRD) of co-crystalline Form C3 of Daprodustat and L-proline.
  • Figure 4 shows an X-ray powder diffraction pattern (PXRD) of crystalline Form C4 of Daprodustat.
  • Figure 5 shows DSC curve of crystalline Form C4 of Daprodustat.
  • Figure 6 shows a TGA thermogram curve of crystalline Form C4 of Daprodustat.
  • Figure 7 shows an X-ray powder diffraction pattern (PXRD) of co-crystalline Form C5 of Daprodustat and maltol.
  • Figure 8 shows DSC curve of crystalline Form C5 of Daprodustat.
  • Figure 9 shows a TGA thermogram curve of co-crystalline Form C5 of Daprodustat and maltol.
  • the present invention describes new crystalline Daprodustat forms.
  • Daprodustat can be provided in new stable crystalline forms with improved purity and solubility.
  • crystal or “crystalline form” refers to the solid being identified by the X-ray diffraction pattern shown herein.
  • Those skilled in the art are able to understand that physicochemical properties discussed herein can be characterized. The experimental errors depend on the instrument conditions, the sampling processes and the purity of samples. In particular, those skilled in the art generally know that the X-ray diffraction pattern typically varies with the experimental conditions.
  • the present invention discloses Daprodustat polymorphic Forms, namely Form C1, Form C2, Form C3 (L-Proline cocrystal of Daprodustat), Form C4 and Form C5 (maltol cocrystal of Daprodustat).
  • the present invention provides a crystalline polymorph of Daprodustat, referred to as Form C1.
  • the crystalline Form C1 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks at 4.9, 6.9, 10.9, 21.9, 23.2 and 25.0 ⁇ 0.2 °2 ⁇ .
  • the crystalline Form C1 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks as depicted in Figure 1(a).
  • the crystalline Form C1 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) comprising an endothermic peak as depicted in Figure 1(b).
  • DSC Differential Calorimetry Thermogram
  • the crystalline Form C1 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) having an endothermic peak temperature at 243 ⁇ 5oC.
  • the crystalline Form C1 of Daprodustat may be further characterized by a Thermogravimetric analysis (TGA) data as depicted in Figure 1(c).
  • TGA Thermogravimetric analysis
  • Form C1 of Daprodustat has a thermal weight loss of about 0.119% (w/w) as measured by TGA.
  • the crystalline Form C1 of Daprodustat may be further characterized by data selected from one or more of the above mentioned PXRD, DSC, TGA in relation to the crystalline Form C1 or any combination of these data.
  • the present invention provides a crystalline polymorph of Daprodustat, referred to as Form C2.
  • the crystalline Form C2 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks at 4.9, 7.6, 8.0, 10.9, 13.8, 15.4, 23.2 and 24.9 ⁇ 0.2°2 ⁇ .
  • the crystalline Form C2 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks as depicted in Figure 2(a).
  • the crystalline Form C2 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) comprising an endotherm having a peak at 246 ⁇ 5oC.
  • DSC Differential Calorimetry Thermogram
  • the crystalline Form C2 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) having an endothermic peak as depicted in Figure 2(b).
  • the crystalline Form C2 of Daprodustat may be further characterized by a Thermogravimetric analysis (TGA) data as depicted in Figure 2(c).
  • TGA Thermogravimetric analysis
  • Form C2 of Daprodustat has a thermal weight loss of about 0.248% (w/w) as measured by TGA.
  • the crystalline Form C2 of Daprodustat may be further characterized by data selected from one or more of the following: (a) an X-ray powder diffraction pattern (PXRD) having peaks at 4.9, 7.6, 8.0, 10.9, 13.8, 15.4, 23.2 and 24.9 ⁇ 0.2°2 ⁇ or PXRD having peaks as depicted in Figure 2(a); (b) by a Differential Calorimetry Thermogram (DSC) comprising an endotherm having a peak at 246 ⁇ 5oC or DSC comprising an endothermic peak as depicted in Figure 2(b); (c) a Thermogravimetric analysis (TGA) data as depicted in Figure 2(c) or has a thermal weight loss of about 0.248% (w/w) as measured by TGA; and (d)combinations of these data.
  • PXRD X-ray powder diffraction pattern
  • DSC Differential Calorimetry Thermogram
  • TGA Thermogravimetric analysis
  • the combinations may be any combinations of the data (a), (b) and (c), for example, (a) + (b), (a) + (c), (b) + (c), (a)+(b)+(c).
  • the present invention provides a co-crystalline form of Daprodustat.
  • the co- crystal of Daprodustat comprises L-Proline as the co-former.
  • the L-Proline co-crystal of Daprodustat is referred to as Form C3.
  • the co-crystal of Daprodustat comprising Daprodustat and L-Proline may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks at 3.3, 6.0, 6.8, 7.7, 9.4, 10.8, 16.3 and 17.0 ⁇ 0.2°2 ⁇ .
  • PXRD X-ray powder diffraction pattern
  • the co-crystal of Daprodustat comprising Daprodustat and L-Proline may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks as depicted in Figure 3.
  • the present invention provides a crystalline polymorph of Daprodustat, referred to as Form C4.
  • the crystalline Form C4 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks at 5.0, 6.4, 7.5, 8.2, 17.9 and 19.9 ⁇ 0.2°2 ⁇ .
  • the crystalline Form C4 of Daprodustat may be characterized by an X-ray powder diffraction pattern (PXRD) having peaks as depicted in Figure 4.
  • the crystalline Form C4 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) comprising an endotherm having a peak at 148 ⁇ 5 oC.
  • the crystalline Form C4 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) having an endothermic peak as depicted in Figure 5.
  • crystalline Form C4 of Daprodustat may be characterized by a Thermogravimetric analysis (TGA) as depicted in Figure 6.
  • TGA Thermogravimetric analysis
  • Form C4 of Daprodustat has a thermal weight loss of about 0.181% (w/w) as measured by TGA.
  • the crystalline Form C4 of Daprodustat may be further characterized by data selected from one or more of the PXRD, DSC, TGA data mentioned above in relation to the crystalline Form C4 or any combinations of these data.
  • the present invention provides a co-crystal of Daprodustat, which comprises maltol as the co-former.
  • the maltol co-crystal of Daprodustat is referred to as Form C5.
  • the co-crystal of Daprodustat comprising Daprodustat and maltol may be characterized by an X- ray powder diffraction pattern having peaks at 6.6, 7.4, 12.4, 14.8, 18.7 and 27.7 ⁇ 0.2°2 ⁇ .
  • the co-crystal of Daprodustat comprising Daprodustat and maltol may be characterized by an X- ray powder diffraction pattern (PXRD) having peaks as depicted in Figure 7.
  • the crystalline Form C5 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) comprising an exotherm having a peak at 182 ⁇ 5oC.
  • the crystalline Form C5 of Daprodustat may be further characterized by a Differential Calorimetry Thermogram (DSC) having an exotherm peak as depicted in Figure 8.
  • the co-crystal Form C5 of Daprodustat comprising Daprodustat and maltol may be characterized by a Thermogravimetric analysis (TGA) as depicted in Figure 9.
  • TGA Thermogravimetric analysis
  • the crystalline Form C5 of Daprodustat typically has a thermal weight loss about 0.521% (w/w) as measured by TGA.
  • the crystalline Form C5 of Daprodustat may be further characterized by data selected from one or more of the PXRD, DSC, TGA mentioned above in relation to the crystalline Form C5 or any combinations of these data.
  • the present invention provides a process for preparing of crystalline Form C1 of Daprodustat, the process comprising the steps of: a) Dissolving Daprodustat in a solvent or a mixture of solvents at a temperature of about 45 0 C to about 60 0 C to obtain a solution; b) Optionally, filtering the solution obtained in step a) to obtain a clear solution; c) Pre-chilling the clear solution obtained in step b) in a hydrocarbon solvent at a temperature in the range of about -20 0 C to about -5 0 C, and preferably stirring the solution to obtain a solid.
  • the solid obtained in step c) may be isolated by filtration.
  • the filtered solid may be dried to obtain the crystalline Form C1 of Daprodustat.
  • the solid is dried preferably at a temperature in the range of about 50 0 C to about 75 0 C, preferably of at a temperature in the range of about 60 0 C to about 65 0 C, preferably for a period of about at least 1 hours to 10 hours.
  • the solid is dried for about 10 hrs.
  • the solid may be dried under vacuum for at least 5 to 10 mins.
  • Suitable solvents used in step a) and step c) of the process of preparing the crystalline Form C1 of Daprodustat may be selected from polar aprotic solvents such as esters, ketones; non- polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the solvent is a non-polar solvent.
  • the non-polar solvent includes alkanes such as pentane, hexane, and heptane or mixtures thereof and aromatics such as benzene, toluene, and xylene or mixtures thereof.
  • non-polar solvents include acetic acid, chloroform, diethyl ether, ethyl acetate, methyl acetate, isopropyl acetate, methylene chloride, and pyridine or mixtures thereof.
  • polar solvent includes water, acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, ethanol and methanol or mixtures thereof.
  • the solvent used in step a) is a non-polar solvent which comprises isopropyl acetate, acetone, or a mixture/combination thereof.
  • the non-polar solvent such as the hydrocarbon solvent used in step c) may be heptane.
  • the present invention provides a process for preparing of a crystalline Form C2 of Daprodustat, the process comprising the steps of: a) Dissolving Daprodustat in a solvent at a reflux temperature; and b) Removing the solvent from the solution obtained in step a) to obtain a solid.
  • the solution obtained in step a) of the process of preparing the crystalline Form C2 of Daprodustat may be filtered to remove undissolved particulates.
  • the solvent in step b) in the process of preparing the crystalline Form C2 of Daprodustat is removed using an apparatus such as a rotary evaporator or rota flask, or any device suitable for removing the solvent to obtain the solid.
  • the solvent is removed in step b) by distillation.
  • the distillation of the solvent may be carried out by any suitable method or apparatus.
  • the distillation of the solvent may be carried out under vacuum, using any suitable device such as a Buchi rotavapor at a temperature in the range of about 50 0 C to about 60 0 C, preferably at temperature of about 60 0 C.
  • Daprodustat is dissolved in a solvent at a reflux temperature in the range of about 40 0 C to about 75 0 C, preferably at about 45 0 C to about 60 0 C.
  • Daprodustat may be dissolved in a solvent at a temperature about 50 0 C.
  • the distillation of the solvent is followed by drying to obtain the crystalline Form C2 of Daprodustat.
  • the resulted solid may be dried under vacuum or any suitable means, at a temperature in the range of about 50 0 C to about 60 0 C, preferably for about 3 to about 6 hrs.
  • the obtained solid may be dried at a temperature of about 60 0 C, preferably for about 4 to 5 hrs.
  • the solvent used in step a) of the process of preparing the crystalline Form C2 of Daprodustat may be any suitable solvent or solvent mixtures that aids in the dissolution or solubilization of Daprodustat.
  • Suitable solvent used in step a) of the process of preparing the crystalline Form C2 of Daprodustat may be selected from polar aprotic solvents such as esters, ketones; non-polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the solvent is a non-polar solvent or a mixture of non-polar solvent.
  • the non-polar solvent includes alkanes such as pentane, hexane, and heptane or a mixture thereof, and aromatics such as benzene, toluene, and xylene or a mixture thereof.
  • non-polar solvents include acetic acid, chloroform, diethyl ether, ethyl acetate, methyl acetate, isopropyl acetate, methylene chloride, and pyridine or mixtures thereof.
  • the solvent is a non-polar solvent which comprises methyl acetate.
  • the solution obtained in step a) of the process of preparing the crystalline Form C2 of Daprodustat may be cooled to a desired temperature.
  • the desired temperature may be -1 to -5 °C, preferably -5 °C.
  • An anti-solvent or a mixture of anti-solvents, preferably pre-chilled, may then be added to the solution.
  • the anti-solvent is added to the solution preferably at a temperature in the range of about -15°C to -1°C, more preferably -10°C to -5°C, and may be stirred at this temperature for about 1 to 4 hours, preferably for about 2 to 3 hours to obtain a solid.
  • the solid may be filtered, and then dried under vacuum for about 1 to 4 hours, preferably for about 2 to 3 hours.
  • the step of vacuum drying may then be followed by a further step of drying the solid in any suitable dryer such as a Vacuum Tray Dryer (VTD) or Air Tray Dryer (ATD), preferably for about 1 to 50 hours, more preferably for about 5 to 40 hours, most preferably for about 30 hours.
  • VTD Vacuum Tray Dryer
  • ATD Air Tray Dryer
  • Suitable anti-solvent used in the process of preparing the crystalline Form C2 of Daprodustat may be selected from polar aprotic solvents such as esters, ketones; non-polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the anti-solvent is a non-polar solvent.
  • the non-polar solvent includes alkanes such as pentane, hexane, and heptane or mixtures thereof and aromatics such as benzene, toluene, and xylene, or mixtures thereof.
  • the anti-solvent is a non-polar solvent which comprises heptane, iso propyl acetate or a mixture thereof.
  • the present invention provides a process for preparing a co-crystalline Form C3 of Daprodustat comprising Daprodustat and L-Proline, the process comprising the steps of: a) Dissolving Daprodustat in a solvent at a temperature in the range of about 45 0 C to about 55 0 C; b) Dissolving L-proline in an aqueous solution, preferably at room temperature; c) Adding the aqueous solution of L-proline obtained in step b) to the solution obtained in step a) at a temperature in the range of about 45°C to about 60°C, and optionally stirring the solutions at this temperature; and d) cooling the reaction mass.
  • the aqueous solution of L-proline obtained in step b) is added/charged into the solution obtained in step a) at a temperature in the range of about 50°C to about 55°C, optionally stirring the solutions at the same temperature for about 1 to 6 hrs or preferably for about 3 to 4 hrs.
  • the reaction mass obtained in step d) is cooled to room temperature.
  • reaction mass is isolated by filtration to obtain a solid. The filtered solid may then be dried, preferably at a temperature in the range of about 40°C to about 75°C for about 1 to 6 hours to obtain the cocrystal Form C3 of Daprodustat.
  • the filtered is dried at a temperature in the range of about 50°C to about 60°C for about 3 to about 4 hours to obtain the cocrystal Form C3 of Daprodustat.
  • Suitable solvent for preparing the co-crystalline Form C3 of Daprodustat and L-proline may be selected from polar aprotic solvents such as esters, ketones; non-polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the solvent is a polar solvent, which includes water, acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, ethanol and methanol or mixtures thereof.
  • the solvent is a polar solvent which comprises acetone.
  • the present invention provides a process for preparing a crystalline Form C4 of Daprodustat, the process comprising the steps of: a) Dissolving Daprodustat in a solvent at a reflux temperature; and b) Cooling the clear solution obtained in step (a) at a temperature in the range of about -15° C to about -10° C to obtain a solid, and optionally stirring the solution.
  • the solution may be stirred for about 1 to 4 hrs, preferably the solution is stirred for about 2 to 3 hrs.
  • the solid obtained in step (b) in the process for preparing a crystalline Form C4 of Daprodustat is isolated by filtration.
  • the obtained solid may then be dried, preferably at a temperature in the range of about 30°C to about 75°C for about 6 to about 14 hours to obtain the crystalline Form C4 of Daprodustat.
  • the filtered is dried at a temperature in the range of about 40°C to about 60°C for about 8 to about 12 hours to obtain the cocrystal Form C4 of Daprodustat.
  • Daprodustat in step a) process for preparing a crystalline Form C4 of Daprodustat is dissolved at a reflux temperature in the range of about 40 0 C to about 75 0 C, more preferably at about 60 0 C to about 70 0 C about, most preferably at about 45 0 C to about 55 0 C.
  • Suitable solvent for preparing the crystalline Form C4 of Daprodustat may be selected from polar aprotic solvents such as esters, ketones; non-polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the solvent is a polar solvent.
  • the polar solvent includes water, acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, ethanol and methanol or mixtures thereof.
  • the solvent is a polar solvent which comprises ethanol, methanol, water, or mixtures or combinations of these solvents.
  • the present invention provides a process for preparing a co-crystalline Form C5 of Daprodustat comprising Daprodustat and maltol, the process comprising the steps of: a) suspending Daprodustat in a solvent at a temperature in the range of about 40 0 C to 65 0C to form a Daprodustat solution; b) Dissolving maltol in a solvent at a temperature in the range of about 15 0 C to 40 0 C to form a maltol solution; c) Adding/Charging the solution obtained in step (b) into the solution obtained in step (a) at a temperature in the range of about 40 0 C to 65 0 C, optionally stirring to get a clear solution; d) cooling the clear solution obtained in step (c) at a temperature in the range of about - 05° C to about -20° C to obtain a solid.
  • the solid obtained in step (d) of the process for preparing a co-crystalline Form C5 of Daprodustat is isolated by filtration.
  • the filtered solid obtained may be dried at a temperature in the range of about 40°C to about 70°C, preferably for about 6 to about 14 hours to obtain the co-crystal Form C5 of Daprodustat.
  • the filtered is dried at a temperature in the range of about 50°C to about 60°C, preferably for about 8 to about 12 hours to obtain the cocrystal Form C5 of Daprodustat.
  • Daprodustat is dissolved in a solvent at a temperature in the range of about 50 0 C to about 55 0 C to form a maltol solution.
  • maltol is dissolved in a solvent at a temperature in the range of about 25 0 C to about 30 0 C to form a maltol solution.
  • the solutions are stirred for about 1 to about 3 hours, more preferably about 1 to about 2 hours.
  • the reaction mixture may be maintained for about 1 to about 3 hours, more preferably for about 1 to about 2 hours.
  • Suitable solvent for preparing the co-crystalline Form C5 of Daprodustat may be selected from polar aprotic solvents such as esters, ketones; non-polar solvents such as hydrocarbons; protic polar solvents and the like, alone or in combinations or mixtures thereof.
  • the solvent is a polar solvent.
  • the polar solvent includes water, acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), isopropanol, ethanol and methanol or mixtures thereof.
  • the solvent is ethanol, methanol, water, or mixtures or combinations of these solvents.
  • the solvent used in step a) in the process of preparing the co-crystalline Form C5 of Daprodustat is acetone.
  • the solvent used in step b) in the process of preparing the co-crystalline Form C5 of Daprodustat is water, acetone, or mixtures or combinations thereof.
  • the present invention provides a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat and one or more pharmaceutically acceptable excipient.
  • the novel polymorph of Daprodustat is crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline, crystalline Form C4 of Daprodustat or co-crystalline Form C5 of Daprodustat and maltol respectively.
  • a pharmaceutical composition comprising crystalline Form C2 of Daprodustat and a pharmaceutically acceptable excipient.
  • the present invention provides at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, for use as a medicament.
  • the novel polymorph of Daprodustat is crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline, crystalline Form C4 of Daprodustat or co-crystalline Form C5 of Daprodustat and maltol respectively.
  • the crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising the crystalline Form C2 of Daprodustat is provided for use as a medicament.
  • the present invention provides at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, for use in the treatment of anemia.
  • the novel polymorph of Daprodustat is crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline, crystalline Form C4 of Daprodustat or co-crystalline Form C5 of Daprodustat and maltol respectively.
  • the crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising crystalline Form C2 of Daprodustat is provided for use the treatment of anemia.
  • the anemia may be anemia secondary to chronic kidney disease or anemia in patients with chronic kidney failure (CKD).
  • the present invention provides a method of treating anemia, comprising administering a therapeutically effective amount of at least one of the novel polymorphs of Daprodustat, or a pharmaceutical composition comprising at least one of the novel polymorphs of Daprodustat, to a subject in need of the treatment, is provided.
  • the novel polymorph of Daprodustat is crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline, crystalline Form C4 of Daprodustat or co-crystalline Form C5 of Daprodustat and maltol respectively.
  • the present invention provides a method of treating anemia, comprising administering a therapeutically effective amount of the crystalline Form C2 of Daprodustat or a pharmaceutical composition comprising the crystalline Form C2 of Daprodustat to a subject in need of the treatment.
  • the anemia may be anemia secondary to chronic kidney disease or anemia in patients with chronic kidney failure (CKD).
  • the present invention provides at least one of the novel polymorphs of Daprodustat selected from crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline or co-crystalline Form C5 of Daprodustat and maltol, crystalline Form C4 of Daprodustat, or a pharmaceutical composition of the present invention, for the manufacture of a medicament for treatment of anemia such as anemia secondary to chronic kidney disease, or anemia in patients with chronic kidney failure (CKD).
  • the polymorph of Daprodustat is crystalline Form C2 of Daprodustat.
  • the present invention provides use of at least one of the novel polymorphs of Daprodustat selected from crystalline Form C1, crystalline Form C2, co-crystalline Form C3 of Daprodustat and L-proline, crystalline Form C4 of Daprodustat or co-crystalline Form C5 of Daprodustat and maltol, in the preparation of another solid-state form of Daprodustat, or another Daprodustat salt or solid-state form thereof.
  • the polymorph of Daprodustat is crystalline Form C2 of Daprodustat.
  • the pharmaceutical compositions of the present invention may be manufactured in a manner that is generally known.
  • compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the appropriate formulation is dependent upon the route of administration chosen.
  • the pharmaceutical composition provided by the present invention may be administered through oral (tablets, capsules, orally disintegrating tablets, hard candies, powders, spansules, softgels, liquid or aqueous suspensions), parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), and/or other suitable routes.
  • the pharmaceutical composition provided by the present invention is administered orally.
  • the excipients or carriers may be selected depending upon the route of administration. Suitable pharmaceutically acceptable excipients or carriers include inert solid fillers or diluent, binders, lubricants, glidants and sterile aqueous or organic solutions.
  • the compounds may be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • the pharmaceutical compositions may comprise other active agent(s) or drug(s).
  • the PXRD measurements were carried out at a temperature of 25 ⁇ 3°.
  • the sample was powdered in a mortar and pestle and applied directly on a silicon plate holder.
  • the described peak positions were determined with or without using silicon powder as an internal standard in an admixture with the sample measured.
  • the described peak positions were determined using silicon powder as an internal standard in an admixture with the sample measured.
  • the position of the silicon (Si) peak was corrected to silicone theoretical peak: 28.45 degrees two theta, and the positions of the measured peaks were corrected respectively.
  • Differential Scanning Calorimetry method DSC measurements were done using TA Instruments Discovery, DSC unit.1-3 mg of sample was weighted in pan, hermetically closed with the pin hole. Sample was purged with 50 ml/min of nitrogen flow and heated in the range of 25-280 °C, with heating rate of 10 °C/min.
  • TGA Thermo Gravimetric Analysis
  • Example 1 Preparation of Crystalline Form C1 of Daprodustat 10 gm of Daprodustat was dissolved in 200 ml (20 V) of isopropyl acetate and 200 ml (20 V) of acetone mixture at 50°C to 55 °C, the solution was filtered to remove any undissolved particulate to obtain a clear solution. The obtained clear solution was added to pre-chilled heptane (400 ml, 40 V) at -15°C to -10°C and stirred at this temperature for about 1 to 2 hrs.
  • pre-chilled heptane 400 ml, 40 V
  • Example 2 Preparation of Crystalline Form C2 of Daprodustat Daprodustat (2.0 g) was dissolved in 160 ml (80 volumes) of methyl acetate at a temperature of about 50 °C. The solution was filtered to remove undissolved particulates to obtain a clear solution.
  • Example 3 Preparation of Crystalline Form C2 of Daprodustat Daprodustat (100 gm) was dissolved in 560 ml (5.6 volumes) of toluene and 140 ml (1.4 volumes) of trifluoro acetic acid mixture at a temperature of about 45 to 50 °C.
  • the solution is filtered to obtain to remove any undissolved particulate to form a clear solution.
  • the obtained clear solution was cooled to a temperature of about -5 °C, then a pre-chilled mixture of heptane (1500 ml, 15 V) and iso propyl acetate (200 ml, 2 V) were added to the solution at a temperature of about -10°C to -5°C and stirred at this temperature for about 2 to 3 hours.
  • the obtained solid was filtered and suck dried under vacuum for about 2 to 3 hours, then dried at a temperature of about 50 to 55 °C in VTD for about 30 hours to yield 90.0 gm of crystalline Form C2 of Daprodustat.
  • a PXRD pattern of Form C2 of Daprodustat is shown in Figure 2(a).
  • a DSC pattern and TGA curve of Form C2 of Daprodustat are shown in Figure 2(b) and 2(c).
  • Example 4 Preparation of Daprodustat and L-Proline cocrystal (Form C3)
  • Daprodustat 5.0 gm was dissolved in 200 ml of Acetone (40 V) at a temperature of about 50°C to 55°C.
  • Separately 0.9 gm of L-proline was dissolved in 10 ml of water at room temperature (RT). Charged the L-proline water solution into Daprodustat product solution at a temperature of about 50°C to 55°C and stirred at this temperature for about 3 to 4 hours.
  • Example 5 Preparation of Crystalline Form C4 of Daprodustat 5.0 g of Daprodustat was dissolved in 52 volumes of Ethanol-Methanol-Water (30:20:2 ratio) solvent mixture at a temperature of about 60 °C to 70 °C.
  • a PXRD pattern of co-crystal Form C5 is shown in Figure 7.
  • Example 7 Preparation of Daprodustat and Maltol cocrystal (Form C5)
  • Daprodustat (3g) was suspended in (20 V) of Acetone at a temperature of about 50°C to 55°C.
  • 1.44 gm (1.5 eq) of Maltol was dissolved in 2.0 ml of water and 2.0 ml of Acetone at a temperature of about 25°C to 30°C.
  • the Maltol solution was charged into Daprodustat product solution at a temperature of about 50°C to 55°C and stirred at this temperature for about 1 to 2 hours to get a clear solution.
  • reaction mass was cooled to a temperature of about -15° C to -10° C and maintained for about 1 to 2 hrs.
  • the resulting solid was isolated by filtration and dried at a temperature of about 50°C to 60°C for about 8 to 12 hours to yield 3.5 gm of co-crystal Form C5 of Daprodustat.
  • a PXRD pattern of co-crystal Form C5 is shown in Figure 7.
  • a DSC pattern of Form C5 of Daprodustat is shown in Figure 8 and TGA curve pattern of co-crystal Form C5 is shown in Figure 9.

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Abstract

La présente invention concerne de nouvelles formes cristallines de daprodustat. En particulier, l'invention concerne des nouvelles formes polymorphes cristallines/co-cristaux, nommés forme C1, C2, C3, C4 et C5 de daprodustat. Ces formes sont caractérisées par PXRD et TGA. L'invention concerne également des procédés de préparation des nouvelles formes polymorphes cristallines/co-cristaux et leur utilisation dans des compositions pharmaceutiques.
PCT/GB2024/051521 2023-06-14 2024-06-13 Polymorphes de daprodustat et leurs procédés de préparation Pending WO2024256830A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324208B2 (en) 2006-06-23 2012-12-04 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
WO2019052133A1 (fr) 2017-09-15 2019-03-21 苏州科睿思制药有限公司 Forme cristalline de gsk1278863 et son procédé de préparation et son utilisation pharmaceutique
WO2020102302A1 (fr) 2018-11-15 2020-05-22 Teva Pharmaceuticals International Gmbh Formes solides de daprodustat et leurs procédés de préparation
WO2021031102A1 (fr) 2019-08-20 2021-02-25 深圳仁泰医药科技有限公司 Forme cristalline de daprodustat, son procédé de préparation et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324208B2 (en) 2006-06-23 2012-12-04 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
WO2019052133A1 (fr) 2017-09-15 2019-03-21 苏州科睿思制药有限公司 Forme cristalline de gsk1278863 et son procédé de préparation et son utilisation pharmaceutique
WO2020102302A1 (fr) 2018-11-15 2020-05-22 Teva Pharmaceuticals International Gmbh Formes solides de daprodustat et leurs procédés de préparation
WO2021031102A1 (fr) 2019-08-20 2021-02-25 深圳仁泰医药科技有限公司 Forme cristalline de daprodustat, son procédé de préparation et son utilisation
US20220169619A1 (en) 2019-08-20 2022-06-02 Shenzhen Rentai Pharmatech Ltd. Crystal form of daprodustat, preparation method therefor and use thereof

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