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WO2015011659A1 - Formes polymorphes cristallines du régorafénib et méthodes de préparation de la forme polymorphe i du régorafénib - Google Patents

Formes polymorphes cristallines du régorafénib et méthodes de préparation de la forme polymorphe i du régorafénib Download PDF

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Publication number
WO2015011659A1
WO2015011659A1 PCT/IB2014/063346 IB2014063346W WO2015011659A1 WO 2015011659 A1 WO2015011659 A1 WO 2015011659A1 IB 2014063346 W IB2014063346 W IB 2014063346W WO 2015011659 A1 WO2015011659 A1 WO 2015011659A1
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Prior art keywords
regorafenib
solvent
crystalline form
crystalline
polymorph
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English (en)
Inventor
Javed Iqbal
Sreenivas ORUGANTI
Rajesh Kumar Rapolu
Sundara Lakshmi Kanniah
Vishweshwar Peddy
Ramanaiah CHENNURU
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Definitions

  • aspects of the present application relate to novel polymorphic forms of Regorafenib that are useful in making pharmaceutically acceptable dosage forms, and processes thereof. Aspects of the present application also relate to processes for the preparation of crystalline polymorph I of Regorafenib.
  • Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment and it is indicated for the treatment of patients with colorectal cancer and gastrointestinal stromal tumor (GIST) who have been previously treated with specific prior therapy.
  • the drug compound having the adopted name "Regorafenib” may be represented by structural formula (I) and it has the chemical name 4-[4-( ⁇ [4-chloro-3-(trifluoromethyl) phenyl] carbamoyl ⁇ amino)-3- fluorophenoxy]-N-methylpyridine-2-carboxamide.
  • Regorafenib is the active ingredient in STIVARGA® tablets, sold for the treatment of above said maycer treatments.
  • Regorafenib is a monohydrate and it has a molecular formula C21 H15CIF4N4O3 ⁇ H 2 0 and a molecular weight of 500.83.
  • Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone.
  • Each tablet contains 40 mg of Regorafenib in the anhydrous state, which corresponds to 41 .49 mg of Regorafenib monohydrate.
  • U.S. Patent No. 7,351 ,834 B1 generically discloses Regorafenib, a pharmaceutically acceptable salt thereof, but there is no specific disclosure of Regorafenib in said patent or its equivalents.
  • the patent discloses a process for the preparation of desfluoro analog of Regorafenib i.e. Sorafenib, involving the reaction of 4-chloro-3-(trifluoromethyl) phenyl isocyanate with 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline in dichloromethane.
  • U.S. patent No. 8,637,553 B2 A1 specifically discloses Regorafenib, pharmaceutically acceptable salts thereof and its composition thereof. Also discloses the process for the preparation of Regorafenib by reacting 4-(4-amino-3- fluorophenoxy) pyridine-2-carboxylic acid methylamide in toluene with 4-chloro-3- (trifluoromethyl) phenyl isocyanate. The reaction mass was concentrated under reduced pressure and the residue was triturated with diethyl ether. The resulting solid was collected by filtration and dried to afford Regorafenib.
  • US 20050038080 A1 application discloses the spectroscopic data including NMR and mass values, but does not characterize the physical attributes such as X-ray diffraction, thermal analysis of the solid obtained by the process disclosed therein.
  • U.S. patent application No. 20060058358 A1 discloses a pharmaceutical composition in the form of a solid dispersion wherein Regorafenib is in substantially amorphous form.
  • U.S. patent application No. 20100173953 A1 discloses monohydrate of Regorafenib with water content in an amount of 3.6 % by weight.
  • U.S. patent application No. 20100173953 A1 also discloses that the polymorphic form of Regorafenib prepared by the manner described in U.S. patent No. 8,637,553 B2 A1 corresponds to polymorph I of Regorafenib having a melting point of 186-206°C and represented its characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum and a 13 C-solid state-NMR spectrum.
  • monohydrate form has a clearly differentiable X-ray diffractogram, NIR spectrum, FIR spectrum, IR spectrum, 13 C-solid state NMR spectrum and Raman spectrum to that of polymorph I.
  • U.S. patent applications, 201001 13533 A1 and 201000631 12 A1 disclose the polymorph II and polymorph III of Regorafenib, respectively with characteristic X-ray diffraction peaks, melting point and the characteristic IR wave numbers.
  • U.S. Patent No. 8,748,622 B2 discloses a process for the preparation of Regorafenib as white crystals with melting point of about 187-188°C by drying Regorafenib monohydrate at 90°C under reduced pressure for three hours.
  • polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices.
  • polymorphs refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns.
  • the variation in solid forms may appreciably influence the pharmaceutical properties and in turn such properties may significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, the drug manufacturing companies put efforts into identifying all polymorphic forms of new drug substances e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers.
  • the prior art processes produces Regorafenib which suffers from inconsistent physical properties such as hygroscopicity, compressibility, shelf life, stability against heat and humidity, bulk density, solubility, powder flow ability, handling properties, colour and filtration properties in the production process; which are not desirable in pharmaceutical industry and suffers with various difficulties in the formulation of the active ingredient.
  • the identification of new processes for preparing Regorafenib in desired solid form may provide opportunities to improve the performance characteristics of a pharmaceutical product.
  • aspects of the present application provide novel crystalline forms A, B, C and D of Regorafenib and processes for the preparation of crystalline polymorph I, form A, B, C and D of Regorafenib.
  • the application provides a crystalline form A of Regorafenib characterized by a PXRD pattern comprising the peaks at about 9.13, 12.87, 13.55, 13.89, 21 .48, 22.69, 23.56, 24.84, 28.01 and 29.84.
  • the application provides crystalline form A of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.99, 16.86, 17.41 , 1 8.48 and 25.26 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern comprising peaks at about 4.1 1 , 6.49, 10.06, 15.82 and 17.16 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 8.15, 10.86, 12.21 , 13.20, 13.56, 18.27 and 19.42 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.79, 17.61 and 19.67 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern comprising peaks at about 4.88, 6.97, 9.96, 12.55, 18.88, 20.53 and 25.35 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 1 1 .80, 13.91 , 15.22, 17.24, 17.86, 19.17, 19.47, 20.53 and 26.85 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.60, 19.93 and 30.07 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form D of Regorafenib, characterized by a PXRD pattern comprising peaks at about 5.12, 6.53, 10.17, 12.45, 14.30, 19.04 and 25.68 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form D of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 13.02, 15.55, 18.60 and 27.01 ⁇ 0.2° 2 ⁇ .
  • the present application provides process for preparing crystalline form A of Regorafenib, comprising the steps of,
  • step b) dissolving the product or its salt thereof obtained in step a) in a suitable first solvent or mixture thereof, optionally in the presence of a base;
  • the present application provides process for preparing crystalline form B of Regorafenib, comprising the steps of, a) providing a mixture of Regorafenib in suitable solvent or mixtures thereof; b) stirring the mixture of step a) for suitable time and optionally adding an anti- solvent;
  • the present application provides process for preparing crystalline form C of Regorafenib, comprising the steps of,
  • the present application provides process for preparing crystalline form D of Regorafenib, comprising the steps of,
  • step a) providing a mixture of Regorafenib in suitable solvent or mixtures thereof; b) stirring the mixture of step a) for suitable time and optionally adding an anti- solvent;
  • the present application provides process for preparing crystalline polymorph I of Regorafenib, comprising the steps of,
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • step (b) contacting the reaction mixture of step (a) with an anti-solvent
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • the present application provides pharmaceutical compositions containing a therapeutically effective amount of Regorafenib comprising a crystalline forms A, B, C and D of Regorafenib of present application or mixtures thereof, together with one or more pharmaceutically acceptable excipients.
  • the present application provides pharmaceutical composition comprising crystalline polymorph I of Regorafenib obtained by the processes of present application.
  • Figure 1 depicts a PXRD pattern of crystalline form A of Regorafenib
  • Figure 2 depicts a PXRD pattern of crystalline form B of Regorafenib
  • Figure 3 depicts a PXRD pattern of crystalline form C of Regorafenib
  • Figure 4 depicts a PXRD pattern of crystalline form D of Regorafenib
  • Figure 5 depicts a thermogram of differential scanning calorimetry (DSC) of crystalline polymorph I of Regorafenib obtained by the process of present application.
  • Figure 6 depicts a powder X-ray diffraction (PXRD) pattern of crystalline polymorph I of Regorafenib obtained by the process of present application.
  • PXRD powder X-ray diffraction
  • the present application provides crystalline forms A, B, C and D of Regorafenib and processes for their preparation.
  • the application provides a crystalline form A of Regorafenib characterized by a PXRD pattern comprising the peaks at about 9.13, 12.87, 13.55, 13.89, 21 .48, 22.69, 23.56, 24.84, 28.01 and 29.84.
  • the application provides crystalline form A of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.99, 16.86, 17.41 , 18.48 and 25.26 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form A of Regorafenib, characterized by a PXRD pattern having peaks located substantially as shown in figure 1 .
  • the present application provides process for preparing crystalline form A of Regorafenib, comprising the steps of, a) reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide with 4-chloro-3 (trifluoromethyl) phenyl isocyanate;
  • step b) dissolving the product or its salt thereof obtained in step a) in a suitable first solvent or mixture thereof, optionally in the presence of a base;
  • the starting materials of this aspect 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide and 4-chloro-3 (trifluoromethyl) phenyl isocyanate may be prepared by the methods reported in literature. Starting materials may be purified by techniques known in art like column chromatography, fractional distillation, acid base treatment, slurrying or recrsytallization, before using.
  • step a) of this aspect may be carried out by reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide with 4-chloro-3 (trifluoromethyl) phenyl isocyanate in mole ratio of about 1 : 0.5 to 1 : 2.
  • step a) of this aspect may be carried out by reacting in mole ratio of about 1 : 0.8 to 1 : 1 .2.
  • step a) may be carried out in the presence of an inert solvent.
  • Inert solvent may include, but not limited to: aromatic hydrocarbons, such as toluene; xylene and chlorobenzene ; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 - butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxy
  • step a) of this aspect may be carried out at a suitable temperature to complete the reaction i.e., at about 0°C to boiling point of the solvent; preferably this step may be carried out at about 0 to 80°C, more preferably at about 10-60°C and most preferably at about 20-40°C. In an embodiment, the step a) of this aspect may be carried out for time sufficient for the completion of reaction i.e., about 1 -50 hours, preferably for about 1 - 10 hours and more preferably for about 1-5 hours.
  • product obtained in step a) may be isolated by any known methods which includes cooling crystallization, anti-solvent addition, removal of solvent by evaporation, distillation, filtration of precipitated solid and the like; or any combinations of these methods.
  • isolated product obtained in step a) may be optionally washed with suitable solvent and dried under suitable drying conditions.
  • step b) of this aspect may be carried out by dissolving the product or its salt thereof obtained in step a) in a suitable first solvent or mixtures thereof.
  • Suitable first solvent includes, but not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; nitriles, such as acetonitrile and propionitrile; aprotic non-poplar solvents such as dimethylsulfoxide; formamide, N,
  • product obtained in step a) may be dissolved at a temperature of about 0°C to boiling point of the first solvent or mixture thereof; preferably this step may be carried out at about 0 to 80°C, more preferably at about 15-60°C and most preferably at about 30-50°C.
  • product obtained in step a) may be an acid addition salt.
  • Acid addition salt may be an inorganic salt like hydrochloride, hydrobromide, hydrogen sulphate, phosphate and the like or an organic salt like formate, acetate, oxalate, malonate, citrate, fumarate, mesylate, maleate, tartrate or the like.
  • step b) may be carried out in the presence of a base.
  • Base may be an alkaline base selected from the group consisting of sodium hydroxide, potassium hyrodroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like.
  • step b) may be carried out in the presence of aqueous sodium hydroxide.
  • the reaction mass of this step may be stirred for sufficient time, for example up to 10 hours or longer.
  • the reaction mass may be stirred at about 0 to 80°C, more preferably at about 15-60°C and most preferably at about 30- 50°C.
  • reaction mass of this step may be cooled to desired temperature, for example to less than about 40°C, preferably to less than about 20°C and more preferably to less than about 10°C.
  • step c) may be carried out by removing the first solvent or mixture thereof and treating the reaction mixture with suitable second solvent or mixture thereof.
  • removal of first solvent may be carried out using any of the techniques known in literature including evaporation of solvent like distillation under atmospheric or reduced pressure, spray drying, freeze drying, flash drying; or any other method for removal of solvent known in art.
  • the removal of first solvent may be carried at a suitable temperature of about 30°C to about boiling point of first solvent or mixture thereof.
  • reaction mixture obtained after removal of the first solvent may be treated with suitable second solvent.
  • Suitable second solvent of step c) may include, but not limited to: ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; ethers, such as diethyl ether, diisopropyl ether, methyl ethyl ether and methyl ter.
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone
  • ethers such as diethyl ether, diisopropyl ether, methyl ethyl ether and methyl ter.
  • esters such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate
  • alcohols such as methanol, ethanol, ethylene glycol, 1 -propanol, 2- propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol
  • nitriles such as acetonitrile and propionitrile.
  • reaction mixture obtained after removal of first solvent may be further distilled along with second solvent or mixture thereof to remove the traces of first solvent.
  • the process of treating the reaction mixture obtained after removal of first solvent includes, but not limited to slurrying, re-crystallization, washing, triturating the reaction mass and the like.
  • step d) of this aspect for the isolation of crystalline form A of Regorafenib may be carried out by any known methods which includes cooling crystallization, adding seed crystals to induce crystallization, anti-solvent addition to attain super saturation, removal of solvent by evaporation, distillation, filtration of precipitated solid and the like; or any combinations of these methods.
  • isolated crystalline form A of step d) may be optionally washed with suitable solvent.
  • the crystalline form A of Regorafenib may be dried, if desired, at suitable temperatures of about 60°C, or above, and at atmospheric or reduced pressures, for about 1 -50 hours, or longer, using the drying equipment known in the art.
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern comprising peaks at about 4.1 1 , 6.49, 10.06, 15.82 and 17.16 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 8.15, 10.86, 12.21 , 13.20, 13.56, 18.27 and 19.42 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.79, 17.61 and 19.67 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form B of Regorafenib, characterized by a PXRD pattern having peaks located substantially as shown in figure 2.
  • the application provides process for preparing the crystalline form B of Regorafenib comprising the steps of,
  • step a) providing a mixture of Regorafenib in suitable solvent or mixtures thereof; b) stirring the mixture of step a) for a suitable time and optionally adding an anti-solvent;
  • suitable solvent may include, but not limited to ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1 - propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso-butyl alcohol, t- butyl alcohol, 2-ethoxyethanol; nitriles, such as acetonitrile and propionitrile; aprotic non-poplar solvents such as dimethylsulfoxide; form
  • ethers such
  • step a) mixture of Regorafenib in suitable solvent may be prepared at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof.
  • the mixture of Regorafenib in suitable solvent may be prepared preferably at about 10°C to 80°C, more preferably at about 20°C to 40°C.
  • the mixture of Regorafenib of step a) may be filtered to make particle free solution.
  • the obtained solution may be treated with a decolorizing agent, such as carbon, before filtration.
  • step b) mixture of step a) may be stirred for sufficient time and followed by optionally the anti-solvent may be added to precipitate the desired compound or a reverse mode of addition may also be employed.
  • the mixture may be stirred for sufficient time, preferably for about 1 hour, more preferably for about 0.5 hour and most preferably for about 5 minutes.
  • the anti solvent may also be added to the stirred mixture of step a).
  • the suitable anti-solvents may include, but not limited to pentane, isopentane, neopentane, n-hexane, cyclohexane, cylcoheptane, n-heptane, diethyl ether, methyl ter. butyl ether, di isopropyl ether and the like.
  • suitable anti- solvent may be n-hexane.
  • anti-solvent addition may be carried out at suitable temperatures, such as at about 0°C to 50°C.
  • suitable temperature may be at about 10 to 40°C, more preferably at about 15 to 30°C, most preferably at about 20-30°C.
  • anti-solvent addition may be carried out for sufficient time to complete isolation of crystalline form B of Regorafenib. In an embodiment, anti-solvent addition may be carried out in sufficient volume to complete isolation of crystalline form B of Regorafenib.
  • step b) of this aspect for the isolation of crystalline form B of Regorafenib may be carried out by any known methods which includes removal of solvent by evaporation, distillation, filtration of precipitated solid and the like. ; cooling crystallization, adding seed crystals to induce crystallization, anti-solvent addition to attain super saturation or any combinations of these methods.
  • the crystalline form B obtained in step c) may be optionally washed with anti-solvent with sufficient volume to remove traces of solvent from wet solid.
  • the crystalline form B of Regorafenib obtained as above may be dried, if desired, at suitable temperatures of about 60°C, or above.
  • the drying may be performed at atmospheric or reduced pressures, for about 1 -50 hours, or longer by using the drying equipment known in the art.
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern comprising peaks at about 4.88, 6.97, 9.96, 12.55, 18.88, 20.53 and 25.35 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 1 1 .80, 13.91 , 15.22, 17.24, 17.86, 19.17, 19.47, 20.53 and 26.85 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 14.60, 19.93 and 30.07 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form C of Regorafenib, characterized by a PXRD pattern having peaks located substantially as shown in figure 3.
  • the present application provides process for preparing crystalline form C of Regorafenib, comprising the steps of,
  • drying crystalline form B may be carried out at temperatures suitable for the formation of crystalline form C of Regorafenib. In an embodiment, drying may be carried out at temperatures ranging from about 25°C to boiling point of solvent / anti solvents used for the preparation of form B of Regorafenib. Drying may be carried out preferably at about 25-100°C, more preferably at about 40 to 80°C, most preferably at about 50-70°C.
  • drying may be carried out in suitable drying equipment.
  • suitable drying equipment may include, but not limited to air tray drier, vacuum drier, flash drier, freeze drier or any other drying equipment known in the art.
  • drying may be carried out at atmospheric or reduced pressures. In preferred embodiments drying may be carried out at atmospheric pressure.
  • drying may be carried out for about 1 -50 hours or longer. In preferred embodiments drying may be carried out for about 1 -25 hours, more preferably for about 1 -10 hours, most preferably for about 1 -5 hours.
  • the application provides a crystalline form D of Regorafenib, characterized by a PXRD pattern comprising peaks at about 5.12, 6.53, 10.17, 12.45, 14.30, 19.04 and 25.68 ⁇ 0.2° 2 ⁇ . Still in other embodiments, the application provides a crystalline form D of Regorafenib, characterized by a PXRD pattern having one or more additional peaks at about 13.02, 15.55, 18.60 and 27.01 ⁇ 0.2° 2 ⁇ .
  • the application provides a crystalline form D of Regorafenib, characterized by a PXRD pattern having peaks located substantially as shown in Figure 4.
  • the application provides process for preparing the crystalline form D of Regorafenib comprising the steps of,
  • step a) providing a mixture of Regorafenib in suitable solvent or mixtures thereof; b) stirring the mixture of step a) and optionally adding an anti-solvent;
  • suitable solvent may include, but not limited to ethers, such as ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; nitriles, such as acetonitrile and propionitrile; aprotic non-poplar solvents such as di
  • the mixture of Regorafenib in suitable solvent may be prepared at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof.
  • the mixture of Regorafenib in suitable solvent may be prepared preferably at about 10°C to 80°C, more preferably at about 20°C to 40°C.
  • the mixture of Regorafenib of step a) may be filtered to make particle free solution.
  • the obtained solution may be treated with a decolorizing agent, such as carbon, before filtration.
  • step b) the reaction mixture of step a) may be stirred for sufficient time optionally the anti-solvent may be added to precipitate the desired compound or a reverse mode of addition may also be employed.
  • the mixture may be stirred for sufficient time, preferably for about 1 hour, more preferably for about 0.5 hour and most preferably for about 5 minutes.
  • the anti-solvent may be added to the stirred mixture of step a).
  • the suitable anti-solvents may include, but not limited to pentane, isopentane, neopentane, n-hexane, cyclohexane, cylcoheptane, n-heptane, diethyl ether, methyl ter. butyl ether, di isopropyl ether and the like.
  • suitable anti- solvent may be n-hexane.
  • anti-solvent addition may be carried out at suitable temperatures, such as at about 0°C to 50°C.
  • suitable temperature may be at about 10 to 40°C, more preferably at about 15 to 30°C, most preferably at about 20-30°C.
  • anti-solvent addition may be carried out for sufficient time to complete isolation of crystalline form D of Regorafenib.
  • anti-solvent addition may be carried out in sufficient volume to complete isolation of crystalline form D of Regorafenib.
  • step b) of this aspect for the isolation of crystalline form D of Regorafenib may be carried out by any known methods which includes removal of solvent by evaporation, distillation, filtration of precipitated solid and the like; cooling crystallization, adding seed crystals to induce crystallization, anti-solvent addition to attain super saturation or any combinations of these methods.
  • the crystalline form D obtained in step c) may be optionally washed with anti-solvent with sufficient volume to remove traces of solvent from wet solid.
  • the crystalline form D of Regorafenib obtained as above may be dried, if desired, at suitable temperatures of about 60°C, or above.
  • the drying may be performed at atmospheric or reduced pressures, for about 1 -50 hours, or longer by using the drying equipment known in the art.
  • the present application provides process for preparing crystalline polymorph I of Regorafenib, comprising the steps of,
  • drying crystalline form D may be carried out at temperatures suitable for the formation of crystalline polymorph I of Regorafenib. In an embodiment, drying may be carried out at temperatures ranging from about 25°C to boiling point of solvent / anti-solvents used for the preparation of form D. Drying may be carried out preferably at about 25-100°C, more preferably at about 40 to 80°C, most preferably at about 50-70°C.
  • drying may be carried out in suitable drying equipment.
  • suitable drying equipment may include, but not limited to: air tray drier, vacuum drier, flash drier, freeze drier or any other drying equipment known in the art.
  • drying may be carried out at atmospheric or reduced pressures. In preferred embodiments drying may be carried out at atmospheric pressure.
  • drying may be carried out for about 1 -50 hours or longer. In preferred embodiments drying may be carried out for 1 -25 hours, more preferably 1 -10 hours, most preferably for about 1 -5 hours.
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • step (b) contacting the reaction mixture of step (a) with an anti-solvent
  • Regorafenib of step (a) may be prepared according to any of the methods known in the literature.
  • Regorafenib of step (a) may be in crystalline or amorphous form.
  • Crystalline form of Regorafenib may be polymorphic form selected from the group consisting of crystalline polymorph II, polymorph III, monohydrate form, Form A, Form B, Form C, Form D or any other polymorphic form of Regorafenib or mixtures thereof.
  • Regorafenib of step (a) may be dissolved in a suitable inert solvent.
  • the inert solvent may be an organic solvent.
  • Organic solvents include, but not limited to alcohols like methanol, ethanol, 2- propanol, n- propanol, butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters like ethyl acetate, methyl acetate, isopropyl acetate; amides like dimethyl formamide, dimethyl acetamide; tetrahydrofuran; acetonitrile or mixture thereof.
  • suitable solvent may be methanol.
  • Regorafenib of step (a) may be dissolved at suitable temperature of about 40°C and above. Preferably, at about 50°C and above. More preferably, at about 60°C and above.
  • reaction mixture of step a) may be filtered to make particle free solution.
  • the obtained solution may be treated with a decolorizing agent, such as carbon, before making the reaction mixture as particle free.
  • reaction mixture of step (a) may be contacted with an anti- solvent.
  • the anti-solvent may be a solvent in which Regorafenib has low solubility and which include, but not limited to water; hydrocarbons like n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, toluene; ethers like diethyl ether, di isopropyl ether or mixtures thereof.
  • the suitable anti-solvent may be water.
  • the anti-solvent of step (b) may be contacted with the reaction mixture either by adding anti-solvent to the reaction mixture of step (a) or by adding the reaction mixture of step (a) to the anti-solvent.
  • the anti-solvent of step (b) may be contacted with reaction mixture of step (a) for sufficient time for the crystallization of polymorph I of Regorafenib. In an embodiment, the anti-solvent of step (b) may be contacted with reaction mixture of step (a) either in one portion or multiple small portions or by drop wise addition.
  • anti-solvent of step (b) may be contacted with reaction mixture at suitable temperature of about 40°C and above. Preferably, at about 50°C and above. More preferably, at about 60°C and above.
  • anti-solvent may be contacted in sufficient quantity to crystallize polymorph I of Regorafenib from the reaction mixture.
  • the ratio of quantity of anti-solvent to the quantity of solution containing Regorafenib in a suitable solvent may be atleast about 1 :1 to about 1 : 50.
  • the reaction mixture of step (b) may be stirred for sufficient time to complete the formation of crystalline polymorph I of Regorafenib at a suitable temperature. In an embodiment, the reaction mixture of step (b) may be stirred for about 0.5 hour or more. Preferably, for about 10 hours or more. More preferably, for about 1 5 hours or more.
  • the reaction mixture of step (b) may be stirred at suitable temperature of about 40°C and above. Preferably, at about 50°C and above. More preferably, at about 60°C and above. In an embodiment, the reaction mixture of step (b) may be cooled to relatively suitable lower temperatures wherein crystalline polymorph I of Regorafenib is stable.
  • step c) may be carried out by known suitable methods for the isolation of crystalline polymorph I of Regorafenib such as filtration, evaporation, centrifugation, sublimation or any combination methods thereof.
  • crystalline polymorph I of Regorafenib may be isolated by filtration of the reaction mixture of step (b). Filtration may be carried out at suitable temperature of about 35°C and above. Preferably, at about 50°C and above. More preferably, at about 60°C and above.
  • crystalline polymorph I of Regorafenib of step (c) may be dried under suitable drying conditions. Drying may be carried out preferably at about 40°C to boiling temperature of solvent. Drying may be carried out preferably until constant weight is obtained and for time sufficient to completely remove the traces of solvent. Drying may be carried out in Vacuum drier, Air drier, Freeze drier or any other drying equipment known in art.
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • Regorafenib of step (a) may be prepared according to any of the methods known in the literature.
  • Regorafenib of step (a) may be in crystalline or amorphous form.
  • Crystalline form of Regorafenib may be polymorphic form selected from the group consisting of crystalline polymorph II, polymorph III, monohydrate form, Form A, Form B, Form C, Form D or any other polymorphic form of Regorafenib or mixtures thereof.
  • step (a) of this aspect may be carried out by treating Regorafenib with a suitable solvent.
  • the process of treating Regorafenib may include, but not limited to suspending, slurring, dispersing, leaching, washing or any other techniques known in the art in the presence of suitable solvent.
  • treating Regorafenib with suitable solvent may be carried out in the presence of an inert solvent.
  • the inert solvent may include, but not limited to hydrocarbons like n-pentane, n-hexane, n-heptane, Toluene; alcohols like methanol, ethanol, propanol, isopropanol, butanol; esters like methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, ethers like diethyl ether, isopropyl ether, dioxane, tetrahydrofuran; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone; nitriles like acetonitrile, propionitrile; amides like formamides, ⁇ , ⁇ -dimethyl formamide, ⁇ , ⁇ ,
  • step (a) may be carried out at suitable temperature for the formation of crystalline polymorph I of Regorafenib. In an embodiment, step (a) may be carried out in between ambient temperature and boiling temperature of the solvent. In an embodiment, step (a) may be carried out at temperature of about 30°C and above; preferably at about 90°C and above.
  • step (a) may be carried out for sufficient time for the formation of crystalline polymorph I of Regorafenib. In an embodiment, step (a) may be carried out for atleast 0.5 hour or more. In an embodiment, step (a) may be carried out for about 10 hours or more; preferably for about 24 hours or more.
  • reaction mixture of step (a) may be cooled to relatively suitable lower temperatures wherein polymorph I of Regorafenib is stable. In an embodiment, the reaction mixture of step (a) may be cooled to temperature of about 30°C and above.
  • reaction mixture of step (a) may be optionally stirred at same temperature after cooling for sufficient time to complete the formation of crystalline polymorph I of Regorafenib. In an embodiment, the reaction mixture may be stirred for atleast 0.5 hour or more.
  • step (b) of this aspect may be carried out by isolating crystalline polymorph I of Regorafenib by filtration, evaporation, centrifugation, sublimation or any other method known to person skilled in art.
  • crystalline polymorph I of Regorafenib may be isolated by filtration of the reaction mixture. Filtration may be carried out at suitable temperature at about 35° C and above. Preferably, at about 50° C and above. More preferably, at about 60° C and above.
  • crystalline polymorph I of Regorafenib of step (b) may be dried under suitable drying conditions. Drying may be carried out preferably at about 40°C to boiling temperature of solvent. Drying may be carried out preferably until constant weight is obtained and for sufficient time to completely remove the traces of solvent. Drying may be carried out in Vacuum drier, Air drier, Freeze drier or any other drying equipment known in art.
  • the inventors of the present application have found that the filtration of the reaction mixture at higher temperature may be favourable for the isolation of pure crystalline polymorph I of Regorafenib as described in different processes of the instant application.
  • the crystalline polymorph I of Regorafenib obtained by the processes of present application may be free of other polymorphic forms of Regorafenib.
  • the suitable higher temperature may be the temperature above ambient temperature, which may be about 35°C or above. Preferably, about 40°C or above. More preferably, at about 50°C or above.
  • the application provides a process for the preparation of crystalline polymorph I of Regorafenib, comprising the steps of,
  • Regorafenib of step (a) may be prepared according to any of the methods known in the literature.
  • Regorafenib of step (a) may be in crystalline or amorphous form.
  • Crystalline form of Regorafenib may be polymorphic form selected from the group consisting of crystalline polymorph II, polymorph III, monohydrate form, Form A, Form B, Form C, Form D or any other polymorphic form of Regorafenib or mixtures thereof.
  • Step a) of this aspect may be carried out by combining Regorafenib with suitable solvent at suitable temperature.
  • Regorafenib may be dissolved in a suitable inert solvent.
  • Inert solvent may include, but not limited to alcohols like methanol, ethanol, 2- propanol, n-propanol, butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvent like acetonitrile, propionitrile; esters like ethyl acetate, methyl acetate, isopropyl acetate; amides like dimethyl formamide, dimethyl acetamide; tetrahydrofuron or mixture thereof.
  • Regorafenib may be dissolved at suitable temperature of about 30°C to boiling point of the solvent used. Preferably at about 50°C and above.
  • the reaction mixture of step a) may be filtered to make particle free solution.
  • the obtained solution may be treated with a decolorizing agent, such as carbon, before making the reaction mixture as particle free.
  • Step b) of this aspect may be carried out by crystallizing Regorafenib polymorph I from the reaction mixture of step a).
  • Regorafenib polymorph I may be crystallized from the reaction mixture according to any of the methods known in art or by the procedures described or exemplified in the present application.
  • Regorafenib polymorph I may be crystallized by techniques known to a person skilled in art that include, but not limited to: cooling the reaction mass, removal of solvent, etc., or combination of techniques thereof. Crystallization by cooling the reaction mass includes, but not limited to: crystallization by controlled cooling, crash cooling of the reaction mass and the like. Crystallization by cooling the reaction mass may be carried out optionally in the presence of suitable seed crystals of Polymorph I.
  • Crystallization by cooling the reaction mixture may be carried out by stirring the reaction mixture of step a) for sufficient time to completely crystallize Regorafenib polymorph I.
  • Crystallization by solvent removal includes, but not limited to: solvent evaporation under atmospheric pressure or under reduced pressure / vacuum, spray drying, freeze drying and the like.
  • reaction mixture of step a) may be cooled to crystallize Regorafenib polymorph I to a suitable temperature of about 30°C or below. Preferably, to about 10°C and below.
  • reaction mixture of step a) may be subjected to evaporation to crystallize Regorafenib polymorph I under suitable conditions such as suitable temperature and pressure.
  • Evaporation of solvent may be carried out at suitable temperature of about 30°C to boiling point of the solvent used. Preferably, at 50°C and above.
  • the Regorafenib polymorph I may be crystallized by combining the techniques of evaporative and cooling crystallization in suitable sequence. Reaction mass of step a) may be partially evaporated to attain required saturation of the solution and then cooled to crystallize Regorafenib polymorph I.
  • Polymorph I of Regorafenib crystallized from step b) may be recovered by employing any of the techniques known to a person skilled in art. Techniques for the isolation of Regorafenib polymorph I may include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
  • Polymorph I of Regorafenib obtained by the processes of this aspect may dried at suitable temperatures, such as about 30°C to boiling point of solvent used and suitable pressures, using drying equipment known in the art, such as air dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product.
  • Regorafenib which is used as the starting material for the preparation of crystalline polymorph I, form A, B, C and D of the present application may be prepared by any method, including methods known in art.
  • Regorafenib which is used as the starting material may be purified by using any methods known in art to enhance chemical purity.
  • present application provides crystalline polymorph I, form A, B, C and D of Regorafenib with a chemical purity of greater than about 99%, or greater than about 99.5%, or greater than about 99.8% as determined by using high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the application provides crystalline polymorph I of Regorafenib which may be stable under humid conditions for more than 10 days at about 75% RH and more than 7 days at about 90% RH.
  • the application provides crystalline form A of Regorafenib which may be stable under humid conditions for more than 10 days at about 75% RH and more than 7 days at about 90% RH.
  • the application provides crystalline polymorph I of Regorafenib which may be stable for more than 10 days under thermal conditions at about 90°C.
  • the application provides crystalline form A of Regorafenib which may be stable for more than 10 days under thermal conditions at about 90°C.
  • the present application provides crystalline polymorph I of Regorafenib with a melting point of about 190°C by DSC method.
  • the present application provides crystalline form A of Regorafenib with a melting point of about 167°C by DSC method.
  • the application provides Polymorph I of Regorafenib with water content less than 0.25% by KF method.
  • the application provides form A of Regorafenib with water content less than 0.25% by KF method.
  • crystalline polymorph I, form A, B, C and D of Regorafenib may be stable which refers to both chemical stability as well as polymorph stability.
  • the present application provides pharmaceutical composition comprising crystalline polymorph I of Regorafenib obtained by the process of present application.
  • the processes of present application may produce crystalline polymorph I, form A, B, C and D of Regorafenib with a chemical purity of greater than about 99%, or greater than about 99.5%, or greater than about 99.8% as determined by using high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Crystalline polymorph I, form A, B, C and D of Regorafenib according to the present application may be milled or micronized by any of the processes known in the art, such as ball milling, jet milling, wet milling and the like, to produce desired particle sizes and particle size distributions.
  • the present application provides pharmaceutical compositions containing a therapeutically effective amount of Regorafenib comprising the crystalline polymorph I, form A, B, C and D of Regorafenib or mixtures thereof, together with one or more pharmaceutically acceptable excipients.
  • Formulations may be in the form of immediate release, delayed release or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations
  • modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems.
  • the compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.
  • compositions that are useful in the present application include, but are not limited to, any one or more of: diluents such as starches, pregelatinized starches, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragamayth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubrimayts such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as
  • X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer or PANalytical Expert pro X- ray diffractometer with a copper K-alpha radiation source.
  • a diffraction angle (2 ) in powder X-ray diffractometry may have an error in the range of ⁇ 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ⁇ 0.2°.
  • the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ⁇ 0.2°.
  • the phrase "having a diffraction peak at a diffraction angle (2D) ⁇ 0.2° of 6.3°” means “having a diffraction peak at a diffraction angle (2 D) of 6.1 ° to 6.5°.
  • the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form.
  • the relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values.
  • Regorafenib (700 mg) was dissolved in N-methyl pyrrolidone (1 mL) at 26°C and stirred for 5 min. n-hexane (4 mL) was added at 26°C and stirred for 10 min at same temperature. The solid was filtered and washed with n-hexane (2 mL) to obtain the title compound.
  • the wet compound obtained in example 1 was dried in air tray drier at 60°C for 5.5 hours to obtain title compound.
  • Regorafenib (200 mg) was dissolved in dimethylformamide (0.1 mL) at 26°C and stirred for 6 min. n-hexane (1 mL) was added at 26°C and stirred for 6 min at same temperature. The solid was filtered and washed with n-hexane (2 mL) to obtain the title compound.
  • the wet compound obtained in example 4 was dried in air tray drier at 65°C for 4 hours to obtain title compound.
  • Example-6 Preparation of crystalline polymorph I of Regorafenib from Regorafenib monohydrate.
  • Regorafenib Monohydrate (1 .0 g) was dissolved in methanol (20 mL) at 60°C and then water (20 mL) was added at 60°C. Stirred the reaction mass at 60°C for 20 hours and filtered the solid. Wet solid was dried at 50°C in air tray drier for 1 hour to obtain title compound.
  • Example-7 Preparation of crystalline polymorph I of Regorafenib from crystalline polymorph II I of Regorafenib.
  • Regorafenib polymorph III (0.5 g) was dissolved in methanol (20 mL) at 60°C and then water (20 mL) was added at 60°C. Stirred the reaction mass at 60°C for 17 hours and filtered the solid. Wet solid was dried at 50°C in air tray drier for 1 hour to obtain title compound.
  • Example-8 Preparation of crystalline polymorph I of Regorafenib from crystalline polymorph II I of Regorafenib.
  • Regorafenib Polymorph III (300 mg) was suspended in mixture of acetone (1 mL) and n-heptane (9 mL) at 50°C and stirred for 24 hours at same temperature and filtered the solid. Wet solid was dried at 50°C in air tray drier for 1 hour to obtain title compound.
  • Example-9 Preparation of crystalline polymorph I of Regorafenib from mixture of crystalline Form A and polymorph I of Regorafenib.
  • Example-10 Preparation of crystalline polymorph I of Regorafenib from Regorafenib Monohydrate.
  • Regorafenib Monohydrate (0.5 g) was suspended in Toluene (10 mL) at 90°C and stirred for 1 .5 hours at same temperature. Cooled the reaction mixture to 50°C in 1 hour and stirred for 1 .5 hours at same temperature. Filtered the solid at 50°C and dried at 50°C in air tray drier for 1 hour to obtain title compound. Yield: 0.4 g
  • Example-11 Preparation of crystalline polymorph I of Regorafenib from Regorafenib Monohydrate.
  • Regorafenib (1 g) was dissolved in ethyl acetate (50 mL) at 70°C and stirred the reaction mass for 10 minutes at same temperature. The clear solution was cooled to 10°C in 1 hour and stirred at the same temperature for 16 hours. The solid was filtered and dried at 40°C for 1 hour to obtain the title compound. Yield: 0.75 g.
  • Regorafenib (1 g) was dissolved in Acetone (25 mL) at 80°C and stirred the reaction mass for 5 minutes at same temperature. The clear solution was cooled to 10°C in 1 hour and stirred at the same temperature for 15 hours. The solid was filtered and dried at 50°C for 1 hour to obtain the title compound. Yield: 0.32 g.
  • Regorafenib (1 g) was dissolved in methanol (50 mL) at 80°C and stirred the reaction mass for 10 minutes at same temperature. The clear solution was cooled to 10°C in 1 hour and stirred at the same temperature for 15 hours. The solid was filtered and dried at 50°C for 1 hour to obtain the title compound. Yield: 0.68 g.
  • Example-16 Preparation of crystalline polymorph I of Regorafenib Regorafenib (1 g) was dissolved in acetone (25 mL) at 60°C and the clear solution was subjected to evaporation in rotavapour at 60°C under reduced pressure to obtain the title compound. Yield: 0.63 g.
  • Regorafenib (1 g) was dissolved in methanol (50 mL) at 60°C and the clear solution was subjected to evaporation in rotavapour at 60°C under reduced pressure to obtain the title compound. Yield: 0.71 g.

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Abstract

L'invention concerne la nouvelle forme polymorphe cristalline A, B, C et D du régorafénib, et des méthodes associées. Elle concerne également les méthodes de préparation de la forme polymorphe I du régorafénib.
PCT/IB2014/063346 2013-07-24 2014-07-23 Formes polymorphes cristallines du régorafénib et méthodes de préparation de la forme polymorphe i du régorafénib Ceased WO2015011659A1 (fr)

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CN105136956A (zh) * 2015-09-11 2015-12-09 江苏嘉逸医药有限公司 一种快速测定瑞戈非尼含量的方法
WO2016038590A1 (fr) * 2014-09-12 2016-03-17 Mylan Laboratories Ltd Procédé de préparation de la forme cristalline i du régorafénib
CN105985287A (zh) * 2015-02-13 2016-10-05 上海京新生物医药有限公司 一种瑞戈非尼新晶型
CN110294706A (zh) * 2019-07-25 2019-10-01 李斌 抗肿瘤药物及其制法和用途
CN115974777A (zh) * 2022-12-19 2023-04-18 江苏希迪制药有限公司 一种瑞戈非尼的精制方法

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WO2005009961A2 (fr) * 2003-07-23 2005-02-03 Bayer Pharmaceuticals Corporation Omega-carboxyaryldiphenyluree fluoro-subtituee pour le traitement et la prevention de maladies et d'etats pathologiques
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016038590A1 (fr) * 2014-09-12 2016-03-17 Mylan Laboratories Ltd Procédé de préparation de la forme cristalline i du régorafénib
CN105985287A (zh) * 2015-02-13 2016-10-05 上海京新生物医药有限公司 一种瑞戈非尼新晶型
CN105985287B (zh) * 2015-02-13 2018-07-17 上海京新生物医药有限公司 一种瑞戈非尼新晶型
CN105136956A (zh) * 2015-09-11 2015-12-09 江苏嘉逸医药有限公司 一种快速测定瑞戈非尼含量的方法
CN110294706A (zh) * 2019-07-25 2019-10-01 李斌 抗肿瘤药物及其制法和用途
CN115974777A (zh) * 2022-12-19 2023-04-18 江苏希迪制药有限公司 一种瑞戈非尼的精制方法

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