WO2011076711A2 - Polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide - Google Patents

Polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide Download PDF

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WO2011076711A2
WO2011076711A2 PCT/EP2010/070198 EP2010070198W WO2011076711A2 WO 2011076711 A2 WO2011076711 A2 WO 2011076711A2 EP 2010070198 W EP2010070198 W EP 2010070198W WO 2011076711 A2 WO2011076711 A2 WO 2011076711A2
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sorafenib
phenoxy
trifluoromethyl
chloro
phenyl
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PCT/EP2010/070198
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French (fr)
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WO2011076711A3 (en
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Ramesh Matioram Gidwani
Vikas S Wakchaure
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Ratiopharm Gmbh
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to polymorphs of 4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide, polymorphs of salts thereof and pharmaceutical compositions comprising the same.
  • Sorafenib is a small molecular inhibitor of several protein kinases, including RAF, VEGFR- 2PK30, and PDGFR kinases. These enzymes are all molecular targets of interest for the treatment of hyper-proliferative diseases, including cancer. ⁇ -Carboxylaryl substituted diphenyl ureas including Sorafenib and its synthesis are disclosed in WO 2000/42012. This document also discloses various pharmaceutically acceptable salts of the compounds.
  • WO 2006/026501 discloses pharmaceutical compositions comprising a solid dispersion of Sorafenib.
  • WO 2006/034796 discloses a process for preparing Sorafenib and its tosylate salt.
  • the tosylate salt is obtained in crystalline form.
  • WO 2006/034797 discloses polymorphic forms of Sorafenib tosylate, as well as a monomethanol solvate and a monoethanol solvate. The polymorphs are designated polymorph I and polymorph III, whereas the polymorph obtainable as described in WO 00/42012 is designated polymorph II.
  • Sorafenib is administered orally, as this route provides comfort and convenience of dosing.
  • these known forms are not optimal in regard to bioavailability, inter-patient variability, and safety.
  • the known forms of Sorafenib are not optimal in regard to polymorphic and chemical stability, flow properties, compressibility, dissolution rate, and they are at least to some extent hygroscopic and show electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions, such as tablets.
  • Sorafenib it is therefore an object of the present invention to provide further polymorphic forms of Sorafenib, as well as pharmaceutical compositions comprising the same, which do not encounter the above problems.
  • polymorphic forms of Sorafenib which show improved bioavailability, reduced inter-patient variability, improved overall therapeutic efficacy, improved polymorphic and/or chemical stability, excellent flow properties, good compressibility, an improved dissolution profile, and which are non-hygroscopic and/or do not electrostatically charge.
  • the polymorphic forms of Sorafenib show advantageous properties in at least one of the mentioned aspects.
  • the present invention relates to crystalline Sorafenib sulphate, to crystalline Sorafenib naphthalene-1 ,5-disulphonate, to crystalline Sorafenib ethane-sulphonate, and to processes for preparing them.
  • the present invention further relates to a pharmaceutical composition comprising the above salts and polymorphs of Sorafenib.
  • polymorphic form includes amorphous or different crystalline structures of the same compound as well as solvates including hydrates thereof and co-crystals.
  • crystalline refers to any substantially non-amorphous form of a substance.
  • amorphous form refers to a form of the substance which has substantially no long-range order like crystalline structures.
  • the atoms or molecules of a material present in amorphous form are arranged in a non-uniform array. It is for example possible to distinguish amorphous forms from crystalline forms of a substance by powder X-ray diffraction.
  • a crystalline compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % amorphous fractions.
  • An amorphous compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % crystalline fractions.
  • pharmaceutical composition refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition is in a single dosage form the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell.
  • the active pharmaceutical ingredient i.e. the Sorafenib in its forms as described herein, can be present in the pharmaceutical composition in an amount of 10 to 90 % by weight, preferably 20 to 80 % by weight, more preferably 40 to 55 % by weight of the total weight of the composition.
  • the active ingredient, composition or pharmaceutical composition of the present invention has a mean particle size of 1 to 300 pm, preferably 5 to 200 pm, more preferably 10 to 100 ⁇ .
  • a bulk density of the active ingredient, composition or the pharmaceutical composition ranging from 0.3 to 0.9 g/ml, preferably 0.4 to 0.85 g/ml, more preferably 0.5 to 0.8 g/ml is advantageous.
  • the active ingredient, composition or pharmaceutical composition preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.1 to 1.5.
  • the Hausner factor is the ratio of bulk density to tapped density.
  • the pharmaceutical composition of the present invention can comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers.
  • pharmaceutically acceptable excipients such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers.
  • pharmaceutically acceptable excipients conventional excipients known to a person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
  • fillers are lactose, mannitol, sorbitol and microcrystalline cellulose.
  • the filler is suitably present in an amount of 0 to 90 % by weight, preferably of 30 to 80 % by weight of the total weight of the composition.
  • the binding agent can be microcrystalline cellulose (MCC) or hydroxypropylmethyl cellulose (HPMC).
  • MCC microcrystalline cellulose
  • HPMC hydroxypropylmethyl cellulose
  • the binding agent is suitably present in an amount of 1 to 25 % by weight, preferably of 2 to 10 % by weight of the total weight of the composition.
  • the lubricant is preferably a stearate, more preferably an earth alkali metal stearate, such as magnesium stearate.
  • the lubricant is suitably present in an amount of 0.1 to 2 % by weight, preferably of about 1 % by weight of the total weight of the composition.
  • Preferred disintegrating agents are croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone (crospovidone).
  • the disintegrating agent is suitably present in an amount of 0.1 to 20 % by weight, more preferably of 0.5 to 7 % by weight of the total weight of the composition.
  • the flow enhancer can be colloidal silicon dioxide.
  • the flow enhancer is suitably present in an amount of 0.5 to 8 % by weight, more preferably of 0.5 to 3 % by weight of the total weight of the composition.
  • the antisticking agent is for example talcum and may be present in an amount of 1 to 5 % by weight, preferably of 1.5 to 3 % by weight of the total weight of the composition.
  • an improvement of the solubility of the active pharmaceutical ingredient can be achieved by the addition of complex forming agents/compounds (e.g. sodium benzoate, sodium salicylate or cyclodextrins), alternation of solvent properties (e.g. by adding PVP or polyethylene glycols) or the addition of solubilizers which form tenside micelles (e.g. surfactants).
  • complex forming agents/compounds e.g. sodium benzoate, sodium salicylate or cyclodextrins
  • alternation of solvent properties e.g. by adding PVP or polyethylene glycols
  • solubilizers which form tenside micelles e.g. surfactants.
  • Suitable solubilizers are for example surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, preferably of 1 to 5 % by weight of the total weight of the composition.
  • surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, preferably of 1 to 5 % by weight of the total weight of the composition.
  • pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity. However, pseudo-emulsifiers also possess emulsifying properties.
  • Preferred pseudo-emulsifiers are for example cellulose ethers, gum Arabic or tragacanth and may be present in an amount of 1 to 10 % by weight, preferably of 3 to 7 % by weight of the total weight of the composition.
  • the pharmaceutical composition of the present invention can be formulated in any known form, preferably as tablets, capsules, granules, pellets or sachets.
  • a particularly preferred pharmaceutical composition is in the form of tablets or capsules.
  • the pharmaceutical composition may contain dosage amounts of about 100, 200 or 400 mg of the active pharmaceutical ingredient. Thus the administered amount can be readily varied according to individual tolerance and safety.
  • the pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art.
  • Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants, and can be compressed into tablets or filled into sachets or capsules of suitable size. Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients.
  • Suitable powder or granulate mixtures according to the invention are further obtainable by spray drying, lyophilization, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method.
  • the so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules.
  • Polymorph I of Sorafenib sulphate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
  • suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Methylethylketone (MEK) is especially preferred.
  • aliphatic and aromatic hydrocarbons preferably hexane, benzene, toluene
  • the differential scanning calorimetry (DSC) thermogram of polymorph I of Sorafenib sulphate shows an endothermic peak at 208 +/- 4°C ( Figure 1 a).
  • the melting point, given as onset temperature of the peak in the DSC, is 204 +/- 4°C.
  • Polymorph I of Sorafenib sulphate shows an IR spectrum exhibiting characteristic peaks at 3396 ⁇ 2 cm “1 and 1698 ⁇ 2 cm “1 ( Figure 1 b).
  • Polymorph I of Sorafenib sulphate can be characterized by an XRPD pattern with characteristic peaks at 1 1.9 ⁇ 0.2, 17.9 ⁇ 0.2, 22.8 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees 2-theta ( Figure 1 c).
  • Polymorph II of Sorafenib sulphate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
  • suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Acetonitrile, ethanol, mixtures of water and acetonitrile or MEK and water are especially preferred.
  • aliphatic and aromatic hydrocarbons preferably hexan
  • the DSC thermogram of polymorph II of Sorafenib sulphate shows an endothermic peak at 210 +/- 4°C ( Figure 2a).
  • the melting point given as onset temperature of the peak in the DSC, is 206 +/- 4°C.
  • Polymorph II of Sorafenib sulphate shows an IR spectrum exhibiting characteristic peaks at 3067 ⁇ 2 cm “1 and 1679 ⁇ 2 cm “1 ( Figure 2b).
  • Polymorph II of Sorafenib sulphate can be characterized by an XRPD pattern with characteristic peaks at 16.7 ⁇ 0.2, 20.0 ⁇ 0.2, 21.1 ⁇ 0.2, 21.3 ⁇ 0.2, 27.0 +/- 0.2 and 27.8 ⁇ 0.2 degrees 2-theta ( Figure 2c).
  • Sorafenib naphthalene-1 ,5-disulphonate can be obtained dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding naphthalene-1 ,5-disulphonic acid, isolating and drying the resulting solid.
  • suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile).
  • aliphatic and aromatic hydrocarbons preferably hexane, benzene, toluene or xylene
  • aliphatic alcohols preferably m
  • the DSC thermogram of Sorafenib naphthalene-1 ,5-disulphonate shows an endothermic peak at 293 +/- 4°C followed by another endothermic peak at 298 +/- 4°C ( Figure 3a).
  • the melting point given as onset temperature of the first peak in the DSC, is 282 +/- 4°C.
  • the melting point was further checked using a Labindia Visual Melting point apparatus, and Sorafenib naphthalene-1 ,5-disulphonate was shown to melt under decomposition.
  • Sorafenib naphthalene-1 ,5-disulphonate shows an IR spectrum exhibiting characteristic peaks at 3360 ⁇ 2 cm “1 and 1726 ⁇ 2 cm “1 ( Figure 3b).
  • Sorafenib naphthalene-1 ,5-disulphonate can further be characterised by an XRPD pattern having characteristic peaks at 8.2 + 0.2, 12.4 ⁇ 0.2, 15.5 ⁇ 0.2 and 25.9 ⁇ 0.2 degrees 2- theta ( Figure 3c).
  • Sorafenib ethane-sulphonate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding ethane-sulphonic acid, isolating and drying the resulting solid.
  • suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Methylethylketone (MEK) is especially preferred.
  • aliphatic and aromatic hydrocarbons preferably hexane, benzene, toluene
  • the melting point given as onset temperature of the peak in the DSC, is 204 +/- 4°C.
  • Sorafenib ethane-sulphonate shows an IR spectrum exhibiting characteristic peaks at 3071 ⁇ 2 cm “1 and 1714 ⁇ 2 cm “1 ( Figure 4b).
  • Sorafenib ethane-sulphonate can further be characterised by an XRD pattern having characteristic peaks at 15.9 ⁇ 0.2, 23.5 ⁇ 0.2, 23.7 ⁇ 0.2, 25.7 ⁇ 0.2, 28.6 ⁇ 0.2 and 29.2 ⁇ 0.2 degrees 2-theta ( Figure 4c).
  • Figure 1 a is the DSC thermogram of polymorph I of Sorafenib sulphate.
  • Figure 1 b is the IR spectrum of polymorph I of Sorafenib sulphate.
  • Figure 1 c is the XRPD pattern of polymorph I of Sorafenib sulphate.
  • Figure 2a is the DSC thermogram of polymorph II of Sorafenib sulphate.
  • Figure 2b is the IR spectrum of polymorph II of Sorafenib sulphate.
  • Figure 2c is the XRPD pattern of polymorph II of Sorafenib sulphate.
  • Figure 3a is the DSC thermogram of Sorafenib naphthalene-1 ,5-disulphonate.
  • Figure 3b is the IR spectrum of Sorafenib naphthalene-1 ,5-disulphonate.
  • Figure 3c is the XRPD pattern of Sorafenib naphthalene-1 ,5-disulphonate.
  • Figure 4a is the DSC thermogram of Sorafenib ethane-sulphonate.
  • Figure 4b is the IR spectrum of Sorafenib ethane-sulphonate.
  • Figure 4c is the XRD pattern of Sorafenib ethane-sulphonate.
  • DSC thermograms were obtained using Mettler Toledo Model DSC 822 e ' Heating range : 30°C to 300X, Heating rate : 10°C/min, Purge gas : Nitrogen 50 ml /min, Sample holder: 40 ⁇ Aluminum crucible.
  • Second ⁇ filter Ni filter 0.1 mm (0.5%)
  • IR spectra were obtained using a Perkin Elmer, Model "Spectrum one", DFR mode.
  • Sorafenib was added to a mixture of 4 ml acetonitrile and 0.2 ml water and stirred.
  • a solution of 71.9 mg sulphuric acid in 1 ml acetonitrile was added. Nearly all solid dissolved and the remainders were isolated by decantation. The remaining solid was rinsed with 0.5 ml acetonitrile which was then combined with the decanted solution and stirred. After 20 minutes crystallization occurred and the reaction was stirred for further 2.75 hours.
  • the solid was isolated by filtration, was with 2 ml acetonitrile and dried at 50°C under vacuum for 2 hours.
  • Sorafenib 191 mg Sorafenib was added to a stirring mixture of 4 ml MEK and 0.1 ml water. 52 mg sulphuric acid was added, and the reaction was allowed to stir for 16 hours. The resulting solid was isolated by filtration, washed with 1 ml MEK and dried under vacuum at 50°C for
  • Sorafenib 200 mg Sorafenib was suspended in 8 ml acetonitrile, stirred and heated to reflux resulting in the formation of a clear solution.
  • a solution of 85.25 mg naphtalen-1 ,5- disulphonic acid in 8 ml acetonitrile was slowly added at 82°C, whereupon crystallization occurred immediately.
  • the reaction was refluxed for further 15 minutes and subsequently stirred at 26°C for 1 hour.
  • the solid was isolated by filtration, washed with 1 ml acetonitrile and dried under vacuum at 50°C for 2 hours.

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Abstract

The present invention relates to polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]- carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide.

Description

Polymorphs of
4-[4-[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl- pyridine-2-carboxamide
The present invention relates to polymorphs of 4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide, polymorphs of salts thereof and pharmaceutical compositions comprising the same.
4-[4-[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide, also known as Sorafenib, has the following chemical structure:
Figure imgf000002_0001
Sorafenib is a small molecular inhibitor of several protein kinases, including RAF, VEGFR- 2PK30, and PDGFR kinases. These enzymes are all molecular targets of interest for the treatment of hyper-proliferative diseases, including cancer. ω-Carboxylaryl substituted diphenyl ureas including Sorafenib and its synthesis are disclosed in WO 2000/42012. This document also discloses various pharmaceutically acceptable salts of the compounds.
WO 2006/026501 discloses pharmaceutical compositions comprising a solid dispersion of Sorafenib.
WO 2006/034796 discloses a process for preparing Sorafenib and its tosylate salt. The tosylate salt is obtained in crystalline form. WO 2006/034797 discloses polymorphic forms of Sorafenib tosylate, as well as a monomethanol solvate and a monoethanol solvate. The polymorphs are designated polymorph I and polymorph III, whereas the polymorph obtainable as described in WO 00/42012 is designated polymorph II.
Typically Sorafenib is administered orally, as this route provides comfort and convenience of dosing. Although several salts of Sorafenib and polymorphic forms thereof are known in the art, these known forms are not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known forms of Sorafenib are not optimal in regard to polymorphic and chemical stability, flow properties, compressibility, dissolution rate, and they are at least to some extent hygroscopic and show electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions, such as tablets.
It is therefore an object of the present invention to provide further polymorphic forms of Sorafenib, as well as pharmaceutical compositions comprising the same, which do not encounter the above problems. In particular, it is an object to provide polymorphic forms of Sorafenib which show improved bioavailability, reduced inter-patient variability, improved overall therapeutic efficacy, improved polymorphic and/or chemical stability, excellent flow properties, good compressibility, an improved dissolution profile, and which are non-hygroscopic and/or do not electrostatically charge. The polymorphic forms of Sorafenib show advantageous properties in at least one of the mentioned aspects.
Thus, the present invention relates to crystalline Sorafenib sulphate, to crystalline Sorafenib naphthalene-1 ,5-disulphonate, to crystalline Sorafenib ethane-sulphonate, and to processes for preparing them.
The present invention further relates to a pharmaceutical composition comprising the above salts and polymorphs of Sorafenib.
Herein the term "polymorphic form" includes amorphous or different crystalline structures of the same compound as well as solvates including hydrates thereof and co-crystals.
The term "crystalline" refers to any substantially non-amorphous form of a substance. The term "amorphous form" refers to a form of the substance which has substantially no long-range order like crystalline structures. The atoms or molecules of a material present in amorphous form are arranged in a non-uniform array. It is for example possible to distinguish amorphous forms from crystalline forms of a substance by powder X-ray diffraction. A crystalline compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % amorphous fractions. An amorphous compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % crystalline fractions.
The term "pharmaceutical composition" refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition is in a single dosage form the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell.
The active pharmaceutical ingredient, i.e. the Sorafenib in its forms as described herein, can be present in the pharmaceutical composition in an amount of 10 to 90 % by weight, preferably 20 to 80 % by weight, more preferably 40 to 55 % by weight of the total weight of the composition.
Advantageous properties regarding solubility, homogeneity and flowability are achieved if the active ingredient, composition or pharmaceutical composition of the present invention has a mean particle size of 1 to 300 pm, preferably 5 to 200 pm, more preferably 10 to 100 μιτι.
A bulk density of the active ingredient, composition or the pharmaceutical composition ranging from 0.3 to 0.9 g/ml, preferably 0.4 to 0.85 g/ml, more preferably 0.5 to 0.8 g/ml is advantageous.
The active ingredient, composition or pharmaceutical composition preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.1 to 1.5. The Hausner factor is the ratio of bulk density to tapped density.
The pharmaceutical composition of the present invention can comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers. As pharmaceutically acceptable excipients conventional excipients known to a person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
Preferred examples of fillers are lactose, mannitol, sorbitol and microcrystalline cellulose. The filler is suitably present in an amount of 0 to 90 % by weight, preferably of 30 to 80 % by weight of the total weight of the composition.
The binding agent can be microcrystalline cellulose (MCC) or hydroxypropylmethyl cellulose (HPMC). The binding agent is suitably present in an amount of 1 to 25 % by weight, preferably of 2 to 10 % by weight of the total weight of the composition.
The lubricant is preferably a stearate, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant is suitably present in an amount of 0.1 to 2 % by weight, preferably of about 1 % by weight of the total weight of the composition.
Preferred disintegrating agents are croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone (crospovidone). The disintegrating agent is suitably present in an amount of 0.1 to 20 % by weight, more preferably of 0.5 to 7 % by weight of the total weight of the composition.
The flow enhancer can be colloidal silicon dioxide. The flow enhancer is suitably present in an amount of 0.5 to 8 % by weight, more preferably of 0.5 to 3 % by weight of the total weight of the composition.
The antisticking agent is for example talcum and may be present in an amount of 1 to 5 % by weight, preferably of 1.5 to 3 % by weight of the total weight of the composition.
If desired, an improvement of the solubility of the active pharmaceutical ingredient can be achieved by the addition of complex forming agents/compounds (e.g. sodium benzoate, sodium salicylate or cyclodextrins), alternation of solvent properties (e.g. by adding PVP or polyethylene glycols) or the addition of solubilizers which form tenside micelles (e.g. surfactants).
Suitable solubilizers are for example surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, preferably of 1 to 5 % by weight of the total weight of the composition.
Alternatively, a pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity. However, pseudo-emulsifiers also possess emulsifying properties.
Preferred pseudo-emulsifiers are for example cellulose ethers, gum Arabic or tragacanth and may be present in an amount of 1 to 10 % by weight, preferably of 3 to 7 % by weight of the total weight of the composition.
The pharmaceutical composition of the present invention can be formulated in any known form, preferably as tablets, capsules, granules, pellets or sachets. A particularly preferred pharmaceutical composition is in the form of tablets or capsules. The pharmaceutical composition may contain dosage amounts of about 100, 200 or 400 mg of the active pharmaceutical ingredient. Thus the administered amount can be readily varied according to individual tolerance and safety.
The pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art. Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants, and can be compressed into tablets or filled into sachets or capsules of suitable size. Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients. Suitable powder or granulate mixtures according to the invention are further obtainable by spray drying, lyophilization, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method. The so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules. The above mentioned methods known in the art also include grinding and sieving techniques permitting the adjustment of desired particle size distributions.
The following polymorphic forms of Sorafenib and salts thereof have been found to have advantageous properties over the known polymorphic forms.
I) Polymorph I of Sorafenib sulphate
Polymorph I of Sorafenib sulphate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
Examples of suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Methylethylketone (MEK) is especially preferred.
The differential scanning calorimetry (DSC) thermogram of polymorph I of Sorafenib sulphate shows an endothermic peak at 208 +/- 4°C (Figure 1 a). The melting point, given as onset temperature of the peak in the DSC, is 204 +/- 4°C.
Polymorph I of Sorafenib sulphate shows an IR spectrum exhibiting characteristic peaks at 3396 ± 2 cm"1 and 1698 ± 2 cm"1 (Figure 1 b).
Polymorph I of Sorafenib sulphate can be characterized by an XRPD pattern with characteristic peaks at 1 1.9 ± 0.2, 17.9 ± 0.2, 22.8 ± 0.2 and 24.5 ± 0.2 degrees 2-theta (Figure 1 c).
The most characteristic peaks of the XRPD pattern shown in Figure 1 c are summarized in the following table 1. Table 1
Angle 2-Theta° (± 0.2°) Relative Intensity %
10.6 31.6
1 1.9 44.2
13.1 19.9
14.6 21 .2
15.6 31.2
16.5 25.7
17.2 21 .7
17.9 61.3
18.3 25.1
19.5 28.8
20.5 40.0
21.1 22.5
22.4 24.3
22.8 100
23.4 39.6
23.7 40.7
24.1 57.2
24.5 63.4
24.7 40.5
26.2 25.7
26.8 29.2
27.0 22.3
27.6 19.3
28.1 19.0
28.5 42.6
28.9 21.9
30.6 21.9
31.5 19.0
32.2 32.2 II) Polymorph II of Sorafenib sulphate
Polymorph II of Sorafenib sulphate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
Examples of suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Acetonitrile, ethanol, mixtures of water and acetonitrile or MEK and water are especially preferred.
The DSC thermogram of polymorph II of Sorafenib sulphate shows an endothermic peak at 210 +/- 4°C (Figure 2a). The melting point, given as onset temperature of the peak in the DSC, is 206 +/- 4°C.
Polymorph II of Sorafenib sulphate shows an IR spectrum exhibiting characteristic peaks at 3067 ± 2 cm"1 and 1679 ± 2 cm"1 (Figure 2b).
Polymorph II of Sorafenib sulphate can be characterized by an XRPD pattern with characteristic peaks at 16.7 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 21.3 ± 0.2, 27.0 +/- 0.2 and 27.8 ± 0.2 degrees 2-theta (Figure 2c).
The most characteristic peaks of the XRPD pattern in Figure 2c are summarized in the following table 2. Table 2
Angle 2-Theta0 (± 0.2°) Relative Intensity %
10.0 8.8
14.5 13.7
16.7 25.2
18.6 16.1
19.1 1 1.7
20.0 50.4
21.1 79.1
21.3 100
23.0 14.2
23.7 13.6
25.1 10.1
25.5 13.3
25.8 10.5
27.0 24.0
27.8 24.9
30.0 10.8
III) Sorafenib naphthalene-1,5-disulphonate
Sorafenib naphthalene-1 ,5-disulphonate can be obtained dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding naphthalene-1 ,5-disulphonic acid, isolating and drying the resulting solid.
Examples of suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Acetonitrile, acetone and MEK are especially preferred. The DSC thermogram of Sorafenib naphthalene-1 ,5-disulphonate shows an endothermic peak at 293 +/- 4°C followed by another endothermic peak at 298 +/- 4°C (Figure 3a). The melting point, given as onset temperature of the first peak in the DSC, is 282 +/- 4°C. The melting point was further checked using a Labindia Visual Melting point apparatus, and Sorafenib naphthalene-1 ,5-disulphonate was shown to melt under decomposition.
Sorafenib naphthalene-1 ,5-disulphonate shows an IR spectrum exhibiting characteristic peaks at 3360 ± 2 cm"1 and 1726 ± 2 cm"1 (Figure 3b).
Sorafenib naphthalene-1 ,5-disulphonate can further be characterised by an XRPD pattern having characteristic peaks at 8.2 + 0.2, 12.4 ± 0.2, 15.5 ± 0.2 and 25.9 ± 0.2 degrees 2- theta (Figure 3c).
The most characteristic peaks of the XRPD pattern in Figure 3c are summarized in the following table 3.
Table 3
Angle 2-Theta" (± 0.2°) Relative Intensity %
7.3 95.6
8.2 20.4
9.9 24.7
1 1.5 10.5
12.4 50.5
15.5 40.6
15.9 12.4
16.3 25.2
18.2 17.0
18.8 43.9
19.2 19.7
20.0 28.1
21 .5 19.4
23.1 21.1
24.6 29.6
24.9 32.1
25.9 100
26.6 17.3
27.1 1 1.6
IV) Sorafenib ethane-sulphonate
Sorafenib ethane-sulphonate can be obtained by dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding ethane-sulphonic acid, isolating and drying the resulting solid.
Examples of suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethylacetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Methylethylketone (MEK) is especially preferred.
The DSC thermogram of Sorafenib ethane-sulphonate shows an endothermic peak at 206 +/- 4°C (Figure 4a).
The melting point, given as onset temperature of the peak in the DSC, is 204 +/- 4°C.
Sorafenib ethane-sulphonate shows an IR spectrum exhibiting characteristic peaks at 3071 ± 2 cm"1 and 1714 ± 2 cm"1 (Figure 4b).
Sorafenib ethane-sulphonate can further be characterised by an XRD pattern having characteristic peaks at 15.9 ± 0.2, 23.5 ± 0.2, 23.7 ± 0.2, 25.7 ± 0.2, 28.6 ± 0.2 and 29.2 ± 0.2 degrees 2-theta (Figure 4c).
The most characteristic peaks of the XRPD pattern in Figure 4c are summarized in the following table 4.
Table 4
Angle 2-Theta° (± 0.2°) Relative Intensity %
8.2 20.2
8.5 12.8
10.2 13.6
12.2 15.2
13.7 21.6
14.2 26.1
15.9 73.3
16.4 21.4
17.0 38.1
18.4 27.0
18.9 14.5
20.0 20.6
20.4 26.1
23.5 100
23.7 62.2
25.7 44.8
28.6 43.6
29.2 40.3
30.7 25.5
31.8 22.7
32.0 23.0
36.1 19.4
37.2 16.7
The attached Figures show:
Figure 1 a is the DSC thermogram of polymorph I of Sorafenib sulphate. Figure 1 b is the IR spectrum of polymorph I of Sorafenib sulphate.
Figure 1 c is the XRPD pattern of polymorph I of Sorafenib sulphate. Figure 2a is the DSC thermogram of polymorph II of Sorafenib sulphate.
Figure 2b is the IR spectrum of polymorph II of Sorafenib sulphate. Figure 2c is the XRPD pattern of polymorph II of Sorafenib sulphate. Figure 3a is the DSC thermogram of Sorafenib naphthalene-1 ,5-disulphonate. Figure 3b is the IR spectrum of Sorafenib naphthalene-1 ,5-disulphonate. Figure 3c is the XRPD pattern of Sorafenib naphthalene-1 ,5-disulphonate. Figure 4a is the DSC thermogram of Sorafenib ethane-sulphonate. Figure 4b is the IR spectrum of Sorafenib ethane-sulphonate. Figure 4c is the XRD pattern of Sorafenib ethane-sulphonate.
DSC thermograms were obtained using Mettler Toledo Model DSC 822e' Heating range : 30°C to 300X, Heating rate : 10°C/min, Purge gas : Nitrogen 50 ml /min, Sample holder: 40 μΙ Aluminum crucible.
XRPD samples were analysed on a Bruker-AXS D8 Advance powder X-Ray
diffractometer. The measurement conditions were as follows :
Measurement in Bragg-Brentano-Geometry on vertical goniometer (reflection, theta/theta,
435 mm measurement circle diameter)
with sample rotation (30 rpm) on 9 position sample stage
Radiation: Cu Ka1 (1 .5406A), Tube (Siemens FLCu2K), power 38kV/40mA
Detector: position sensitive detector VANTEC-1
3° capture angle (2theta),
variable anti scatter slit V6 (no divergence slit) detector slit 10.39 mm
4° soller slit,
primary beam stop (<1 ° 2theta) Monochromator: None
Second β filter: Ni filter 0.1 mm (0.5%)
Start angle: 1 °
End Angle: 55°
Measurement time: 1 1 min
Step: 0.016° 2Theta
Software: EVA (Bruker-AXS, Karlsruhe)
IR spectra were obtained using a Perkin Elmer, Model "Spectrum one", DFR mode.
Melting points were measured using a Labindia Visual Melting point apparatus Model No. Labindia MR-VIS.
The invention is further illustrated by the following examples which are not intended to be limiting.
Example 1 : Preparation of Polymorph I of Sorafenib sulphate
3 g Sorafenib was added to 60 ml methylethylketone (MEK), and the mixture was stirred. To the stirring mixture a solution of sulphuric acid in MEK (0.63 g in 15 ml MEK) was slowly added. After 3 hours of stirring at 26°C a white solid crystallized from the solution which was allowed to stir for further 2 hours. The solid was isolated by filtration and dried at 60°C under vacuum for 12 hours.
(Yield: 90.9 %)
Example 2a: Preparation of Polymorph H of Sorafenib sulphate
200 mg Sorafenib was added to 5 ml acetonitrile. The mixture was stirred and warmed to 45°C, and 42.2 mg sulphuric acid was added under continued stirring. Crystallization occurred after one hour, the reaction was stirred for further 16 hours at 26°C. The solid was isolated by filtration and dried at 60°C under vacuum for 3 hours.
(Yield: 75.1 %) Example 2b: Preparation of Polymorph II of Sorafenib sulphate
205 mg Sorafenib was added to a mixture of 4 ml acetonitrile and 0.2 ml water and stirred. To the resulting suspension a solution of 71.9 mg sulphuric acid in 1 ml acetonitrile was added. Nearly all solid dissolved and the remainders were isolated by decantation. The remaining solid was rinsed with 0.5 ml acetonitrile which was then combined with the decanted solution and stirred. After 20 minutes crystallization occurred and the reaction was stirred for further 2.75 hours. The solid was isolated by filtration, was with 2 ml acetonitrile and dried at 50°C under vacuum for 2 hours.
(Yield: 69.5%)
Example 2c: Preparation of Polymorph II of Sorafenib sulphate
300 mg Sorafenib was added to 15 ml ethanol and stirred. To the stirring mixture a solution of 76 mg sulphuric acid in 3 ml ethanol was slowly added. The resulting solution was stirred at 26°C for 2 hours. The resulting white solid was isolated by filtration and dried under vacuum at 50°C for 1 hour and subsequently at 60°C for 4 hours.
(Yield: 68.9 %)
Example 2d: Preparation of Polymorph II of Sorafenib sulphate
191 mg Sorafenib was added to a stirring mixture of 4 ml MEK and 0.1 ml water. 52 mg sulphuric acid was added, and the reaction was allowed to stir for 16 hours. The resulting solid was isolated by filtration, washed with 1 ml MEK and dried under vacuum at 50°C for
2 hours.
(Yield: 63.5 %)
Example 3a: Preparation of Sorafenib naphthalene-1,5-disulphonate
3 g Sorafenib was dissolved in 150 ml acetone at 45°C. To this solution a solution of 2.32 g naphtalen-1 ,5-disulphonic acid in 30 ml acetone was added over a period of 10 minutes at 26°C, resulting in immediate crystallization. The reaction mass was stirred for further 2 hours. The solid was isolated by filtration, washed with 6 ml acetone and dried under vacuum at 60°C for 5 hours.
(Yield: 73.19%)
Example 3b: Preparation of Sorafenib naphthalene-1,5-disulphonate
200 mg Sorafenib was suspended in 8 ml acetonitrile, stirred and heated to reflux resulting in the formation of a clear solution. To the solution a solution of 85.25 mg naphtalen-1 ,5- disulphonic acid in 8 ml acetonitrile was slowly added at 82°C, whereupon crystallization occurred immediately. The reaction was refluxed for further 15 minutes and subsequently stirred at 26°C for 1 hour. The solid was isolated by filtration, washed with 1 ml acetonitrile and dried under vacuum at 50°C for 2 hours.
(Yield: 67.9 %)
Example 4: Preparation of Sorafenib ethane-sulphonate
3 g Sorafenib and 0.71 g ethane-suiphonic acid were added to 45 ml MEK and stirred at 26°C for 3 hours. The resulting solid was isolated by filtration and dried under vacuum at 60°C for 13 hours. (Yield: 88.9 %)

Claims

Claims
1. Polymorph I of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylarriino]phenoxy]- N-methyl-pyridine-2-carboxamide sulphate characterized by an XRPD pattern with peaks at 1 1 .9 ± 0.2, 17.9 ± 0.2, 22.8 ± 0.2 and 24.5 ± 0.2 degrees 2-theta.
2. Polymorph I of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide sulphate according to claim 1 characterized by a melting point of 204 +/- 4°C.
3. Polymorph II of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide sulphate characterized by an XRPD pattern with peaks at 16.7 ± 0.2, 20.0 ± 0.2, 21.1 ± 0.2, 21.3 ± 0.2, 27.0 +/- 0.2 and 27.8 ± 0.2 degrees 2-theta.
4. Polymorph II of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide sulphate according to claim 3 characterized by a melting point of 206 +/- 4°C.
5. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide naphthalene-1 ,5-disulphonate.
6. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide naphthalene-1 , 5-disulphonate according to claim 5 characterized by an XRPD pattern with peaks at 8.2 ± 0.2, 12.4 ± 0.2, 15.5 ± 0.2 and 25.9 ± 0.2 degrees 2-theta.
7. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide naphthalene-1 , 5-disulphonate according to claim 5 or 6 characterized by a melting point of 282 +/- 4°C.
8. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide ethane-sulphonate.
9. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide ethane-sulphonate according to claim 8 characterized by an XRPD pattern with peaks at 15.9 ± 0.2, 23.5 ± 0.2, 23.7 ± 0.2, 25.7 ± 0.2, 28.6 ± 0.2 and 29.2 ± 0.2 degrees 2-theta.
10. Crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]- N-methyl-pyridine-2-carboxamide ethane-sulphonate according to claim 8 or 9 characterized by a melting point of 204 +/- 4°C.
1 1. Pharmaceutical composition comprising at least one of the compounds according to any of claims 1 to 10.
12. Process for the preparation of polymorph I of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]-carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide sulphate comprising dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
13. Process for the preparation of polymorph II of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]-carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide sulphate comprising dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding sulphuric acid, isolating and drying the resulting solid.
14. Process for the preparation of crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]- carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide naphthalene-1 ,5- disulphonate comprising dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding naphthalene-1 ,5-disulphonic acid, isolating and drying the resulting solid.
15. Process for the preparation of crystalline 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]- carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide ethane-sulphonate comprising dissolving Sorafenib in a suitable inert solvent or a mixture of 2 or more solvents, adding ethane-sulphonic acid, isolating and drying the resulting solid.
PCT/EP2010/070198 2009-12-23 2010-12-20 Polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methylpyridine-2-carboxamide WO2011076711A2 (en)

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