WO2023095162A1 - Cocrystal of roxadustat and nicotinamide - Google Patents

Cocrystal of roxadustat and nicotinamide Download PDF

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Publication number
WO2023095162A1
WO2023095162A1 PCT/IN2022/051019 IN2022051019W WO2023095162A1 WO 2023095162 A1 WO2023095162 A1 WO 2023095162A1 IN 2022051019 W IN2022051019 W IN 2022051019W WO 2023095162 A1 WO2023095162 A1 WO 2023095162A1
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Prior art keywords
roxadustat
nicotinamide
cocrystal
methyl
form iii
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PCT/IN2022/051019
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French (fr)
Inventor
Ramakoteswara Rao Jetti
Ramamohana Rao Golivi
Sureshbabu JAYACHANDRA
Jagadeesh Babu Nanubolu
Lohit KOTTE
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Mylan Laboratories Limited
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Publication of WO2023095162A1 publication Critical patent/WO2023095162A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

Definitions

  • the present invention relates to novel crystalline forms of Roxadustat Nicotinamide Cocrystal (1:1) and its preparation thereof.
  • Roxadustat is chemically known as [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid and is represented by Formula 1.
  • Roxadustat is for the treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III clinical development in US.
  • US patent 8883823 disclosed crystalline Form A, Form B, Form C & Form D [DMSO: water solvate], crystalline sodium salt, crystalline L-arginine salt, crystalline L-lysine salt, crystalline ethanolamine salt, crystalline diethanolamine salt, crystalline tromethamine salt and their preparations thereof.
  • IN201641016266 patent application disclosed amorphous solid dispersion comprising Roxadustat and a pharmaceutically acceptable carrier and its preparation thereof.
  • IN201741007950 patent application disclosed Cocrystal of Roxadustat comprising Roxadustat and Cocrystal former selected from caffeine, adenine, thymine, saccharine or the like.
  • the inventors of the present invention have developed novel crystalline forms of Roxadustat Nicotinamide Cocrystal suitable for formulation development.
  • the main object of the present invention provides crystalline forms of Roxadustat Nicotinamide Cocrystal and its preparation thereof.
  • the present invention provides Cocrystal of Roxadustat and Nicotinamide in the molar ratio of 1 : 1.
  • the present invention provides Cocrystal of Roxadustat Nicotinamide designated as Form II.
  • the present invention provides Cocrystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern as shown in Figure 1.
  • the present invention provides cocrystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern having peaks at 10.00, 13.31, 15.64, 21.80, 22.65, 26.07, 28.17 ⁇ 0.2° 20.
  • the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form II as shown in table 1 below:
  • the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form II comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, and d) isolating cocrystal of Roxadustat Nicotinamide Form II.
  • the present invention provides Cocrystal of Roxadustat Nicotinamide designated as Form III. In yet another aspect, the present invention provides Cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern as shown in Figure 2.
  • the present invention provides cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern having peaks at 3.86, 7.63, 11.42, 14.76, 15.22, 17.87, 23.0, 24.84, 28.69 ⁇ 0.2° 26.
  • the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form III as shown in table 2 below:
  • the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass c) adding an anti-solvent, d) cooling the reaction mass, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
  • the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, d) adding reaction mass obtained in step c to a precooled solvent containing seeds of Roxadustat Nicotinamide Form III, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
  • Figure 1 depicts the Powder X-Ray Diffraction (PXRD) pattern of Roxadustat Nicotinamide Cocrystal (1:1) Form II.
  • Figure 2 depicts the Powder X-Ray Diffraction (PXRD) pattern of Roxadustat Nicotinamide Cocrystal (1:1) Form III.
  • FIG. 4 depicts TGA/DTA of 1:1 Cocrystal of Roxadustat Nicotinamide Form II.
  • Figure 5 depicts DSC of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
  • FIG. 6 depicts TGA/DTA of 1:1 Cocrystal of Roxadustat Nicotinamide Form III
  • Figure 7 depicts ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form
  • Crystal structure of Form II shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H -O and N-H- • • O interactions.
  • Figure 8 depicts ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form
  • Crystal structure of Form III shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H -O and N-H- • • O interactions.
  • Figure 9(a) depicts Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form II
  • Figure 9(b) depicts Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
  • Figure 10 depicts Comparison of simulated and bulk PXRDs of 1:1 Cocrystal of Roxadustat Nicotinamide Form II.
  • Figure 11 depicts Comparison of simulated and bulk PXRDs of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
  • the present invention relates to Cocrystal of Roxadustat with Nicotinamide and its preparation thereof.
  • the present invention relates to Cocrystal of Roxadustat and Nicotinamide in the molar ratio of 1 : 1.
  • the present invention relates to Cocrystal of Roxadustat Nicotinamide designated as Form II.
  • the present invention relates to the Co-crystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern as shown in Figure 1.
  • the present invention relates to Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern having peaks at 10.00, 13.31, 15.64, 21.80, 22.65, 26.07, 28.17 ⁇ 0.2° 20.
  • the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form II as shown in table 1 below:
  • the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form II comprising the steps of: a) dissolving Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, and d) removing the solvent to isolate cocrystal of Roxadustat Nicotinamide Form II.
  • Roxadustat and Nicotinamide may be dissolved in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl Tetrahydro furan, Acetonitrile, tert-Butanol, Dimethyl sulfoxide, N,N- Dimethylformamide at temperature of about 70-90°C followed by cooling to room temperature and further cooling to about -80°C using precooled solution of methanol and dry ice or under liquid nitrogen for about 2-3 minutes.
  • the frozen material may be subjected to freeze drying for about 3 to 16 hours to obtain Cocrystal of Roxadustat Nicotinamide Form II.
  • the present invention relates to Cocrystal of Roxadustat Nicotinamide designated as Form III.
  • the present invention relates to Cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern as shown in Figure 2.
  • the present invention relates to cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern having peaks at 3.86, 7.63, 11.42, 14.76, 15.22, 17.87, 23.0, 24.84, 28.69+ 0.2° 26.
  • the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form III as shown in table 2 below:
  • the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) adding an anti-solvent, d) cooling the reaction mass, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
  • Roxadustat and Nicotinamide may be contacted in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2- Methyltetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1- Butanol, 2-Butanol, Dimethyl sulfoxide, Methyl isobutyl ketone, N,N- Dimethylformamide.
  • an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2- Methyltetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1- Butanol, 2-Butanol, Dimethyl sulfoxide, Methyl isobutyl ketone, N,N- Dimethylformamide.
  • the resultant reaction mass may be heated to about 60-85°C to obtain clear solution and added antisolvent selected from toluene, Heptane, Cyclohexane, Methylcyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether followed by cooling to 0-5°C.
  • the solid formed may be filtered and dried to obtain Cocrystal of Roxadustat Nicotinamide Form III.
  • the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, d) adding reaction mass obtained in step c to a precooled solvent containing seeds of Roxadustat Nicotinamide Form III, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
  • Roxadustat and Nicotinamide may be contacted in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl tetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1 -Butanol, 2- Butanol, Dimethyl sulfoxide, Methyl isobutyl ketone, N,N-Dimethylformamide.
  • the resultant reaction mass may be heated to about 60-85°C to obtain clear solution.
  • the obtained clear solution may be added to precooled solvent selected from Toluene, Heptane, Cyclohexane, Methylcyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether, esters selected from ethyl acetate, n-prolyl acetate, n-butyl acetate, alcohols selected from methanol, ethanol, isopropyl alcohol, 2-butanol, ketones selected form acetone, methyl ethyl ketone, methyl butyl ketone containing seeds of Roxadustat Nicotinamide Form III at about 0-5°C.
  • the solid formed may be filtered and dried to obtain Cocrystal of Roxadustat Nicotinamide Form III.
  • the Cocrystal of Roxadustat Nicotinamide may be isolated by employing one or more techniques selected from the group consisting of precipitation, filtration, decantation, distillation, concentration.
  • a pharmaceutical composition comprising of Cocrystal of Roxadustat Nicotinamide Form II or Form III and a pharmaceutically acceptable excipient.
  • compositions of the present invention may be formulated in accordance with conventional methods and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration.
  • DSC measurements were carried out on TA Q1000 of TA instruments. TGA/DTA data was recorded using the instrument TA Q5000 of TA instruments. DSC of Form II is shown in Figure 3.
  • Figure 4 shows the TGA/DTA data of Form II.
  • the DSC of 1:1 Cocrystal of Roxadustat Nicotinamide Form III shows a single melting endotherm at 149.82°C corresponding to melting of Form III ( Figure 5).
  • Figure 6 shows the TGA/DTA data of Form III.
  • SCXRD Single crystal X-ray diffraction
  • FIG. 7 ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form II. Crystal structure of Form II shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H—O and N-H—O interactions.
  • FIG. 8 ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form III. Crystal structure of Form III shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H—O and N-H—O interactions. Further the crystal structure analysis shows in Form II the carboxamide group of Roxadustat molecule forms N-H—N hydrogen bond with the pyridine functionality of Nicotinamide ( Figure 9a) whereas in Form III the carboxamide group of Nicotinamide is involved in N-H—N hydrogen bond with the pyridine functionality of Nicotinamide ( Figure 9b) and extends their crystal packing into the two- dimensional space.
  • phase purity of 1:1 Cocrystal of Roxadustat Nicotinamide Form II and Form III were analyzed by comparing the simulated PXRD patterns, calculated from the single crystal X-ray data of Form II and Form III, with the corresponding bulk PXRD patterns of Form II and Form III ( Figure 10 and 11).
  • the comparable PXRD patterns of simulated and experimental data further confirms the Co-crystal integrity of Roxadustat Nicotinamide Form II and Form III.
  • the physical and chemical stability of 1:1 Cocrystal of Roxadustat Nicotinamide Form III was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for six months as shown in below Table 4. The samples were analyzed by PXRD and purity by HPLC. The 1:1 Cocrystal of Roxadustat Nicotinamide Form III was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions up to six months.
  • Crystals of 1:1 cocrystal of Roxadustat Nicotinamide Form II and III were grown by dissolving respective forms in a mixture of 1,4-Dioxane/Toluene and allowing the clear solution to slowly evaporate over several days at 25 ⁇ 2°C. Further, good quality crystals of 1:1 cocrystal of Roxadustat Nicotinamide Form III (crystal 2) were grown by vapor diffusion technique in 1,4-Dioxane and Toluene after 4-5 days.
  • the DSC measurement was carried out on a TA Q2000 instrument. The experiment was conducted from 30°C to 250°C at a heating rate of 10.0°C/min with nitrogen purging at a flow rate of 50 mL/min. Standard aluminum pans covered by lids with three pinholes were used. Thermogravimetric Analysis (TGA)
  • the TGA measurement was carried out on TA Q5000 instrument. The experiment was conducted from ambient temperature to 300°C at a heating rate of 10.0 °C/min and purging with nitrogen at a flow rate of 25 mL/min.
  • the powder X-ray diffraction patterns of said polymorphs of the invention were measured on a PANalytical X’Pert PRO powder diffractometer equipped with a goniometer of 9/9 configuration and X'Celerator detector or Bruker D8 ADVANCE powder diffractometer equipped with a goniometer of 9/29 configuration and LYNXEYE detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.033° step size and 50- or 62-seconds step time.
  • Single crystal X-ray data were collected at room temperature on a Bruker D8 QUEST equipped with a four-circle kappa diffractometer and PHOTON 100 area detector.
  • a combination of Phi and Omega scans were used to collect the necessary data.
  • the raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite programs.
  • the structure was solved by intrinsic phasing method and further refined with the SHELXL module using ShelXle GUI software.
  • Anisotropic displacement parameters were included for all non-hydrogen atoms. The H atoms were positioned geometrically and treated as riding on their parent atoms.
  • Example 1 Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form II

Abstract

The present invention provides Cocrystal of Roxadustat Nicotinamide Form II and Cocrystal of Roxadustat Nicotinamide Form III, processes for their preparation and pharmaceutical composition thereof.

Description

COCRYSTAL OF ROXADUSTAT AND NICOTINAMIDE
CROSS-REFERENCE TO RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN202141054823 filed on November 26, 2021.
FIELD OF THE INVENTION:
The present invention relates to novel crystalline forms of Roxadustat Nicotinamide Cocrystal (1:1) and its preparation thereof.
BACKGROUND OF THE INVENTION:
Roxadustat is chemically known as [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid and is represented by Formula 1. Roxadustat is for the treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III clinical development in US.
Figure imgf000002_0001
Formula I
Roxadustat was first disclosed in US7323475 patent.
US patent 8883823 disclosed crystalline Form A, Form B, Form C & Form D [DMSO: water solvate], crystalline sodium salt, crystalline L-arginine salt, crystalline L-lysine salt, crystalline ethanolamine salt, crystalline diethanolamine salt, crystalline tromethamine salt and their preparations thereof.
US patent 9206134 disclosed crystalline forms I, II, III, IV, V, VI & VII of Roxadustat and their preparation thereof.
IN201641016266 patent application disclosed amorphous solid dispersion comprising Roxadustat and a pharmaceutically acceptable carrier and its preparation thereof. IN201741007950 patent application disclosed Cocrystal of Roxadustat comprising Roxadustat and Cocrystal former selected from caffeine, adenine, thymine, saccharine or the like.
IN201741028591 patent application disclosed L-proline co-crystal of Roxadustat, crystalline forms of Roxadustat [Form-6 & Form-y], urea co-crystal of Roxadustat and Nicotinamide co-crystal of Roxadustat.
The inventors of the present invention have developed novel crystalline forms of Roxadustat Nicotinamide Cocrystal suitable for formulation development.
OBJECT AND SUMMARY OF THE INVENTION:
The main object of the present invention provides crystalline forms of Roxadustat Nicotinamide Cocrystal and its preparation thereof.
In one aspect, the present invention provides Cocrystal of Roxadustat and Nicotinamide in the molar ratio of 1 : 1.
In yet another aspect, the present invention provides Cocrystal of Roxadustat Nicotinamide designated as Form II.
In yet another aspect, the present invention provides Cocrystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern as shown in Figure 1.
In yet another aspect, the present invention provides cocrystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern having peaks at 10.00, 13.31, 15.64, 21.80, 22.65, 26.07, 28.17± 0.2° 20.
In yet another aspect, the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form II as shown in table 1 below:
Table 1. Single Crystal X-ray Diffraction Data of 1:1 Cocrystal of Roxadustat
Nicotinamide Form II
Figure imgf000004_0001
Yet in another aspect, the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form II comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, and d) isolating cocrystal of Roxadustat Nicotinamide Form II.
In yet another aspect, the present invention provides Cocrystal of Roxadustat Nicotinamide designated as Form III. In yet another aspect, the present invention provides Cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern as shown in Figure 2.
In yet another aspect, the present invention provides cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern having peaks at 3.86, 7.63, 11.42, 14.76, 15.22, 17.87, 23.0, 24.84, 28.69± 0.2° 26.
In yet another aspect, the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form III as shown in table 2 below:
Table 2. Single Crystal X-ray Diffraction Data of 1:1 Cocrystal of Roxadustat
Nicotinamide Form III
Figure imgf000005_0001
Yet in another aspect, the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass c) adding an anti-solvent, d) cooling the reaction mass, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
Yet in another aspect, the present invention provides a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, d) adding reaction mass obtained in step c to a precooled solvent containing seeds of Roxadustat Nicotinamide Form III, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
Brief description of the figures:
Figure 1 depicts the Powder X-Ray Diffraction (PXRD) pattern of Roxadustat Nicotinamide Cocrystal (1:1) Form II.
Figure 2 depicts the Powder X-Ray Diffraction (PXRD) pattern of Roxadustat Nicotinamide Cocrystal (1:1) Form III.
Figure 3 depicts DSC of 1:1 Cocrystal of Roxadustat Nicotinamide Form II
Figure 4 depicts TGA/DTA of 1:1 Cocrystal of Roxadustat Nicotinamide Form II.
Figure 5 depicts DSC of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
Figure 6 depicts TGA/DTA of 1:1 Cocrystal of Roxadustat Nicotinamide Form III
Figure 7 depicts ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form
II. Crystal structure of Form II shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H -O and N-H- • • O interactions.
Figure 8 depicts ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form
III. Crystal structure of Form III shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H -O and N-H- • • O interactions.
Figure 9(a) depicts Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form II
Figure 9(b) depicts Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
Figure 10 depicts Comparison of simulated and bulk PXRDs of 1:1 Cocrystal of Roxadustat Nicotinamide Form II.
Figure 11 depicts Comparison of simulated and bulk PXRDs of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to Cocrystal of Roxadustat with Nicotinamide and its preparation thereof.
In one embodiment, the present invention relates to Cocrystal of Roxadustat and Nicotinamide in the molar ratio of 1 : 1.
In yet another embodiment, the present invention relates to Cocrystal of Roxadustat Nicotinamide designated as Form II.
In yet another embodiment, the present invention relates to the Co-crystal of Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern as shown in Figure 1.
In yet another embodiment, the present invention relates to Roxadustat Nicotinamide Form II characterized by powder X-ray diffraction pattern having peaks at 10.00, 13.31, 15.64, 21.80, 22.65, 26.07, 28.17 ± 0.2° 20.
In yet another aspect, the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form II as shown in table 1 below:
Table 1. Single Crystal X-ray Diffraction Data of 1:1 Cocrystal of Roxadustat Nicotinamide Form II
Figure imgf000008_0001
Yet in another embodiment, the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form II comprising the steps of: a) dissolving Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, and d) removing the solvent to isolate cocrystal of Roxadustat Nicotinamide Form II.
According to the present invention, Roxadustat and Nicotinamide may be dissolved in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl Tetrahydro furan, Acetonitrile, tert-Butanol, Dimethyl sulfoxide, N,N- Dimethylformamide at temperature of about 70-90°C followed by cooling to room temperature and further cooling to about -80°C using precooled solution of methanol and dry ice or under liquid nitrogen for about 2-3 minutes. The frozen material may be subjected to freeze drying for about 3 to 16 hours to obtain Cocrystal of Roxadustat Nicotinamide Form II.
In yet another embodiment, the present invention relates to Cocrystal of Roxadustat Nicotinamide designated as Form III.
In yet another embodiment, the present invention relates to Cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern as shown in Figure 2.
In yet another embodiment, the present invention relates to cocrystal of Roxadustat Nicotinamide Form III characterized by powder X-ray diffraction pattern having peaks at 3.86, 7.63, 11.42, 14.76, 15.22, 17.87, 23.0, 24.84, 28.69+ 0.2° 26.
In yet another aspect, the present invention provides single crystal X-ray diffraction data of Cocrystal of Roxadustat Nicotinamide Form III as shown in table 2 below:
Table 2. Single Crystal X-ray Diffraction Data of 1:1 Cocrystal of Roxadustat
Nicotinamide Form III
Figure imgf000009_0001
Figure imgf000010_0001
Yet in another embodiment, the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) adding an anti-solvent, d) cooling the reaction mass, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
According to the present invention, Roxadustat and Nicotinamide may be contacted in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2- Methyltetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1- Butanol, 2-Butanol, Dimethyl sulfoxide, Methyl isobutyl ketone, N,N- Dimethylformamide. The resultant reaction mass may be heated to about 60-85°C to obtain clear solution and added antisolvent selected from toluene, Heptane, Cyclohexane, Methylcyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether followed by cooling to 0-5°C. The solid formed may be filtered and dried to obtain Cocrystal of Roxadustat Nicotinamide Form III. Yet in another embodiment, the present invention relates to a process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, d) adding reaction mass obtained in step c to a precooled solvent containing seeds of Roxadustat Nicotinamide Form III, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
According to the present invention, Roxadustat and Nicotinamide may be contacted in an organic solvent selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl tetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1 -Butanol, 2- Butanol, Dimethyl sulfoxide, Methyl isobutyl ketone, N,N-Dimethylformamide. The resultant reaction mass may be heated to about 60-85°C to obtain clear solution. The obtained clear solution may be added to precooled solvent selected from Toluene, Heptane, Cyclohexane, Methylcyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether, esters selected from ethyl acetate, n-prolyl acetate, n-butyl acetate, alcohols selected from methanol, ethanol, isopropyl alcohol, 2-butanol, ketones selected form acetone, methyl ethyl ketone, methyl butyl ketone containing seeds of Roxadustat Nicotinamide Form III at about 0-5°C. The solid formed may be filtered and dried to obtain Cocrystal of Roxadustat Nicotinamide Form III.
According to the present invention, the Cocrystal of Roxadustat Nicotinamide may be isolated by employing one or more techniques selected from the group consisting of precipitation, filtration, decantation, distillation, concentration.
A pharmaceutical composition comprising of Cocrystal of Roxadustat Nicotinamide Form II or Form III and a pharmaceutically acceptable excipient.
The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration.
DSC and TGA analysis
The DSC measurements were carried out on TA Q1000 of TA instruments. TGA/DTA data was recorded using the instrument TA Q5000 of TA instruments. DSC of Form II is shown in Figure 3. Figure 4 shows the TGA/DTA data of Form II. The DSC of 1:1 Cocrystal of Roxadustat Nicotinamide Form III shows a single melting endotherm at 149.82°C corresponding to melting of Form III (Figure 5). Figure 6 shows the TGA/DTA data of Form III.
Single Crystal X-ray Diffraction analysis
Single crystal X-ray diffraction (SCXRD) data of 1:1 Cocrystal of Roxadustat Nicotinamide Form II and Form III were collected on a Bruker D8 QUEST diffractometer equipped with a PHOTON-III detector, using graphite monochromated Mo Ka radiation at 293K. The crystallographic data of Form II and Form III are shown in Tables 1 and 2. Figure 7 and Figure 8 represents ORTEP diagrams of 1:1 Cocrystal of Roxadustat Nicotinamide Form II and Form III. Crystal structure analysis shows 1:1 Co-crystal of Roxadustat Nicotinamide Form II crystallizes in Monoclinic P2i/c space group whereas 1:1 Co-crystal of Roxadustat Nicotinamide Form III crystallizes in Monoclinic P2i space group with the asymmetric unit containing one molecule of Roxadustat and one molecule of Nicotinamide which are held together by acid-amide heterosynthon (Figure 7 and 8) through the O-H—O and N-H—O hydrogen bonds.
Figure 7. ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form II. Crystal structure of Form II shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H—O and N-H—O interactions.
Figure 8. ORTEP diagram of 1:1 Cocrystal of Roxadustat-Nicotinamide Form III. Crystal structure of Form III shows the asymmetric unit consists of neutral molecules of Roxadustat and Nicotinamide hydrogen bonded through O-H—O and N-H—O interactions. Further the crystal structure analysis shows in Form II the carboxamide group of Roxadustat molecule forms N-H—N hydrogen bond with the pyridine functionality of Nicotinamide (Figure 9a) whereas in Form III the carboxamide group of Nicotinamide is involved in N-H—N hydrogen bond with the pyridine functionality of Nicotinamide (Figure 9b) and extends their crystal packing into the two- dimensional space.
Figure 9. (a) Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form II (b) Crystal structure of 1:1 Cocrystal of Roxadustat Nicotinamide Form III.
The phase purity analysis
The phase purity of 1:1 Cocrystal of Roxadustat Nicotinamide Form II and Form III were analyzed by comparing the simulated PXRD patterns, calculated from the single crystal X-ray data of Form II and Form III, with the corresponding bulk PXRD patterns of Form II and Form III (Figure 10 and 11). The comparable PXRD patterns of simulated and experimental data further confirms the Co-crystal integrity of Roxadustat Nicotinamide Form II and Form III.
Stress stability study
The lab stress stability study on polymorphs of 1:1 Cocrystal of Roxadustat Nicotinamide Form II and Form III shows Form II is highly unstable to heat and humidity whereas Form III is stable to heat and humidity as shown in Table 3.
Table 3
Figure imgf000013_0001
Indicative Stability Study
In yet another embodiment, the physical and chemical stability of 1:1 Cocrystal of Roxadustat Nicotinamide Form III was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for six months as shown in below Table 4. The samples were analyzed by PXRD and purity by HPLC. The 1:1 Cocrystal of Roxadustat Nicotinamide Form III was found to be physically and chemically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions up to six months.
Table 4
Figure imgf000014_0001
Table 1. Single Crystal X-ray Diffraction Data of 1:1 Cocrystal of Roxadustat Nicotinamide Form II
Crystal growth procedure for Cocrystal of Roxadustat Nicotinamide Form II and III
Crystals of 1:1 cocrystal of Roxadustat Nicotinamide Form II and III were grown by dissolving respective forms in a mixture of 1,4-Dioxane/Toluene and allowing the clear solution to slowly evaporate over several days at 25±2°C. Further, good quality crystals of 1:1 cocrystal of Roxadustat Nicotinamide Form III (crystal 2) were grown by vapor diffusion technique in 1,4-Dioxane and Toluene after 4-5 days.
Instrument details
Differential Scanning Calorimetry (DSC)
The DSC measurement was carried out on a TA Q2000 instrument. The experiment was conducted from 30°C to 250°C at a heating rate of 10.0°C/min with nitrogen purging at a flow rate of 50 mL/min. Standard aluminum pans covered by lids with three pinholes were used. Thermogravimetric Analysis (TGA)
The TGA measurement was carried out on TA Q5000 instrument. The experiment was conducted from ambient temperature to 300°C at a heating rate of 10.0 °C/min and purging with nitrogen at a flow rate of 25 mL/min.
Powder X-Ray Diffraction (PXRD)
The powder X-ray diffraction patterns of said polymorphs of the invention were measured on a PANalytical X’Pert PRO powder diffractometer equipped with a goniometer of 9/9 configuration and X'Celerator detector or Bruker D8 ADVANCE powder diffractometer equipped with a goniometer of 9/29 configuration and LYNXEYE detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.033° step size and 50- or 62-seconds step time.
Single Crystal X-Ray Diffraction (SCXRD)
Single crystal X-ray data were collected at room temperature on a Bruker D8 QUEST equipped with a four-circle kappa diffractometer and PHOTON 100 area detector. An Ips microfocus Molybdenum source (k=0.71073A) supplied the multi-mirror monochromated incident X-ray beam. A combination of Phi and Omega scans were used to collect the necessary data. The raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite programs. The structure was solved by intrinsic phasing method and further refined with the SHELXL module using ShelXle GUI software. Anisotropic displacement parameters were included for all non-hydrogen atoms. The H atoms were positioned geometrically and treated as riding on their parent atoms.
The following example is provided for illustrative purpose only and is not intended to limit the scope of the invention in anyway.
EXAMPLES:
Example 1: Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form II
In a RBF charged Roxadustat (500mg), Nicotinamide (170mg) and 1,4-Dioxane (6mL). Heated the contents to 80-85°C and stir for 5-10minutes. The obtained clear solution was cooled to 25±5°C, filtered and immersed in precooled solution of Methanol and dry ice at -80°C for about 2-3 minutes. The frozen material was subjected to freeze drying for about 4 hours using VirTis Advantage lyophilizer. The product obtained was confirmed by PXRD as 1:1 cocrystal of Roxadustat Nicotinamide Form II.
Example 2: Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form II
In a RBF charged Roxadustat (1.0g), Nicotinamide (0.34g) and 1,4-Dioxane (13mL). Heated the contents to 80-85°C and stir for 10-15minutes. The obtained clear solution was cooled to 25±5°C and filtered through hyflo to remove any undissolved particulate matter and then subjected to lyophilization for about 16h using Labocon lyophilizer (Model: LFD-BT-104). The product obtained was confirmed by PXRD as 1:1 cocrystal of Roxadustat Nicotinamide Form II.
Example 3: Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form III
In a RBF, charged Roxadustat (50mg), Nicotinamide (17mg) and 1,4-Dioxane (ImL) at 25±5°C. Heated the contents to 60-70°C and stirred for 5-10min at 60-70°C. To the obtained clear solution added Toluene (ImL) at 60-70°C. The reaction mass was cooled to 0-5°C and maintained under stirring at 0-5°C for 16h. The product obtained was filtered and suck-dried for 10 min at 25-30°C. The solid obtained was identified by PXRD as 1:1 cocrystal of Roxadustat Nicotinamide Form III.
Example 4: Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form III
In a RBF, charged Roxadustat (1.0g), Nicotinamide (0.34g) and 1,4-Dioxane (15mL) at 25±5°C. Heated the contents to 80-85°C and stirred for 5-10min at 80-85°C. To the obtained clear solution added Toluene (ImL) at 80-85°C and maintain for Ih at 80- 85°C. The reaction mass was cooled to 0-5°C and maintained under stirring at 0-5°C for 3-4h. The product obtained was filtered, washed with Toluene (2mL) and suck- dried for 10-15 min at 25-30°C. Further dried the material under vacuum at 40°C for 16h. The solid obtained was identified by PXRD as 1:1 cocrystal of Roxadustat Nicotinamide Form III. Example 5: Process for the preparation of 1:1 cocrystal of Roxadustat Nicotinamide Form III
In a RBF, charged Roxadustat (3.0g), Nicotinamide (1.04g) and 1,4-Dioxane (45mL) at 25±5°C. Heated the contents to 80-85°C and stirred for 5-10 min at 80-85°C. The obtained clear solution was cooled to 25±5°C. Added the above clear solution in to pre-cooled solution of toluene (45mL) containing seeds of Roxadustat Nicotinamide Form III (lOmg) at 0 to -5°C. Maintain the reaction mass for 1.5 h at 0 to -5°C. Filter the solid, wash with Toluene (3mL) and suck-dried for 10-15 min at 25-30°C. Further dried the material under vacuum at 50°C for 14h. The solid obtained was identified by
PXRD as 1:1 cocrystal of Roxadustat Nicotinamide Form III.

Claims

We claim:
1) A Cocrystal of Roxadustat Nicotinamide Form III characterized by power X-ray powder diffraction pattern having peaks at about 3.86, 7.63, 11.42, 14.76, 15.22, 17.87, 23.0, 24.84, 28.69± 0.2° 26.
2) A process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) adding an anti-solvent, d) cooling the reaction mass, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
3) The process as claimed in claim 2, wherein organic solvent used in step (a) selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl tetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1 -Butanol, 2-Butanol, Dimethylsulfoxide, Methyl isobutyl ketone, N,N-Dimethylformamide and antisolvent used in step (c) selected from Toluene, Heptane, Cyclohexane, Methyl cyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether.
4) A process for the preparation of Cocrystal of Roxadustat Nicotinamide Form III comprising the steps of: a) contacting Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, d) adding reaction mass obtained in step c to a precooled solvent containing seeds of Roxadustat Nicotinamide Form III, and e) isolating cocrystal of Roxadustat Nicotinamide Form III.
5) The process as claimed in claim 4, wherein organic solvent used in step (a) selected from 1,4-Dioxane, Tetrahydro furan, 2-Methyl tetrahydrofuran, 1,2-Dimethoxyethane, Methyl ethyl ketone, Acetone, 1 -Butanol, 2-Butanol, Dimethylsulfoxide, Methyl isobutyl ketone, N,N-Dimethylformamide and precooled solvent used in step (d) selected from toluene, Heptane, Cyclohexane, Methyl cyclohexane, Hexanes, Cyclopentyl methyl ether, Anisole, Diethyl ether, Methyl tertiary butyl ether, Diisopropyl ether, esters selected from Ethyl acetate, Prolyl acetate, Butyl acetate, alcohols selected from methanol, ethanol, isopropyl alcohol, 2-butanol, ketones selected form acetone, methyl ethyl ketone, methyl butyl ketone. ) A Cocrystal of Roxadustat Nicotinamide Form II characterized by power X-ray powder diffraction pattern having peaks at about 10.00, 13.31, 15.64, 21.80, 22.65, 26.07, 28.17 + 0.2° 20. ) A process for the preparation of Cocrystal of Roxadustat Nicotinamide Form II comprising the steps of: a) dissolving Roxadustat with Nicotinamide in an organic solvent, b) heating the reaction mass, c) cooling the reaction mass, and d) removing the solvent to isolate cocrystal of Roxadustat Nicotinamide Form II.) The process as claimed in claim 7, wherein organic solvent used in step (a) selected from 1,4-Dioxane, Tetrahydrofuran, 2-Methyl tetrahydrofuran, Acetonitrile, tert- Butanol, Dimethyl sulfoxide, N,N-Dimethylformamide. preferably 1,4-Dioxane.) A pharmaceutical composition comprising the Cocrystal of Roxadustat Nicotinamide as defined in any one of the preceding claims and at least one pharmaceutically acceptable excipient.
PCT/IN2022/051019 2021-11-26 2022-11-22 Cocrystal of roxadustat and nicotinamide WO2023095162A1 (en)

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US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
US9206134B2 (en) 2011-07-22 2015-12-08 Beijing Betta Pharmaceuticals Co. Ltd. Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof
WO2019030711A1 (en) * 2017-08-11 2019-02-14 Dr. Reddy’S Laboratories Limited Polymorphs and co-crystals of roxadustat
CN110218184A (en) * 2018-03-01 2019-09-10 广东东阳光药业有限公司 Nuo Desita eutectic and preparation method thereof

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US7323475B2 (en) 2003-06-06 2008-01-29 Fibrogen, Inc. Nitrogen-containing heteroaryl compounds and methods of use thereof
US9206134B2 (en) 2011-07-22 2015-12-08 Beijing Betta Pharmaceuticals Co. Ltd. Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof
US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
WO2019030711A1 (en) * 2017-08-11 2019-02-14 Dr. Reddy’S Laboratories Limited Polymorphs and co-crystals of roxadustat
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