WO2022064526A1 - Solid state forms of epacadostat and their processes for preparation thereof - Google Patents

Solid state forms of epacadostat and their processes for preparation thereof Download PDF

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Publication number
WO2022064526A1
WO2022064526A1 PCT/IN2021/050940 IN2021050940W WO2022064526A1 WO 2022064526 A1 WO2022064526 A1 WO 2022064526A1 IN 2021050940 W IN2021050940 W IN 2021050940W WO 2022064526 A1 WO2022064526 A1 WO 2022064526A1
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Prior art keywords
epacadostat
acid
crystalline form
solvent
crystal
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PCT/IN2021/050940
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French (fr)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Venkata Narasayya SALADI
Balraju KAMMARI
Bhagya Lakshmi KANDADI
Laxman GANDE
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2022064526A1 publication Critical patent/WO2022064526A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles

Definitions

  • the present invention relates to solid-state forms of Epacadostat of formula- 1 and their processes for preparation thereof. Structure of formula- 1 is shown as follows.
  • Epacadostat is chemically known as 4-( ⁇ 2-[(aminosulfonyl)amino]ethyl ⁇ amino)- N-(3-bromo-4-fluorophenyl)-N'-hydroxy-l,2,5-oxadiazole-3-carboximidamide.
  • US patent number 8088803 discloses the process for the preparation of Epacadostat. US ’803 describe anhydrous crystalline form of Epacadostat of formula- 1.
  • solid-state study of an active pharmaceutical ingredient aims to widen the variety of polymorphs that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.
  • Discovering new solid state forms such as polymorphic forms, solvates or cocrystals of a pharmaceutical product, solid dispersion with pharmaceutically acceptable excipients can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate forms that facilitate conversion to other solid-state forms.
  • New polymorphic forms, solvates or co-crystals, solid dispersions of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, better purity, improved dissolution profile, or improved shelf-life.
  • a co-crystal of a drug is a distinct chemical composition between the drug and the co-crystal former, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and the co-crystal former individually.
  • co-crystals are comprised of neutral species.
  • charge balance unlike a salt, one cannot determine the stoichiometry of a co-crystal former based on charge balance. Indeed, one can often obtain co-crystals having stoichiometric ratios of drug to the cocrystal former of greater than or less than 1: 1.
  • co-crystal or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state.
  • co-crystal and “co-crystal formers” and “coformers” are generally understood to be synonymous terms referring to such a system.
  • co-crystal former The second component in the co-crystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a "co-crystal former".
  • pharmaceutically acceptable co-crystal formers include any molecule considered acceptable as a counter ion for a pharmaceutical salt or known as a pharmaceutical excipient.
  • the first embodiment of the present invention provides solid dispersions comprising Epacadostat of formula- 1 and one or more pharmaceutically acceptable excipients.
  • the second embodiment of the present invention provides a process for the preparation of solid dispersions comprising Epacadostat of formula- 1 and one or more pharmaceutically acceptable excipients.
  • the third embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after designated as crystalline form-M.
  • the fourth embodiment of the present invention provides a process for the preparation of crystalline form M of Epacadostat of formula- 1.
  • the fifth embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1, herein after designated as crystalline form-S.
  • the sixth embodiment of the present invention provides a process for the preparation of crystalline form S of Epacadostat of formula- 1.
  • the seventh embodiment of the present invention provides Co-crystal of Epacadostat and co- crystal former.
  • the eight embodiment of the present invention provides a process for the preparation of Co-crystal of Epacadostat and co- crystal former.
  • the ninth embodiment of the present invention provides a novel crystalline form of Epacadostat and L-proline co-crystal, herein after designated as crystalline form-Nl.
  • the tenth embodiment of the present invention provides a process for the preparation of crystalline form-Nl of Epacadostat and L-proline co-crystal. Brief description of the drawings:
  • Figure-1 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Epacadostat and Co-povidone.
  • Figure-2 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Epacadostat and PVP K-30.
  • Figure-3 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Epacadostat and HPMC-E5.
  • Figure-4 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Epacadostat and HPMC-AS.
  • Figure-5 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of amorphous solid dispersion comprising Epacadostat and HPC-EF.
  • Figure-6 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of crystalline form M of Epacadostat.
  • Figure-7 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of crystalline form S of Epacadostat.
  • Figure-8 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of crystalline form-N of Epacadostat and L-proline co-crystal.
  • Figure-9 Illustrates the powder X-Ray diffraction ⁇ PXRD ⁇ pattern of crystalline form- N 1 of Epacadostat and L-proline co-crystal.
  • solvent used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1,4-di oxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylform
  • compositions or “pharmaceutical formulations” used in the present invention include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • solid dispersion as used in the present invention is a mixture comprises Epacadostat and one or more excipients.
  • solid dispersion and pre-mix are used interchangeably.
  • the first embodiment of the present invention provides solid dispersion comprising Epacadostat and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate, hydroxyprop
  • the ratio of the weight of Epacadostat to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to about 1:5.
  • the solid dispersion the present invention could be either in a crystalline or amorphous form.
  • the second aspect of first embodiment provides the solid dispersions are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
  • the third aspect of first embodiment provides the use solid dispersions of the present invention for the preparation of pharmaceutical formulations.
  • the fourth aspect of first embodiment provides pharmaceutical composition comprising solid dispersions of the present invention and at least one pharmaceutically acceptable excipient.
  • the second embodiment of the present invention provides a process for the preparation of solid dispersion comprising Epacadostat and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Epacadostat and one or more excipients in a solvent, b) obtaining solid dispersion comprising Epacadostat and the corresponding excipient(s).
  • Providing a solution of Epacadostat and excipient(s) in a solvent in step-a) of the above process can be carried out by combining Epacadostat and excipient(s) selected from those defined above with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the reaction mixture to a temperature ranging from 30°C to 150°C based on the solvent used; wherein the solvent used in step-a) is a solvent selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, and n-pentanol, and mixtures thereof.
  • the excipients are preferably selected from PVP, Copovidone, HPC, HPMC-AS, HPMC-E5.
  • the solvent is selected from methanol.
  • Obtaining solid dispersion in step-b) of the above process can be done by removing the solvent from the reaction mixture.
  • the technique used for the removal of the solvent from the reaction mixture is distillation optionally under reduced pressure.
  • Third embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after the said crystalline form is designated as crystalline form-M.
  • the first aspect of third embodiment provides crystalline form-M of Epacadostat of formula- 1 characterized by one or more of the following characteristics: i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8° and 20.2° ⁇ 0.2° 26. ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8°, 20.2°, 23.4°, 24.4° and 36.9° ⁇ 0.2° 20. iii) PXRD pattern illustrated in figure-6.
  • the second aspect of third embodiment provides crystalline form-M of Epacadostat used for the preparation of various pharmaceutical formulations.
  • the third aspect of third embodiment provides a pharmaceutical composition comprising the crystalline form-M of Epacadostat of formula- 1 and at least one pharmaceutically acceptable excipient.
  • Fourth embodiment of the present invention provides process for the preparation of crystalline form-M of Epacadostat of formula- 1, comprising: a) dissolving Epacadostat in a solvent, b) isolating crystalline form-M of Epacadostat of formula- 1.
  • the solvent in step-a) is selected from alcohol solvents, chloro solvents, ether solvents, ketone solvents, ester solvents and/or mixtures thereof; isolating crystalline form-M of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent; wherein anti-solvent is selected from ether solvents, hydrocarbon solvents and/or mixtures thereof.
  • step a) or step-b) optionally involve seeding with crystalline form-M of compound of formula- 1.
  • the fifth embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after the said crystalline form is designated as crystalline form-S.
  • the first aspect of fifth embodiment provides crystalline form-S of Epacadostat of formula- 1 characterized by one or more of the following characteristics: i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3° and 20.8° ⁇ 0.2° 20; or ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3°, 15.9°, 16.8°, 20.8°, 22.3° and 23.2° ⁇ 0.2° 26; or iii) PXRD pattern illustrated in figure-7.
  • the second aspect of fifth embodiment provides crystalline form-S of Epacadostat used for the preparation of various pharmaceutical formulations.
  • the third aspect of fifth embodiment provides a pharmaceutical composition comprising the crystalline form-S of Epacadostat of formula- 1 and at least one pharmaceutically acceptable excipient.
  • Sixth embodiment of the present invention provides a process for the preparation of crystalline form-S of Epacadostat of formula- 1 , comprising: a) dissolving Epacadostat in a solvent comprising dimethyl sulfoxide or a mixture of dimethyl sulfoxide and a solvent, b) isolating crystalline form-S of Epacadostat of formula- 1.
  • the solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof; isolating crystalline form-S of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent.
  • step a) or step-b) optionally involve seeding with crystalline form-S of compound of formula- 1.
  • Seventh embodiment of the present invention provides Co-Crystal of Epacadostat and a co-crystal former.
  • the co-crystal former is at least one acid selected from the group consisting of L-proline, D-proline, DL-proline, DL- pipecolic acid, L-pipecolic acid, D-pipecolic acid, nicotinic acid, pyrazine-2-carboxylic acid, hydrogen fluoride, hydrogen iodide, boric acid, nitric acid, carbonic acid, phosphoric acid, peracetic acid, periodic acid, sulfamic acid, sulfurous acid, thioacetic acid, thiodipropionic acid, trifluoromethane sulfonic acid, trimethylacetic acid, tertiary butylacetic acid, 2,2-dichloro-acetic acid, thiocyanic acid, isethionic acid, acetylaminoacetic acid, propionic acid, 2-mercaptopropionic acid, butyric acid, isobutyric acid, valeric acid, 2-methylval
  • co-crystals of the present invention could be either in a crystalline or amorphous form.
  • the second aspect of seventh embodiment provides Co-Crystal of Epacadostat and a co-crystal former used for the preparation of various pharmaceutical formulations.
  • the third aspect of seventh embodiment provides a pharmaceutical composition comprising Co-Crystal of Epacadostat and a co-crystal former and at least one pharmaceutically acceptable excipient.
  • the fifth aspect of the seventh embodiment provides a crystalline form of CoCrystal of Epacadostat and L-proline of formula- 1 a, herein after the said crystalline form of co-crystal is designated as form-N.
  • the crystalline form-N of Co-Crystal of Epacadostat and L-proline can be characterized by one or more of the following characteristics: i) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3° and 11.2° 20 ⁇ 0.2° 26; or ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3°, 11.2°, 20.0°, 25.6° and 26.1° 20 ⁇ 0.2° 20; or iii)PXRD pattern as depicted in Figure 8.
  • Eighth embodiment of the present invention provides a process for the preparation of Co-Crystal of Epacadostat and a co-crystal former comprises contacting Epacadostat with a co-crystal former in a solvent.
  • the amount of Co-crystal former is about 0.5 mole equivalent to about 5 mole equivalents with respect to Epacadostat.
  • the amount of Co-crystal former is about 0.8 mole equivalent to about 2.5 mole equivalents with respect to Epacadostat.
  • the Co-Crystal of Epacadostat and a co-crystal former may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the Co-Crystal of Epacadostat and a co-crystal former may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof.
  • Ninth embodiment of the present invention provides a novel crystalline form of Epacadostat and L-proline co-crystal of formula- la herein after designated as crystalline form-Nl.
  • the first aspect of the ninth embodiment provides a crystalline form-Nl of Epacadostat and L-proline co-crystal can be characterized by one or more of the following characteristics: i) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9 and 14.8 20 ⁇ 0.2° 20; or ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9, 11.8, 14.8, and 30.1° 20 ⁇ 0.2° 20; or iii) PXRD pattern as depicted in Figure 9.
  • the second aspect of ninth embodiment provides crystalline form-Nl of Epacadostat and L-proline co-crystal used for the preparation of various pharmaceutical formulations.
  • the third aspect of ninth embodiment provides a pharmaceutical composition comprising crystalline form-N 1 of Epacadostat and L-proline co-crystal and at least one pharmaceutically acceptable excipient.
  • Tenth embodiment of the present invention provides a process for preparation of crystalline form-Nl of Epacadostat and L-proline co-crystal comprising the step of exposing crystalline form-N of Epacadostat and L-proline co-crystal to a relative humidity of 75 ⁇ 5% at 40 °C for 48 hours ⁇ 1 hour.
  • Epacadostat is prepared by any of the processes disclosed in literature such as US8088803 B2 or any other references.
  • compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • the eleventh embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of solid state forms of the present invention.
  • the solid-state forms of the present invention produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
  • Example 1 Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and Co-povidone.
  • Example 2 Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and Povidone K-30.
  • Example 3 Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPMC-E5.
  • Example 4 Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPMC-AS.
  • Example 5 Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPC-EF.
  • Epacadostat (1 g) was dissolved in the mixture of acetone (12 ml) and dichloromethane (6 ml) at 25-30°C. This solution was added to pre-cooled mixture of n-heptane (25 ml) and methyl tertiary butyl ether (25 ml) at -40° to -45 °C and slowly raised the temperature to 25-30°C. Filtered the precipitated solid and dried to get crystalline form M of Epacadostat.
  • Epacadostat 250 mg was dissolved in the mixture of acetone (4 ml) and dichloromethane (2 ml) at 25-30°C. This solution was added to pre-cooled mixture of n- heptane (10 ml) and methyl tertiary butyl ether (10 ml) at -40° to -45 °C and slowly raised the temperature to 25-30°C. Filtered the precipitated solid and dried to get crystalline form M of Epacadostat.
  • Epacadostat 500 mg was dissolved in the mixture of dimethylsulfoxide (1 ml) and water (3 ml) at 80-85°C. The obtained solution was cooled to 0-5°C and stirred at the same temperature. Filtered precipitated the solid and dried to get title compound.
  • Example 10 Preparation of crystalline form-Nl of Epacadostat and L-proline cocrystal
  • Epacadostat and L-proline co-crystal (500 mg) obtained in Example-9 was placed in a petri dish and was subjected to a relative humidity of 75% at 40°C for 48 hours to afford title compound.

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Abstract

The present invention relates to solid state forms of Epacadostat of formula-1 which is chemically known as 4- ( { 2- [(amino sulfonyl) amino] ethyl} amino)-N-(3-bromo- 4 - fluoro phenyl) - N' - hydroxy- 1,2,5- oxa diazole- 3 - carboximidamide and processes for preparation the said solid state forms.

Description

Solid state forms of Epacadostat and their processes for preparation thereof
This application claims the benefit of priority of our Indian patent application numbers 202041041791 filed on September 25, 2020, 202041049748 filed on November 13, 2020, 202141003867 filed on Jan 28, 2021 and 202141008205 filed on February 26, 2021 which are incorporated herein by reference.
Field of the invention:
The present invention relates to solid-state forms of Epacadostat of formula- 1 and their processes for preparation thereof. Structure of formula- 1 is shown as follows.
Figure imgf000002_0001
Formula- 1
Background of the invention:
Epacadostat is chemically known as 4-({2-[(aminosulfonyl)amino]ethyl}amino)- N-(3-bromo-4-fluorophenyl)-N'-hydroxy-l,2,5-oxadiazole-3-carboximidamide.
US patent number 8088803 (herein described as US'803) discloses the process for the preparation of Epacadostat. US ’803 describe anhydrous crystalline form of Epacadostat of formula- 1.
There is a still develop further solid-state forms or polymorphs of Epacadostat to meet the pharmaceuticals requirements.
Since the development of new polymorphic forms of an active pharmaceutical ingredient provides new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.
Furthermore, solid-state study of an active pharmaceutical ingredient aims to widen the variety of polymorphs that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.
Discovering new solid state forms such as polymorphic forms, solvates or cocrystals of a pharmaceutical product, solid dispersion with pharmaceutically acceptable excipients can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate forms that facilitate conversion to other solid-state forms. New polymorphic forms, solvates or co-crystals, solid dispersions of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, better purity, improved dissolution profile, or improved shelf-life.
A co-crystal of a drug is a distinct chemical composition between the drug and the co-crystal former, and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the drug and the co-crystal former individually. Unlike salts, which possess a neutral net charge, but which are comprised of charge- balanced components, co-crystals are comprised of neutral species. Thus, unlike a salt, one cannot determine the stoichiometry of a co-crystal former based on charge balance. Indeed, one can often obtain co-crystals having stoichiometric ratios of drug to the cocrystal former of greater than or less than 1: 1. The stoichiometric ratio of an API to cocrystal former is a generally unpredictable feature of a co-crystal. On the other hand, the formation of pharmaceutically acceptable co crystals of active pharmaceutical ingredients provides an alternative approach to the generation of new solid forms of the active substance. In this context a co-crystal, or alternatively co-crystal, is understood to be a binary molecular crystal containing the molecules of the API together with another molecular species in a defined stoichiometric ratio where both components are in their neutral state. In this case, the terms "co-crystal" and "co-crystal formers" and “coformers” are generally understood to be synonymous terms referring to such a system. The second component in the co-crystal (the component other than the active pharmaceutical ingredient) is commonly referred to as a "co-crystal former". Pharmaceutically acceptable co-crystal formers include any molecule considered acceptable as a counter ion for a pharmaceutical salt or known as a pharmaceutical excipient.
Brief description of the invention:
The first embodiment of the present invention provides solid dispersions comprising Epacadostat of formula- 1 and one or more pharmaceutically acceptable excipients.
The second embodiment of the present invention provides a process for the preparation of solid dispersions comprising Epacadostat of formula- 1 and one or more pharmaceutically acceptable excipients.
The third embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after designated as crystalline form-M.
The fourth embodiment of the present invention provides a process for the preparation of crystalline form M of Epacadostat of formula- 1.
The fifth embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1, herein after designated as crystalline form-S.
The sixth embodiment of the present invention provides a process for the preparation of crystalline form S of Epacadostat of formula- 1.
The seventh embodiment of the present invention provides Co-crystal of Epacadostat and co- crystal former.
The eight embodiment of the present invention provides a process for the preparation of Co-crystal of Epacadostat and co- crystal former.
The ninth embodiment of the present invention provides a novel crystalline form of Epacadostat and L-proline co-crystal, herein after designated as crystalline form-Nl.
The tenth embodiment of the present invention provides a process for the preparation of crystalline form-Nl of Epacadostat and L-proline co-crystal. Brief description of the drawings:
Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Epacadostat and Co-povidone.
Figure-2 Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Epacadostat and PVP K-30.
Figure-3: Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Epacadostat and HPMC-E5.
Figure-4: Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Epacadostat and HPMC-AS.
Figure-5: Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Epacadostat and HPC-EF.
Figure-6: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form M of Epacadostat.
Figure-7: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form S of Epacadostat.
Figure-8: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-N of Epacadostat and L-proline co-crystal.
Figure-9: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form- N 1 of Epacadostat and L-proline co-crystal.
Detailed description of the invention:
The “solvent” used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1,4-di oxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and mixtures thereof; “polar solvents” such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.
The term "pharmaceutical compositions" or "pharmaceutical formulations" used in the present invention include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The term “solid dispersion” as used in the present invention is a mixture comprises Epacadostat and one or more excipients. In the present application, solid dispersion and pre-mix are used interchangeably.
The first embodiment of the present invention provides solid dispersion comprising Epacadostat and one or more pharmaceutically acceptable excipients.
The term “pharmaceutically acceptable excipients” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
In the present invention, the ratio of the weight of Epacadostat to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to about 1:5.
The solid dispersion the present invention could be either in a crystalline or amorphous form.
The second aspect of first embodiment provides the solid dispersions are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
The third aspect of first embodiment provides the use solid dispersions of the present invention for the preparation of pharmaceutical formulations.
The fourth aspect of first embodiment provides pharmaceutical composition comprising solid dispersions of the present invention and at least one pharmaceutically acceptable excipient.
The second embodiment of the present invention provides a process for the preparation of solid dispersion comprising Epacadostat and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Epacadostat and one or more excipients in a solvent, b) obtaining solid dispersion comprising Epacadostat and the corresponding excipient(s).
Providing a solution of Epacadostat and excipient(s) in a solvent in step-a) of the above process can be carried out by combining Epacadostat and excipient(s) selected from those defined above with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the reaction mixture to a temperature ranging from 30°C to 150°C based on the solvent used; wherein the solvent used in step-a) is a solvent selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, and n-pentanol, and mixtures thereof.
The excipients are preferably selected from PVP, Copovidone, HPC, HPMC-AS, HPMC-E5. The solvent is selected from methanol.
Obtaining solid dispersion in step-b) of the above process can be done by removing the solvent from the reaction mixture. The technique used for the removal of the solvent from the reaction mixture is distillation optionally under reduced pressure.
Third embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after the said crystalline form is designated as crystalline form-M.
The first aspect of third embodiment provides crystalline form-M of Epacadostat of formula- 1 characterized by one or more of the following characteristics: i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8° and 20.2° ±0.2° 26. ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8°, 20.2°, 23.4°, 24.4° and 36.9° ±0.2° 20. iii) PXRD pattern illustrated in figure-6.
The second aspect of third embodiment provides crystalline form-M of Epacadostat used for the preparation of various pharmaceutical formulations.
The third aspect of third embodiment provides a pharmaceutical composition comprising the crystalline form-M of Epacadostat of formula- 1 and at least one pharmaceutically acceptable excipient.
Fourth embodiment of the present invention provides process for the preparation of crystalline form-M of Epacadostat of formula- 1, comprising: a) dissolving Epacadostat in a solvent, b) isolating crystalline form-M of Epacadostat of formula- 1.
Wherein, dissolving Epacadostat in step-a) at a temperature ranging from about 25 °C to reflux temperature of the solvent used. The solvent in step-a) is selected from alcohol solvents, chloro solvents, ether solvents, ketone solvents, ester solvents and/or mixtures thereof; isolating crystalline form-M of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent; wherein anti-solvent is selected from ether solvents, hydrocarbon solvents and/or mixtures thereof.
In the first aspect of the fourth embodiment, step a) or step-b) optionally involve seeding with crystalline form-M of compound of formula- 1.
The fifth embodiment of the present invention provides a novel crystalline form of Epacadostat of formula- 1 , herein after the said crystalline form is designated as crystalline form-S.
The first aspect of fifth embodiment provides crystalline form-S of Epacadostat of formula- 1 characterized by one or more of the following characteristics: i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3° and 20.8° ± 0.2° 20; or ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3°, 15.9°, 16.8°, 20.8°, 22.3° and 23.2°± 0.2° 26; or iii) PXRD pattern illustrated in figure-7.
The second aspect of fifth embodiment provides crystalline form-S of Epacadostat used for the preparation of various pharmaceutical formulations.
The third aspect of fifth embodiment provides a pharmaceutical composition comprising the crystalline form-S of Epacadostat of formula- 1 and at least one pharmaceutically acceptable excipient.
Sixth embodiment of the present invention provides a process for the preparation of crystalline form-S of Epacadostat of formula- 1 , comprising: a) dissolving Epacadostat in a solvent comprising dimethyl sulfoxide or a mixture of dimethyl sulfoxide and a solvent, b) isolating crystalline form-S of Epacadostat of formula- 1.
Wherein, dissolving Epacadostat in step-a) at a temperature ranging from about 25 °C to reflux temperature of the solvent used. The solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof; isolating crystalline form-S of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent.
The first aspect of the sixth embodiment, step a) or step-b) optionally involve seeding with crystalline form-S of compound of formula- 1.
Seventh embodiment of the present invention provides Co-Crystal of Epacadostat and a co-crystal former.
The first aspect of the seventh embodiment, wherein the co-crystal former is at least one acid selected from the group consisting of L-proline, D-proline, DL-proline, DL- pipecolic acid, L-pipecolic acid, D-pipecolic acid, nicotinic acid, pyrazine-2-carboxylic acid, hydrogen fluoride, hydrogen iodide, boric acid, nitric acid, carbonic acid, phosphoric acid, peracetic acid, periodic acid, sulfamic acid, sulfurous acid, thioacetic acid, thiodipropionic acid, trifluoromethane sulfonic acid, trimethylacetic acid, tertiary butylacetic acid, 2,2-dichloro-acetic acid, thiocyanic acid, isethionic acid, acetylaminoacetic acid, propionic acid, 2-mercaptopropionic acid, butyric acid, isobutyric acid, valeric acid, 2-methylvaleric acid, isovaleric acid, 2-methylbutyric acid, hexanoic acid (caproic acid), 2-ethylbutyric acid, 3 -methylpentanoic acid, 4-methylpentanoic acid, heptanoic acid, (E)-2-heptenoic acid, 2-methylhexanoic acid, 5 -methylhexanoic acid, octanoic acid (caprylic acid), 2-methylheptanoic acid, 4-methyloctanoic acid, nonanoic acid, decanoic acid (capric acid), 4-methylnonanoic acid, undecanoic acid, 4- ethyloctanoic acid, lauric acid, myristic acid, palmitic acid, octadecanoic acid (stearic acid), (E)-2-butenoic acid, trans-2-methyl-2-butenoic acid, 3-methylcrotonic acid, 2- pentenoic acid, 4-pentenoic acid, trans-2-hexenoic acid, 3 -hexenoic acid, 2-methyl-2- pentenoic acid, 2-methyl-3 -pentenoic acid, 2-methyl-4-pentenoic acid, 4-methylpent-2- enoic acid, 2,4-dimethyl-2-pentenoic acid, (E)-2-octenoic acid, (E)-2-nonenoic acid, 4- decenoic acid, 5-decenoic acid, 6-decenoic acid, 9-decenoic acid, (E)-2-decenoic acid, 3,7-dimethyl-6-octenoic acid, 10-undecenoic acid, oleic acid, L-(+)-tartaric acid, dibenzoyltartaric acid, (2S,3S)-dibenzoyl tartaric acid, L-(-)-malic acid, D-(+)-malic acid, L-(+)-lactic acid, (S)-(+)-mandelic acid, glutaric acid, adipic acid, sebacic acid, monomethyl sebacic acid, glycolic acid, 2-hydroxysuccinic acid, linoleic acid, ethanesulfonic acid, ethane- 1 ,2-disulfonic acid, hexane- 1 -sulfonic acid, 4- methylbenzenesulfonic acid, benzenesulfonic acid, camphor- 10-sulfonic acid, (+)- camphor- 10-sulfonic acid, naphthalene 1,5 -disulfonic acid, naphthalene 1 -sulfonic acid, naphthalene 2-sulfonic acid, N-undecylbenzenesulfonic acid, 2-hydroxyethanesulfonic acid, p-chlorobenzenesulfonic acid, laurylsulfuric acid, dodecylsulfuric acid, aconitic acid, cinnamic acid, sorbic acid, glucoheptonic acid, muconic acid, galactaric acid (mucic acid), phenoxyacetic acid, phenylacetic acid, 3 -phenylpropionic acid, benzoic acid, 4- hydroxybenzoic acid, o-(4-hydroxybenzoyl)benzoic acid, 2,4-dihydroxybenzoic acid, salicylic acid, 4-amino salicylic acid, 2,4,6-trimethylbenzoic acid, 2-aminobenzoic acid, 3 -aminobenzoic acid, 4-aminobenzoic acid, 4-acetamido benzoic acid, 2-methoxybenzoic acid, 3-methoxybenzoic acid, anisic acid, N -benzoylanthranilic acid, hydroxynaphthoic acid, naphthoic acid, 1 -hydroxy-2-naphthoic acid, 2-hydroxy- 1 -naphthalenic acid, vanillic acid, gluconic acid, ascorbic acid, L-(+)-ascorbic acid, geranic acid, pyruvic acid, alphaketobutyric acid, levulinic acid, 3-hydroxy-2-oxopropionic acid, 3-methyl-2-oxobutanoic acid, 3-methyl-2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 4-(methylthio)-2- oxobutanoic acid, 2-oxopentanedioic acid, 2-oxo-3-phenylpropionic acid, 2-oxo-glutaric acid, embonic acid (pamoic acid), camphoric acid, cyclamic acid, acesulfamic acid, cyclohexaneacetic acid, cyclohexanecarboxylic acid, cis-2-heptylcyclopropane carboxylic acid, trans-2-heptylcyclopropane carboxylic acid, cyclopentanepropionic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, gentisic acid, orotic acid, 5 -oxo-proline, dehydroacetic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l -carboxylic acid), pyroglutamic acid, lysinic acid, L-lysinic acid, L-asparaginic acid, L-glutamic acid, acetyl glycine, alginic acid, l-hydroxyethylidene-l,l-diphosphonic acid, glycerophosphoric acid, lactobionic acid, gluceptic acid, amino tri(methylene phosphonic acid), hydrogen bromide, sulfuric acid, malic acid, formic acid, tartaric acid, acetic acid, succinic acid, fumaric acid, maleic acid, hippuric acid, methanesulfonic acid, citric acid, lactic acid, mandelic acid, malonic acid, oxalic acid, glutaminic acid, glutamic acid, aminobenzoic acid, a-lipoic acid, aspartic acid, asparaginic acid, saccharin, acetylsalicylic acid, [2-(2,6- dichlorophenylamino)phenyl] acetic acid (Diclofenac), dipyrone[(l,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-lH-pyrazol-4-yl)methylamino]-methanesulfonic acid (Metamizol), 2- (3'-fluorobiphenyl-4-yl)propionic acid (Flurbiprofen), 2-(3-benzoylphenyl)propionic acid (Ketoprofen), (+)-(S)-2-(6-methoxynaphthalen-2-yl)propionic acid (Naproxen) and 2-(4- isobutylphenyl)propionic acid (Ibuprofen).
The co-crystals of the present invention could be either in a crystalline or amorphous form.
The second aspect of seventh embodiment provides Co-Crystal of Epacadostat and a co-crystal former used for the preparation of various pharmaceutical formulations. The third aspect of seventh embodiment provides a pharmaceutical composition comprising Co-Crystal of Epacadostat and a co-crystal former and at least one pharmaceutically acceptable excipient.
The fourth aspect of seventh embodiment provides Co-Crystal of Epacadostat and
L-proline of formula- 1 a
Figure imgf000013_0001
Formula- 1 a
The fifth aspect of the seventh embodiment provides a crystalline form of CoCrystal of Epacadostat and L-proline of formula- 1 a, herein after the said crystalline form of co-crystal is designated as form-N.
Further, the crystalline form-N of Co-Crystal of Epacadostat and L-proline can be characterized by one or more of the following characteristics: i) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3° and 11.2° 20± 0.2° 26; or ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3°, 11.2°, 20.0°, 25.6° and 26.1° 20± 0.2° 20; or iii)PXRD pattern as depicted in Figure 8.
Eighth embodiment of the present invention provides a process for the preparation of Co-Crystal of Epacadostat and a co-crystal former comprises contacting Epacadostat with a co-crystal former in a solvent.
The first aspect of the eighth embodiment, wherein the co-crystal former is same as defined in the seventh embodiment.
The second aspect of eighth embodiment, the amount of Co-crystal former is about 0.5 mole equivalent to about 5 mole equivalents with respect to Epacadostat. Preferably, the amount of Co-crystal former is about 0.8 mole equivalent to about 2.5 mole equivalents with respect to Epacadostat.
The Co-Crystal of Epacadostat and a co-crystal former may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The Co-Crystal of Epacadostat and a co-crystal former may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The third aspect of eighth embodiment provides a process for the preparation of crystalline form-N of Co-Crystal of Epacadostat and L-proline comprises; a) combining Epacadostat or Epacadostat in a solvent with L-proline in a solvent, b) filtering and drying the obtained compound to get crystalline form-N of Co-Crystal of Epacadostat and L-proline.
Wherein, the solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof.
Ninth embodiment of the present invention provides a novel crystalline form of Epacadostat and L-proline co-crystal of formula- la herein after designated as crystalline form-Nl.
Figure imgf000014_0001
Formula- la.
The first aspect of the ninth embodiment provides a crystalline form-Nl of Epacadostat and L-proline co-crystal can be characterized by one or more of the following characteristics: i) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9 and 14.8 20± 0.2° 20; or ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9, 11.8, 14.8, and 30.1° 20± 0.2° 20; or iii) PXRD pattern as depicted in Figure 9.
The second aspect of ninth embodiment provides crystalline form-Nl of Epacadostat and L-proline co-crystal used for the preparation of various pharmaceutical formulations.
The third aspect of ninth embodiment provides a pharmaceutical composition comprising crystalline form-N 1 of Epacadostat and L-proline co-crystal and at least one pharmaceutically acceptable excipient.
Tenth embodiment of the present invention provides a process for preparation of crystalline form-Nl of Epacadostat and L-proline co-crystal comprising the step of exposing crystalline form-N of Epacadostat and L-proline co-crystal to a relative humidity of 75 ±5% at 40 °C for 48 hours ± 1 hour.
Epacadostat is prepared by any of the processes disclosed in literature such as US8088803 B2 or any other references.
As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
The eleventh embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of solid state forms of the present invention.
The solid-state forms of the present invention produced by various processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
P-XRD Method of Analysis:
The PXRD analysis of compound of formula- 1 of the present invention was carried out by using BRUKER/D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A0.
The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
Example 1: Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and Co-povidone.
Dissolved Epacadostat (250 mg) and Co-povidone (250 mg) in methanol (10 ml) at 25- 30°C. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
Yield: 350 mg. PXRD of the obtained compound is illustrated in figure- 1.
Example 2: Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and Povidone K-30.
Dissolved Epacadostat (250 mg) and Povidone K-30 (250 mg) in methanol (10 ml) at 25- 30°C. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
Yield: 350 mg. PXRD of the obtained compound is illustrated in figure-2. Example 3: Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPMC-E5.
Dissolved Epacadostat (250 mg) and HPMC-E5 (250 mg) in methanol (20 ml) at 40- 45°C. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
Yield: 340 mg. PXRD of the obtained compound is illustrated in figure-3.
Example 4: Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPMC-AS.
Dissolved Epacadostat (250 mg) and HPMC-AS (250 mg) in methanol (20 ml) at 40- 45°C. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
Yield: 340 mg. PXRD of the obtained compound is illustrated in figure-4.
Example 5: Preparation of amorphous solid dispersion comprising Epacadostat of formula-1 and HPC-EF.
Dissolved Epacadostat (250 mg) and HPC-EF (250 mg) in methanol (10 ml) at 40-45 °C. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.
Yield: 350 mg. PXRD of the obtained compound is illustrated in figure-5.
Example 6: Preparation of crystalline form M of Epacadostat
Epacadostat (1 g) was dissolved in the mixture of acetone (12 ml) and dichloromethane (6 ml) at 25-30°C. This solution was added to pre-cooled mixture of n-heptane (25 ml) and methyl tertiary butyl ether (25 ml) at -40° to -45 °C and slowly raised the temperature to 25-30°C. Filtered the precipitated solid and dried to get crystalline form M of Epacadostat.
Yield: 550 mg. PXRD of the obtained compound is illustrated in figure-6.
Example 7: Preparation of crystalline form M of Epacadostat
Epacadostat (250 mg) was dissolved in the mixture of acetone (4 ml) and dichloromethane (2 ml) at 25-30°C. This solution was added to pre-cooled mixture of n- heptane (10 ml) and methyl tertiary butyl ether (10 ml) at -40° to -45 °C and slowly raised the temperature to 25-30°C. Filtered the precipitated solid and dried to get crystalline form M of Epacadostat.
Yield: 125 mg. PXRD of the obtained compound is an illustrated in figure-6.
Example 8: Preparation of crystalline form S of Epacadostat
Epacadostat (500 mg) was dissolved in the mixture of dimethylsulfoxide (1 ml) and water (3 ml) at 80-85°C. The obtained solution was cooled to 0-5°C and stirred at the same temperature. Filtered precipitated the solid and dried to get title compound.
Yield: 390 mg. PXRD of the obtained compound is an illustrated in figure-7.
Example 9: Preparation of Crystalline form-N of Epacadostat and L-proline Cocrystal
A mixture of L-proline (525 mg) and ethanol (8.3 ml) and toluene (8.3 ml) was heated to 50-55°C. A mixture of ethanol (8.3 ml) and toluene (8.3 ml) was added to the above mixture. Epacadostat (1 g) was added to the above mixture at 50-55°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 0.98 g. PXRD of the obtained compound is an illustrated in figure-8.
Example 10: Preparation of crystalline form-Nl of Epacadostat and L-proline cocrystal
Epacadostat and L-proline co-crystal (500 mg) obtained in Example-9 was placed in a petri dish and was subjected to a relative humidity of 75% at 40°C for 48 hours to afford title compound.
Yield: 450 mg. PXRD of the obtained compound is an illustrated in figure-9.

Claims

Claims A Solid dispersion comprising Epacadostat and a pharmaceutically acceptable excipient. The solid dispersion of claim 1, wherein the pharmaceutically acceptable excipient comprises Co-povidone, Povidone K-30, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), Hydroxypropyl methylcellulose-E5 (HPMC-E5) and hydroxypropyl cellulose-EF (HPC-EF) or a mixture thereof. A process for the preparation of a solid dispersion comprising Epacadostat and one or more pharmaceutically acceptable excipients comprising: a) providing a solution of Epacadostat and one or more excipients in a solvent, b) obtaining solid dispersion comprising Epacadostat and the corresponding excipient(s). The process as claimed in claim 3, wherein providing a solution of Epacadostat and excipient(s) in a solvent in step-a) is carried out by combining Epacadostat and excipient(s) in a solvent selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, and n-pentanol, and mixtures thereof at a suitable temperature ranging from 0°C to 30°C and optionally heating the reaction mixture to a temperature ranging from 30°C to 150°C based on the solvent used; obtaining solid dispersion in step-b) is by removing the solvent from the mixture by distillation. A pharmaceutical composition comprising a therapeutically effective amount of solid dispersion of Epacadostat of claim 1 along with a pharmaceutically acceptable excipient(s). The pharmaceutical composition as claimed in claim 5, wherein the solid dispersion of Epacadostat is formulated into tablets or capsules. A crystalline form-M of Epacadostat of formula- 1 characterized by one or more of the following characteristics:
(i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8° and 20.2° ±0.2° 26.
(ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 4.0°, 8.0°, 16.8°, 20.2°, 23.4°, 24.4° and 36.9° ±0.2° 20.
(iii) PXRD pattern illustrated in figure-6. A process for the preparation of crystalline form-M of Epacadostat of formula- 1, comprising: a) dissolving Epacadostat in a solvent, b) isolating crystalline form-M of Epacadostat of formula- 1. The process as claimed in claim 8, wherein dissolving Epacadostat in step-a) at a temperature ranging from about 25 °C to reflux temperature of the solvent used; solvent in step-a) is selected from alcohol solvents, chloro solvents, ether solvents, ketone solvents, ester solvents and/or mixtures thereof; isolating crystalline form-M of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent; wherein anti-solvent is selected from ether solvents, hydrocarbon solvents, water and/or mixtures thereof. . A pharmaceutical composition comprising crystalline form-M of Epacadostat of claim 7 and at least one pharmaceutically acceptable excipient. A crystalline form-S of Epacadostat of formula- 1 characterized by one or more of the following characteristics:
(i) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3° and 20.8° ± 0.2° 26; or
(ii) PXRD (Powder X-Ray Diffraction) pattern having peaks at about 7.9°, 10.8°, 15.3°, 15.9°, 16.8°, 20.8°, 22.3° and 23.2°± 0.2° 20; or
(iii) PXRD pattern illustrated in figure-7. . A process for the preparation of crystalline form-S of Epacadostat of formula- 1, comprising: a) dissolving Epacadostat in dimethyl sulfoxide or a mixture of dimethyl sulfoxide and a solvent, b) isolating crystalline form-S of Epacadostat of formula- 1. . The process as claimed in claim 12, wherein dissolving Epacadostat in step-a) at a temperature ranging from about 25 °C to reflux temperature of the solvent used; solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof; isolating crystalline form-S of Epacadostat in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent. . A pharmaceutical composition comprising crystalline form-S of Epacadostat of claim 11 and at least one pharmaceutically acceptable excipient. . A Co-Crystal of Epacadostat and a co-crystal former.
. A process for the preparation of Co-Crystal of Epacadostat and co-crystal former comprises contacting Epacadostat with a co-crystal former in a solvent. . A Co-Crystal of Epacadostat and L-proline of formula- la
Figure imgf000022_0001
Formula- 1 a. . A pharmaceutical composition comprising of Epacadostat and L-proline co-crystal of claim 17 and at least one pharmaceutically acceptable excipient. . A crystalline form-N of Co-Crystal of Epacadostat and L-proline which is characterized by one or more of the following characteristics:
(i) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3° and 11.2° 20± 0.2° 26; or
(ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 9.3°, 9.7°, 10.3°, 11.2°, 20.0°, 25.6° and 26.1° 20± 0.2° 20; or
(iii) PXRD pattern as depicted in Figure 8. . A process for the preparation of crystalline form-N of Co-Crystal of Epacadostat and L-proline comprises; a) combining Epacadostat or Epacadostat in a solvent with L-proline in a solvent, b) filtering and drying the obtained compound to get crystalline form-N of CoCrystal of Epacadostat and L-proline. . The process as claimed in claim 20, wherein solvent in step-a) is selected from alcohol solvents, ether solvents, ketone solvents, ester solvents, water and/or mixtures thereof. A pharmaceutical composition comprising crystalline form-N of Epacadostat and L-proline co-crystal of claim 19 and at least one pharmaceutically acceptable excipient. A crystalline form-N 1 of Epacadostat and L-proline co-crystal which is characterized by one or more of the following characteristics:
(i) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9 and 14.8 20± 0.2° 20; or
(ii) PXRD (powder X-Ray diffraction) pattern having peaks at about 5.9, 7.5, 10.9, 11.8, 14.8, and 30.1° 20± 0.2° 20; or
(iii) PXRD pattern as depicted in Figure 9. A process for preparation of crystalline form-N 1 of Epacadostat and L-proline cocrystal comprising the step of exposing crystalline form-N of Epacadostat and L- proline co-crystal to a relative humidity of 75±5% at 40°C for 48 hours ± 1 hour. A pharmaceutical composition comprising crystalline form-N 1 of Epacadostat and L-proline co-crystal of claim 23 and at least one pharmaceutically acceptable excipient. The use of solid state forms of Epacadostat according to any of preceding claims for the preparation of pharmaceutical formulations.
22
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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2017124822A1 (en) * 2016-01-20 2017-07-27 Yong Xu Method for preparing ido inhibitor epacadostat
EP3360873A1 (en) * 2008-07-08 2018-08-15 Incyte Holdings Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase

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Publication number Priority date Publication date Assignee Title
EP3360873A1 (en) * 2008-07-08 2018-08-15 Incyte Holdings Corporation 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
WO2017124822A1 (en) * 2016-01-20 2017-07-27 Yong Xu Method for preparing ido inhibitor epacadostat

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CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, ISBN: 978-3-540-36760-4, DOI: 10.1007/3-540-69178-2-5 *

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