WO2015028828A1 - Sorafenib salts - Google Patents

Sorafenib salts Download PDF

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Publication number
WO2015028828A1
WO2015028828A1 PCT/HU2014/000074 HU2014000074W WO2015028828A1 WO 2015028828 A1 WO2015028828 A1 WO 2015028828A1 HU 2014000074 W HU2014000074 W HU 2014000074W WO 2015028828 A1 WO2015028828 A1 WO 2015028828A1
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WIPO (PCT)
Prior art keywords
sorafenib
salt
salts
naphthalene
sulfonic acid
Prior art date
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PCT/HU2014/000074
Other languages
French (fr)
Inventor
Imre KIRÁLY
János Levente HÉDER
Tamás GREGOR
Balázs VOLK
Mária TÓTHNÉ LAURITZ
László Pongó
Katalin BÜTE
Gyula LUKÁCS
Zoltán VARGA
András DANCSÓ
Original Assignee
Egis Gyógyszergyár Zrt.
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Filing date
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Application filed by Egis Gyógyszergyár Zrt. filed Critical Egis Gyógyszergyár Zrt.
Publication of WO2015028828A1 publication Critical patent/WO2015028828A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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 invention relates to new salts of 4-(4- ⁇ [4-chloro-3- 5 (trifluoromethyl)phenyl]carbamoylamino ⁇ phenoxy)-N-methyl-pyridine-2-carboxamide,
  • sorafenib is an inhibitor of several kinases such as vascular endothelial growth factor receptor (VEGF-R2), thrombocyte-derived growth factor receptor, Raf-kinase.
  • VEGF-R2 vascular endothelial growth factor receptor
  • Raf-kinase vascular endothelial growth factor receptor
  • the dysfunctions of these enzymes are in the background of the emergence of several type carcinomas. By inhibiting such enzymes, the formation of tumor cells and tumor angiogenesis can be prevented.
  • sorafenib can be effectively used against
  • !0 cancerous disorder of the kidney renal cell carcinoma, RCC
  • RCC renal cell carcinoma
  • HCC hepatocellular carcinoma
  • UPC unresectable pancreatics cancer
  • APC advanced gastric cancer cases
  • Sorafenib was first described in published International Patent Application WO '.5 2000/42012. This application discloses in Example 42 the synthesis of the free base which is characterized by melting point, thin layer chromatography (R f value) and MS data. The claims list several salts, including the hydrogen-bromide and the naphthalene-2-sulfonic acid salts, without providing an example or any characterization thereto.
  • sorafenib salts (hydrochloride III, hydrobromide, mesylate, amorph sulfate) have been disclosed. These salts are fully characterized by powder X-ray diffraction patterns, infrared spectra and by thermogravimetric methods.
  • the object of the present invention is to provide morphologically uniform new sorafenib salts of high purity which possess more favourable physical-chemical properties than the known salts and have at least as high chemical stability as the known salts and which can be prepared in a reproducible manner suitable for industrial scale manufacture.
  • the above object is solved according to the present invention by the preparation of the new salts of sorafenib, namely by salts formed with hydrogen-bromide and with naphthalene- 2-sulfonic acid.
  • the common inventive idea of the present invention resides in the preparation of new sorafenib salts exhibiting the stability and solubility properties of sorafenib tosylate and by their preparation process wherein formation of genotoxic components (alkyl-mesylates, - ethanesulfonates,- tosylates) is excluded.
  • Figure 1 The X-ray powder diffraction pattern of the sorafenib hydrogen-bromide (1: 1) monoacetonitrile solvate salt.
  • Figure 2 The X-ray powder diffraction pattern of the sorafenib hydrogen-bromide (1 :1) hemihydrate salt.
  • Figure 4 The X-ray powder diffraction pattern of the anhydrous sorafenib naphthalene-2- sulfonic acid (1 :1) salt form II.
  • Figure 5 The X-ray powder diffraction pattern of the anhydrous sorafenib naphthalene-2- sulfonic acid (1 :1) salt form III.
  • the invention relates to stoichiometric (1 :1) salts of sorafenib and the hydrate and solvate forms thereof. More specifically the invention concerns:
  • the invention relates to the crystalline sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt which has the following characteristic X-ray powder diffraction
  • the present invention is also concerned with the sorafenib hydrogen-bromide (1 :1) hemihydrate salt having the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 13.338; 18.409; 23.178; 23.799; 25.531. More particularly characterizing are the following peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 12.612; 13.338; 15.339; 18.409; 21.784; 23.178; 23.799; 25.531; 26.801; 27.624; 31.540.
  • this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 7.645; 10.71 1 ; 12.612; 13.338; 14.292; 15.339; 16.713; 17.640; 18.409; 19.490; 20.494; 21.004; 21.784; 23.178; 23.799; 25.531 ; 26.801 ; 27.624; 28.540; 28.861 ; 30.600; 31.120; 31.540; 32.420; 32.634; 33.184; 33.913; 34.321.
  • the characteristic X-ray powder diffractogram of the product is shown on Figure 2 and the signals having an intensity larger than 4% are summarized in Table 1 below:
  • the present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I having the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 17.609; 19.481 20.785; 21.570; 23.368. More particularly characterizing are the following peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 10.331 ; 13.594; 14.169; 16.651; 17.609; 19.481; 19.905; 20.785; 21.570; 22.340; 22.695; 23.100; 23.368; 24.278; 25.066; 25.820; 28.742.
  • the salt can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.476; 5.114; 6.629; 7.023; 9.526; 10.331; 10.623; 11.446; 12.431; 12.988; 13.594; 14.169; 14.698; 16.200; 16.651; 17.078; 17.609; 18.185; 18.451 ; 19.481 ; 19.905; 20.785; 21.570; 22.340; 22.695; 23.100; 23.368; 24.278; 24.633; 25.066; 25.820; 26.504; 27.876; 28.341; 28.742; 29.076; 29.467; 29.862; 30.141; 30.465; 31.052; 31.827; 32.128; 32.446.
  • Table 3 The characteristic X-ray powder diffractogram of the product is shown on Figure 3 and the signals having an intensity larger than 1% are summarized in Table
  • the present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form II having the following characteristic X- ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 16.174; 19.772; 20.188; 22.314. More particularly characterizing are the following peaks: °20 ( ⁇ 0.2 °2 ⁇ ): 4.268; 13.034; 14.212; 15.670; 16.174; 17.572; 18.393; 19.403; 19.772; 20.188; 20.861 ; 21.294; 22.314; 22.750; 23.344; 23.836; 24.222; 25.1 17; 25.972.
  • said salt can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.268; 10.323; 10.604; 12.367; 13.034; 14.212; 14.591 ; 15.092; 15.670; 16.174; 17.200; 17.572; 18.393; 18.907; 19.403; 19.772; 20.188; 20.861; 21.294; 22.314; 22.750; 23.344; 23.836; 24.222; 25.117; 25.972; 26.671; 27.028; 27.870; 28.304; 28.807; 29.231 ; 29.869; 30.737; 31.000; 31.528; 32.127; 32.518; 32.872; 33.266; 33.724.
  • the present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form III which has the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 10.749; 19.509; 20.033; 22.983; 23.169. More particularly characterizing to this salt are the following peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 9.648; 10.749; 14.187; 16.168; 17.233; 17.659; 18.494; 18.921 ; 19.509; 20.033; 20.738; 21.386; 22.688; 22.983; 23.169; 23.486; 24.246; 27.093; 27.391.
  • this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.666; 9.648; 10.280; 10.749; 11.625; 12.885; 13.676; 14.187; 15.090; 16.168; 16.883; 17.233; 17.659; 18.494; 18.921; 19.509; 20.033; 20.738; 21.386; 21.706; 22.053; 22.688; 22.983; 23.169; 23.486; 24.020; 24.246; 24.440; 24.906; 25.438; 25.815; 26.145; 26.604; 27.093; 27.391; 27.625; 28.045; 28.905; 29.275; 29.389; 29.905; 30.370; 31.025; 31.379; 31.708; 32.011; 32.457; 33.558; 34.312; 34.727.
  • the characteristic X-ray powder diffractogram of the product is shown
  • the present invention is also concerned with the sorafenib naphthalene-2- sulfonic acid (1 :1) monoethanol solvate salt having the following characteristic X-ray powder diffraction peaks: °20 ( ⁇ 0.2 °20): 8.510; 18.453; 21.848; 25.210.
  • °2 ⁇ ⁇ 0.2 °2 ⁇
  • the above-mentioned product can be characterized by the following characteristic X-ray powder diffraction peaks: °2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.367; 6.667; 8.510; 9.219; 9.969; 10.680; 1 1.846; 12.012; 12.293; 12.635; 13.451 ; 13.817; 14.101; 14.451 ; 14.723; 15.610; 15.794; 16.324; 16.800; 17.260; 17.982; 18.453; 19.086; 19.431 ; 20.1 18; 20.400; 20.847; 21.206; 21.444; 21.848; 22.495; 22.830; 23.483; 24.291; 25.210; 25.813; 26.427; 26.764; 27.864; 28.770; 29.542; 29.993; 30.383; 30.668; 31.700; 31.952; 32.161; 32.886; 33.415; 33.587.
  • the characteristic X-ray powder diffrac
  • a process for the preparation of a sorafenib salt of the present invention which comprises reacting sorafenib base in an organic solvent or in a mixture of an organic solvent and water with an organic or inorganic acid, preferably hydrogen-bromide or naphthalene-2-sulfonic acid and separating the sorafenib salt formed and if desired, drying.
  • the salts according to the present invention can be prepared by reacting sorafenib free base of the Formula (1) in an organic solvent with the desired acid at suitable temperature, separating the crystallized salt and if desired washing with organic solvent and after that drying at suitable temperature.
  • the salts according to the present invention can also be prepared by drying the appropriate salt at suitable conditions whilst there is a solid phase morphologic conversion to another crystalline form. This conversion can cause a change of the solvent proportion in the unit cell of the crystal.
  • the salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuum, or under pressure or by using a centrifuge.
  • the process can be carried out in an organic solvent, e.g. C 1-4 aliphatic alcohol, C 1-5 linear or cyclic ether, Ci -6 ester or acetonitrile or a mixture thereof, optionally in admixture with water.
  • organic solvent e.g. C 1-4 aliphatic alcohol, C 1-5 linear or cyclic ether, Ci -6 ester or acetonitrile or a mixture thereof, optionally in admixture with water.
  • organic solvent C 1-4 ether, ester or alcohol or a dipolar-aprotic solvent, particularly preferably tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanoI or a mixture thereof is preferred.
  • the acid used for salt forming is preferably applied in a 0.5-2.5 molar equivalent amount, more preferably 0.9-2.0 molar equivalent amount related to the amount of the sorafenib of the Formula (1).
  • One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between (-20) °C and the boiling point of the solvent, or at the boiling point of the solvent.
  • the precipitated product is separated preferably by filtration.
  • the new sorafenib salts of the Formula (1) of the present invention can be prepared by suspending sorafenib base in a suitable solvent, preferably Ci- alcohol, particularly ethanol, or acetonitrile and adding at temperature between (-10) °C and 30 °C a 0.5-2.5 molar equivalent amount, preferably a 0.9-2.0 molar equivalent amount of an acid as a solution. If the salt precipitates at the temperature of the addition, after the crystallization time, the product should be filtered, washed and dried. If the precipitation does not spontaneously take place, the crystallization is initiated by adding seed crystals.
  • a suitable solvent preferably Ci- alcohol, particularly ethanol, or acetonitrile
  • the sorafenib hydrogen-bromide (1 :1) acetonitrile solvate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in the mixture of acetonitrile and water and adding to the suspension an aqueous hydrogen-bromide solution or a mixture of acetonitrile and hydrogen-bromide solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature.
  • the reaction mixture is crystallized at room temperature. If desired, seed crystals are added to the mixture.
  • the precipitated product is filtered off, optionally washed and dried.
  • the sorafenib hydrogen-bromide (1 :1) hemihydrate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension an aqueous hydrogen-bromide solution or a mixture of acetonitrile and hydrogen-bromide solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature.
  • the reaction mixture is crystallized at room temperature while stirring. If desired, seed crystals are added to the mixture.
  • the precipitated product is filtered off, optionally washed and dried.
  • the anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of acetonitrile and naphthalene- 2-sulfonic acid solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature.
  • the reaction mixture is crystallized at room temperature while stirring. If desired, seed crystals are added to the mixture.
  • the precipitated product is filtered off, optionally washed and dried.
  • the anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form II is preferably prepared by drying of anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I in exsiccator between 50 °C and 150 °C, preferably between 90 °C and 110 °C.
  • the anhydrous sorafenib naphthalene-2-sulfonic acid (1: 1) salt form III is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of acetonitrile and naphthalene- 2-sulfonic acid solution at a temperature between (-20) °C and 25 °C, preferably between (- 15) °C and (-5) °C.
  • the reaction mixture is crystallized between (-15) °C and (-5) °C while stirring. If desired, seed crystals are added to the mixture.
  • the precipitated product is filtered off, and if desired, washed and dried.
  • the sorafenib naphthalene-2-sulfonic acid (1 :1) monoethanolate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in ethanol and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of ethanol and naphthalene-2- sulfonic acid solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature.
  • the reaction mixture is crystallized at room temperature while stirring, if necessary, seed crystals are added to the mixture.
  • the precipitated product is filtered off, optionally washed and dried.
  • the salt-forming agents used for the preparation of active substances of the pharmaceuticals have to be pharmaceutically acceptable and the amount thereof in the product cannot exceed the tolerance limit. Moreover, it is important to pay attention to the amount of the process-related impurities. There are especially strict criteria for the purportedly genotoxic
  • sorafenib salts according to the invention fulfill those criteria which is essential relating to minimalization of the harmful effects of pharmaceuticals exerted in the human body.
  • sorafenib hydrobromide exists in crystalline form(s) not described in the state of the art. Furthermore, the state of the art is silent about the L5 preparation or characterization of sorafenib naphthalene-2-sulfonic acid salts.
  • compositions comprising a therapeutically effective amount of a sorafenib salt of the present invention and if desired, a pharmaceutically acceptable auxiliary agent.
  • a pharmaceutically acceptable auxiliary agent e.g., a pharmaceutically acceptable auxiliary agent for the preparation of pharmaceutical compositions.
  • compositions of the present invention may be administered preferably orally.
  • Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
  • compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents.
  • carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc. can be used.
  • the carrier often serves as the capsule wall material so that no
  • Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration solid forms are the tablets, powders, capsules, pirules, chartula and lozenges.
  • the tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
  • the powders are prepared by admixing the finely powdered active ingredient with the finely powdered carriers.
  • the liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions. Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous.
  • Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
  • compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient.
  • the dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder.
  • the term "dosage unit" relates to the capsules, tablets, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
  • a process for the preparation of the above pharmaceutical compositions which comprises admixing a sorafenib salt according to the invention or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture into a pharmaceutical dosage form.
  • compositions of the present invention can be prepared by conventional methods of pharmaceutical industry.
  • the pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new sorafenib salts according to the invention or mixtures thereof.
  • sorafenib salts as pharmaceutically active ingredient.
  • any of the sorafenib salts for the preparation of pharmaceutical compositions for the treatment of cancer.
  • any of the sorafenib salts for the treatment of cancer such as cancerous disorder of the kidney (renal cell carcinoma RCC), cancerous disorder of the liver (hepatocellular carcinoma HCC) or other types of cancer including gastric and thyroid carcinoma.
  • cancerous disorder of the kidney renal cell carcinoma RCC
  • cancerous disorder of the liver hepatocellular carcinoma HCC
  • other types of cancer including gastric and thyroid carcinoma.
  • any of the sorafenib salts for preparing high-purity sorafenib base additionally the use of any of the sorafenib salts as an intermediate in preparing sorafenib base, their salts or solvates.
  • the advantage of the present invention is that the new sorafenib salt compounds of the present invention are substances of uniform morphology and have an advantageous crystal form. For this reason the salts of the present invention possess preferable and reproducible properties, such as dissolution rate, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
  • the active ingredients of the present invention may be prepared by procedures readily suitable for industrial scale manufacture.
  • sorafenib base used in the following examples was prepared from sorafenib tosylate by general methods well known for the person skilled in the art. Substances: sorafenib hydrogen-bromide (1 : 1) monoacetonitrile solvate salt, sorafenib hydrogen-bromide (1 : 1) hemihydrate salt, anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form I, anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form II, anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form III, sorafenib naphthalene-2- sulfonic acid (1 : 1) monoethanol solvate salt.
  • Orifices source side: automatic and 1.25 ° divergence
  • Measuring range continuous ⁇ /2 ⁇ scan, 3 - 35 °2 ⁇
  • Sample preparation the powdered sample was levelled on a zero background Si single crystal sample holder
  • thermogravimetric measurements 32 minutes The conditions of the thermogravimetric measurements were the following:
  • Atmosphere N 2 stream 40 ml/minute
  • the loss of weight of the product measured by thermogravimetry was 1.3 w/w% (calculated 1.6 w/w%)

Abstract

The invention relates to novel (1:1) salts of sorafenib and the hydrate and solvate forms thereof. More specifically the invention concerns: - the sorafenib hydrogen-bromide (1:1) monoacetonitrile solvate salt, - the sorafenib hydrogen-bromide (1:1) hemihydrate salt, - the sorafenib naphthalene-2-sulfonic acid (1:1) anhydrous (form I, II and III) salt, - the sorafenib naphthalene-2-sulfonic acid (1:1) monoethanol solvate salt. Moreover the invention relates to preparing the mentioned sorafenib salts, pharmaceutical compositions comprising them for the treatment of carcinoma.

Description

SORAFENIB SALTS
Technical Field
The invention relates to new salts of 4-(4-{[4-chloro-3- 5 (trifluoromethyl)phenyl]carbamoylamino}phenoxy)-N-methyl-pyridine-2-carboxamide,
anhydrous forms, hydrates and solvates thereof, process for the preparation thereof, pharmaceutical compositions containing the same and use of said salts in therapy.
The structure of 4-(4-{ [4-chloro-3-
(trifluoromethyl)phenyl]carbamoylamino}phenoxy)-N-methyl-pyridine-2-carboxamide (INN: L0 sorafenib) [CAS: 284461-73-0] of the Formula (1) is:
Figure imgf000002_0001
Background Art
.5 It is known in the art that sorafenib is an inhibitor of several kinases such as vascular endothelial growth factor receptor (VEGF-R2), thrombocyte-derived growth factor receptor, Raf-kinase. The dysfunctions of these enzymes are in the background of the emergence of several type carcinomas. By inhibiting such enzymes, the formation of tumor cells and tumor angiogenesis can be prevented. Specifically, sorafenib can be effectively used against
!0 cancerous disorder of the kidney (renal cell carcinoma, RCC) and the liver (hepatocellular carcinoma, HCC). The use of the agent is promising in case of thyroid carcinoma (RIRTC, Phase III), but there are trials conducted in patients having unresectable pancreatics cancer (UPC, Phase I) and also in advanced gastric cancer cases (AGC, Phase I-II).
Sorafenib was first described in published International Patent Application WO '.5 2000/42012. This application discloses in Example 42 the synthesis of the free base which is characterized by melting point, thin layer chromatography (Rf value) and MS data. The claims list several salts, including the hydrogen-bromide and the naphthalene-2-sulfonic acid salts, without providing an example or any characterization thereto.
In International Patent Application WO 2011/036648, further sorafenib salts (hydrochloride III, hydrobromide, mesylate, amorph sulfate) have been disclosed. These salts are fully characterized by powder X-ray diffraction patterns, infrared spectra and by thermogravimetric methods.
The subjects of International Patent Application WO2011/092663 are the polymorphic form of sorafenib dimethyl-sulfoxide solvate (form III), and a process for preparation thereof. Additionally, the application describes the preparation process of sorafenib acid addition salts starting from the above-mentioned solvate polymorph. There are disclosed many hypotethic acid addition salts including the hydrogen-bromide and the naphthalene-2-sulfonic acid salts. However an example is provided for the preparation and HPLC-characterization for tosylate salt only, and there are no further examples for the other acid addition salts or characterization of them.
Summary of Invention
Recently there has been a serious need in pharmaceutical industry for reproducible manufacturing methods of morphologically uniform products. This is a fundamental demand for active ingredients required to meet the requirements of pharmaceutical formulation, quality assurance and those authorities responsible for marketing authorization. It is well- known in the state of the art that various salts and polymorphs differ from each other in important properties such as solubility, chemical stability, polymorph stability, dissolution rate, bioavailability, amenability to filtration or drying and in tabletting properties. From the point of view of the economy of manufacturing, it is highly important that the product should be prepared by a process suitable for industrial scale manufacture in a reproducible manner to provide a morphologically uniform salt free from contamination.
The object of the present invention is to provide morphologically uniform new sorafenib salts of high purity which possess more favourable physical-chemical properties than the known salts and have at least as high chemical stability as the known salts and which can be prepared in a reproducible manner suitable for industrial scale manufacture.
The above object is solved according to the present invention by the preparation of the new salts of sorafenib, namely by salts formed with hydrogen-bromide and with naphthalene- 2-sulfonic acid.
The common inventive idea of the present invention resides in the preparation of new sorafenib salts exhibiting the stability and solubility properties of sorafenib tosylate and by their preparation process wherein formation of genotoxic components (alkyl-mesylates, - ethanesulfonates,- tosylates) is excluded.
Brief Description of Drawings
Figure 1 - The X-ray powder diffraction pattern of the sorafenib hydrogen-bromide (1: 1) monoacetonitrile solvate salt.
Figure 2 - The X-ray powder diffraction pattern of the sorafenib hydrogen-bromide (1 :1) hemihydrate salt.
Figure 3 - The X-ray powder diffraction pattern of the anhydrous sorafenib naphthalene-2- sulfonic acid (1 :1) salt form I.
Figure 4 - The X-ray powder diffraction pattern of the anhydrous sorafenib naphthalene-2- sulfonic acid (1 :1) salt form II. Figure 5 - The X-ray powder diffraction pattern of the anhydrous sorafenib naphthalene-2- sulfonic acid (1 :1) salt form III.
Figure 6 - The X-ray powder diffraction pattern of the sorafenib naphthalene-2-sulfonic acid (1 :1) monoethanol solvate salt. Detailed description of the invention
The invention relates to stoichiometric (1 :1) salts of sorafenib and the hydrate and solvate forms thereof. More specifically the invention concerns:
- the sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt,
5 - the sorafenib hydrogen-bromide (1 :1) hemihydrate salt,
- the anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I, II and III
- the sorafenib naphthalene-2-sulfonic acid (1 : 1) monoethanol solvate salt.
Particularly the invention relates to the crystalline sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt which has the following characteristic X-ray powder diffraction
L0 peaks: °2Θ (±0.2 °2Θ): 20.409; 23.367; 24.082; 24.825; 25.152; 25.842. More particularly characterizing are the following peaks: °2Θ (±0.2 °2Θ): 11.796; 13.131 ; 15.419; 20.018; 20.409; 23.367; 24.082; 24.825; 25.152; 25.842; 26.145; 26.322; 29.376. The most specifically, this product can be characterized by the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °2Θ): 7.631; 7.950; 9.410; 11.600; 1 1.796; 12.671; 13.131 ;
L5 15.419; 15.646; 16.279; 17.692; 18.432; 18.724; 19.652; 20.018; 20.409; 21.057; 21.786;
23.367; 24.082; 24.825; 25.152; 25.842; 26.145; 26.322; 26.600; 27.277; 27.682; 28.352; 28.838; 29.115; 29.376; 30.458; 31.132; 32.543; 32.901 ; 34.017; 34.162. The characteristic X-ray powder diffractogram of the product is shown on Figure 1 , where the y axis represents the counts per second (Cps) on linear scale [Lin(Cps)] and the signals having an intensity
ZO larger than 3 % are summarized in Table 1 below:
Table 1 : Sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt
(relative intensity >3%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 7.631 11.5760 5
2 7.950 11.1114 9
3 9.410 9.3910 6
4 11.600 7.6225 14
5 11.796 7.4960 23 6 12.671 6.9806 15
7 13.131 6.7368 17
8 15.419 5.7421 17
9 15.646 5.6591 14
10 16.279 5.4407 14
1 1 17.692 5.0091 14
12 18.432 4.8097 13
13 18.724 4.7354 8
14 19.652 4.5137 6
15 20.018 4.4320 20
16 20.409 4.3479 31
17 21.057 4.2157 1 1
18 21.786 4.0762 10
19 23.367 3.8038 27
20 24.082 3.6925 27
21 24.825 3.5836 66
22 25.152 3.5378 100
23 25.842 3.4449 31
24 26.145 3.4057 23
25 26.322 3.3832 22
26 26.600 3.3484 12
27 27.277 3.2668 12
28 27.682 3.2199 10
29 28.352 3.1453 6 30 28.838 3.0934 7
31 29.115 3.0647 12
32 29.376 3.0380 15
33 30.458 2.9325 10
34 31.132 2.8705 4
35 32.543 2.7492 4
36 32.901 2.7201 10
37 34.017 2.6334 5
38 34.162 2.6225 6
The present invention is also concerned with the sorafenib hydrogen-bromide (1 :1) hemihydrate salt having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 13.338; 18.409; 23.178; 23.799; 25.531. More particularly characterizing are the following peaks: °2Θ (±0.2 °2Θ): 12.612; 13.338; 15.339; 18.409; 21.784; 23.178; 23.799; 25.531; 26.801; 27.624; 31.540. The most specifically, this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 7.645; 10.71 1 ; 12.612; 13.338; 14.292; 15.339; 16.713; 17.640; 18.409; 19.490; 20.494; 21.004; 21.784; 23.178; 23.799; 25.531 ; 26.801 ; 27.624; 28.540; 28.861 ; 30.600; 31.120; 31.540; 32.420; 32.634; 33.184; 33.913; 34.321. The characteristic X-ray powder diffractogram of the product is shown on Figure 2 and the signals having an intensity larger than 4% are summarized in Table 1 below:
Table 2: Sorafenib hydrogen-bromide (1 :1) hemihydrate salt
(relative intensity >4%)
Peak 20 (°) d (A) Relative intensity (%)
1 7.645 11.5546 8
2 10.711 8.2534 5 3 12.612 7.0130 18
4 13.338 6.6328 39
5 14.292 6.1923 5
6 15.339 5.7720 25
7 16.713 5.3003 9
8 17.640 5.0239 7
9 18.409 4.8155 44
10 19.490 4.5509 14
1 1 20.494 4.3302 5
12 21.004 4.2261 7
13 21.784 4.0765 25
14 23.178 3.8345 51
15 23.799 3.7358 58
16 25.531 3.4861 100
17 26.801 3.3238 16
18 27.624 3.2266 23
19 28.540 3.1251 13
20 28.861 3.0910 15
21 30.600 2.9192 6
22 31.120 2.8716 10
23 31.540 2.8343 17
24 32.420 2.7594 9
25 32.634 2.7418 10
26 33.184 2.6976 5 27 33.913 2.6413 6
28 34.321 2.6108 8
The present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 17.609; 19.481 20.785; 21.570; 23.368. More particularly characterizing are the following peaks: °2Θ (±0.2 °2Θ): 10.331 ; 13.594; 14.169; 16.651; 17.609; 19.481; 19.905; 20.785; 21.570; 22.340; 22.695; 23.100; 23.368; 24.278; 25.066; 25.820; 28.742. Most specifically, the salt can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.476; 5.114; 6.629; 7.023; 9.526; 10.331; 10.623; 11.446; 12.431; 12.988; 13.594; 14.169; 14.698; 16.200; 16.651; 17.078; 17.609; 18.185; 18.451 ; 19.481 ; 19.905; 20.785; 21.570; 22.340; 22.695; 23.100; 23.368; 24.278; 24.633; 25.066; 25.820; 26.504; 27.876; 28.341; 28.742; 29.076; 29.467; 29.862; 30.141; 30.465; 31.052; 31.827; 32.128; 32.446. The characteristic X-ray powder diffractogram of the product is shown on Figure 3 and the signals having an intensity larger than 1% are summarized in Table 3 below:
Table 3: anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form I
(relative intensity >1%)
Peak 20 (°) d (A) Relative intensity (%)
1 4.476 19.7268 1 1
2 5.114 17.2648 4
3 6.629 13.3231 2
4 7.023 12.5762 2
5 9.526 9.2766 2
6 10.331 8.5561 20
7 10.623 8.3209 10 8 11.446 7.7245 8
9 12.431 7.1146 2
10 12.988 6.8108 3
1 1 13.594 6.5088 19
12 14.169 6.2456 19
13 14.698 6.0222 3
14 16.200 5.4670 4
15 16.651 5.3200 30
16 17.078 5.1879 11
17 17.609 5.0326 46
18 18.185 4.8744 14
19 18.451 4.8047 13
20 19.481 4.5530 84
21 19.905 4.4568 21
22 20.785 4.2702 100
23 21.570 4.1166 53
24 22.340 3.9764 23
25 22.695 3.9149 31
26 23.100 3.8472 22
27 23.368 3.8037 45
28 24.278 3.6632 16
29 24.633 3.6112 12
30 25.066 3.5497 15
31 25.820 3.4477 26 32 26.504 3.3603 5
33 27.876 3.1979 4
34 28.341 3.1465 12
35 28.742 3.1035 20
36 29.076 3.0687 6
37 29.467 3.0288 6
38 29.862 2.9896 13
39 30.141 2.9626 13
40 30.465 2.9319 7
41 31.052 2.8777 2
42 31.827 2.8094 5
43 32.128 2.7838 4
44 32.446 2.7573 6
The present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form II having the following characteristic X- ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 16.174; 19.772; 20.188; 22.314. More particularly characterizing are the following peaks: °20 (±0.2 °2Θ): 4.268; 13.034; 14.212; 15.670; 16.174; 17.572; 18.393; 19.403; 19.772; 20.188; 20.861 ; 21.294; 22.314; 22.750; 23.344; 23.836; 24.222; 25.1 17; 25.972. The most specifically, said salt can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.268; 10.323; 10.604; 12.367; 13.034; 14.212; 14.591 ; 15.092; 15.670; 16.174; 17.200; 17.572; 18.393; 18.907; 19.403; 19.772; 20.188; 20.861; 21.294; 22.314; 22.750; 23.344; 23.836; 24.222; 25.117; 25.972; 26.671; 27.028; 27.870; 28.304; 28.807; 29.231 ; 29.869; 30.737; 31.000; 31.528; 32.127; 32.518; 32.872; 33.266; 33.724. The characteristic X-ray powder diffractogram of the product is shown on Figure 4 and the signals having an intensity larger than 2% are summarized in Table 4 below: Table 4: anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form II
(relative intensity >2%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.268 20.6874 16
2 10.323 8.5628 5
3 10.604 8.3362 11
4 12.367 7.1513 6
5 13.034 6.7870 43
6 14.212 6.2269 40
7 14.591 6.0661 6
8 15.092 5.8658 4
9 15.670 5.6506 18
10 16.174 5.4758 61
11 17.200 5.1513 7
12 17.572 5.0431 49
13 18.393 4.8197 23
14 18.907 4.6898 9
15 19.403 4.5711 50
16 19.772 4.4867 89
17 20.188 4.3951 62
18 20.861 4.2548 47
19 21.294 4.1693 23
20 22.314 3.9810 100
21 22.750 3.9056 25 22 23.344 3.8076 17
23 23.836 3.7301 24
24 24.222 3.6716 30
25 25.117 3.5427 29
26 25.972 3.4280 31
27 26.671 3.3396 5
28 27.028 3.2964 8
29 27.870 3.1987 13
30 28.304 3.1506 6
31 28.807 3.0967 9
32 29.231 3.0528 12
33 29.869 2.9889 8
34 30.737 2.9065 10
35 31.000 2.8825 8
36 31.528 2.8354 7
37 32.127 2.7838 5
38 32.518 2.7512 5
39 32.872 2.7224 4
40 33.266 2.691 1 4
41 33.724 2.6556 3
The present invention is also concerned with the anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form III which has the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 10.749; 19.509; 20.033; 22.983; 23.169. More particularly characterizing to this salt are the following peaks: °2Θ (±0.2 °2Θ): 9.648; 10.749; 14.187; 16.168; 17.233; 17.659; 18.494; 18.921 ; 19.509; 20.033; 20.738; 21.386; 22.688; 22.983; 23.169; 23.486; 24.246; 27.093; 27.391. Most specifically, this product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 4.666; 9.648; 10.280; 10.749; 11.625; 12.885; 13.676; 14.187; 15.090; 16.168; 16.883; 17.233; 17.659; 18.494; 18.921; 19.509; 20.033; 20.738; 21.386; 21.706; 22.053; 22.688; 22.983; 23.169; 23.486; 24.020; 24.246; 24.440; 24.906; 25.438; 25.815; 26.145; 26.604; 27.093; 27.391; 27.625; 28.045; 28.905; 29.275; 29.389; 29.905; 30.370; 31.025; 31.379; 31.708; 32.011; 32.457; 33.558; 34.312; 34.727. The characteristic X-ray powder diffractogram of the product is shown on Figure 5 and the signals having an intensity larger than 2% are summarized in Table 5 below:
Table 5: anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form III
(relative intensity >2%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 4.666 18.9221 13
2 9.648 9.1598 18
3 10.280 8.5982 9
4 10.749 8.2243 40
5 11.625 7.6059 5
6 12.885 6.8651 5
7 13.676 6.4697 3
8 14.187 6.2376 17
9 15.090 5.8666 13
10 16.168 5.4776 30
1 1 16.883 5.2472 j
12 17.233 5.1416 31
13 17.659 5.0184 22 14 18.494 4.7936 29
15 18.921 4.6865 29
16 19.509 4.5466 100
17 20.033 4.4287 97
18 20.738 4.2797 24
19 21.386 4.1515 18
20 21.706 4.0910 13
21 22.053 4.0275 4
22 22.688 3.9162 25
23 22.983 3.8665 50
24 23.169 3.8358 37
25 23.486 3.7848 24
26 24.020 3.7019 8
27 24.246 3.6679 24
28 24.440 3.6392 8
29 24.906 3.5722 10
30 25.438 3.4987 6
31 25.815 3.4484 9
32 26.145 3.4056 7
33 26.604 3.3480 14
34 27.093 3.2886 21
35 27.391 3.2535 22
36 27.625 3.2265 11
37 28.045 3.1791 9 38 28.905 3.0864 10
39 29.275 3.0483 14
40 29.389 3.0367 14
41 29.905 2.9854 12
42 30.370 2.9408 7
43 31.025 2.8802 11
44 31.379 2.8485 3
45 31.708 2.8197 3
46 32.011 2.7937 4
47 32.457 2.7563 4
48 33.558 2.6684 4
49 34.312 2.6114 4
50 34.727 2.5812 7
The present invention is also concerned with the sorafenib naphthalene-2- sulfonic acid (1 :1) monoethanol solvate salt having the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °20): 8.510; 18.453; 21.848; 25.210. More particularly characterizing are the following peaks: °2Θ (±0.2 °2Θ): 5.367; 8.510; 10.680; 13.451 ; 13.817; 14.101 ; 16.324; 16.800; 17.260; 17.982; 18.453; 19.086; 19.431; 20.118; 20.847; 21.206; 21.444; 21.848; 22.830; 23.483; 24.291; 25.210; 25.813; 26.427; 26.764; 27.864; 29.542. The most specifically, the above-mentioned product can be characterized by the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 5.367; 6.667; 8.510; 9.219; 9.969; 10.680; 1 1.846; 12.012; 12.293; 12.635; 13.451 ; 13.817; 14.101; 14.451 ; 14.723; 15.610; 15.794; 16.324; 16.800; 17.260; 17.982; 18.453; 19.086; 19.431 ; 20.1 18; 20.400; 20.847; 21.206; 21.444; 21.848; 22.495; 22.830; 23.483; 24.291; 25.210; 25.813; 26.427; 26.764; 27.864; 28.770; 29.542; 29.993; 30.383; 30.668; 31.700; 31.952; 32.161; 32.886; 33.415; 33.587. The characteristic X-ray powder diffractogram of the product is shown on Figure 6 and the signals having an intensity larger than 3% are summarized in Table 6 below:
Table 6: sorafenib naphthalene-2 -sulfonic acid (1 : 1) monoethanol solvate salt
(relative intensity >3%)
Peak 2Θ (°) d (A) Relative intensity (%)
1 5.367 16.4533 27
2 6.667 13.2476 3
3 8.510 10.3824 96
4 9.219 9.5850 9
5 9.969 8.8652 4
6 10.680 8.2773 23
7 11.846 7.4646 12
8 12.012 7.3620 13
9 12.293 7.1941 5
10 12.635 7.0005 11
11 13.451 6.5775 52
12 13.817 6.4040 38
13 14.101 6.2755 22
14 14.451 6.1244 12
15 14.723 6.01 18 10
16 15.610 5.6723 11
17 15.794 5.6064 9
18 16.324 5.4257 15
19 16.800 5.2730 30 20 17.260 5.1335 47
21 17.982 4.9289 64
22 18.453 4.8042 72
23 19.086 4.6464 23
24 19.431 4.5647 17
25 20.1 18 4.4103 24
26 20.400 4.3499 8
27 20.847 4.2576 26
28 21.206 4.1864 25
29 21.444 4.1404 59
30 21.848 4.0648 100
31 22.495 3.9493 1 1
32 22.830 3.8921 14
33 23.483 3.7853 14
34 24.291 3.6611 27
35 25.210 3.5298 83
36 25.813 3.4487 36
37 26.427 3.3699 14
38 26.764 3.3283 16
39 27.864 3.1993 47
40 28.770 3.1006 9
41 29.542 3.0213 15
42 29.993 2.9769 11
43 30.383 2.9395 6 44 30.668 2.9129 5
45 31.700 2.8203 4
46 31.952 2.7987 4
47 32.161 2.7810 4
48 32.886 2.7213 5
49 33.415 2.6794 5
50 33.587 2.6661 6
According to a further aspect of the present invention there is provided a process for the preparation of a sorafenib salt of the present invention, which comprises reacting sorafenib base in an organic solvent or in a mixture of an organic solvent and water with an organic or inorganic acid, preferably hydrogen-bromide or naphthalene-2-sulfonic acid and separating the sorafenib salt formed and if desired, drying.
The salts according to the present invention can be prepared by reacting sorafenib free base of the Formula (1) in an organic solvent with the desired acid at suitable temperature, separating the crystallized salt and if desired washing with organic solvent and after that drying at suitable temperature.
The salts according to the present invention can also be prepared by drying the appropriate salt at suitable conditions whilst there is a solid phase morphologic conversion to another crystalline form. This conversion can cause a change of the solvent proportion in the unit cell of the crystal. The salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuum, or under pressure or by using a centrifuge.
The process can be carried out in an organic solvent, e.g. C1-4 aliphatic alcohol, C1-5 linear or cyclic ether, Ci-6 ester or acetonitrile or a mixture thereof, optionally in admixture with water. The use as organic solvent C1-4 ether, ester or alcohol or a dipolar-aprotic solvent, particularly preferably tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanoI or a mixture thereof is preferred.
The acid used for salt forming is preferably applied in a 0.5-2.5 molar equivalent amount, more preferably 0.9-2.0 molar equivalent amount related to the amount of the sorafenib of the Formula (1). One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between (-20) °C and the boiling point of the solvent, or at the boiling point of the solvent.
One may particularly preferably proceed by reacting the suspension of sorafenib of the Formula (1) prepared in ethanol or acetonitrile with a solution containing a 0.5-2.5 molar equivalent of the acid at a temperature between (-10) °C and 30 °C. The precipitated product is separated preferably by filtration.
The new sorafenib salts of the Formula (1) of the present invention can be prepared by suspending sorafenib base in a suitable solvent, preferably Ci- alcohol, particularly ethanol, or acetonitrile and adding at temperature between (-10) °C and 30 °C a 0.5-2.5 molar equivalent amount, preferably a 0.9-2.0 molar equivalent amount of an acid as a solution. If the salt precipitates at the temperature of the addition, after the crystallization time, the product should be filtered, washed and dried. If the precipitation does not spontaneously take place, the crystallization is initiated by adding seed crystals. The sorafenib hydrogen-bromide (1 :1) acetonitrile solvate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in the mixture of acetonitrile and water and adding to the suspension an aqueous hydrogen-bromide solution or a mixture of acetonitrile and hydrogen-bromide solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The reaction mixture is crystallized at room temperature. If desired, seed crystals are added to the mixture. The precipitated product is filtered off, optionally washed and dried.
The sorafenib hydrogen-bromide (1 :1) hemihydrate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension an aqueous hydrogen-bromide solution or a mixture of acetonitrile and hydrogen-bromide solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The reaction mixture is crystallized at room temperature while stirring. If desired, seed crystals are added to the mixture. The precipitated product is filtered off, optionally washed and dried. The anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of acetonitrile and naphthalene- 2-sulfonic acid solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The reaction mixture is crystallized at room temperature while stirring. If desired, seed crystals are added to the mixture. The precipitated product is filtered off, optionally washed and dried.
The anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form II is preferably prepared by drying of anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I in exsiccator between 50 °C and 150 °C, preferably between 90 °C and 110 °C. The anhydrous sorafenib naphthalene-2-sulfonic acid (1: 1) salt form III is preferably prepared by stirring the free sorafenib base of the Formula (1) in acetonitrile and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of acetonitrile and naphthalene- 2-sulfonic acid solution at a temperature between (-20) °C and 25 °C, preferably between (- 15) °C and (-5) °C. The reaction mixture is crystallized between (-15) °C and (-5) °C while stirring. If desired, seed crystals are added to the mixture. The precipitated product is filtered off, and if desired, washed and dried.
The sorafenib naphthalene-2-sulfonic acid (1 :1) monoethanolate salt is preferably prepared by stirring the free sorafenib base of the Formula (1) in ethanol and adding to the suspension naphthalene-2-sulfonic acid solution or a mixture of ethanol and naphthalene-2- sulfonic acid solution at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The reaction mixture is crystallized at room temperature while stirring, if necessary, seed crystals are added to the mixture. The precipitated product is filtered off, optionally washed and dried. The salt-forming agents used for the preparation of active substances of the pharmaceuticals have to be pharmaceutically acceptable and the amount thereof in the product cannot exceed the tolerance limit. Moreover, it is important to pay attention to the amount of the process-related impurities. There are especially strict criteria for the purportedly genotoxic
5 components where the tolerance limit is set below few hundred ppm. Often there is a need for dedicated methods and equipement to analyze in this impurity-range. Therefore it is necessary to proceed with special care during the development of mesylate, ethanesulfonate, besylate and tosylate salts because the alkyl-derivatives of them are intensively genotoxic. Thus there is a need for providing new salt-forming agents and salt-forms which do not yield process-
L0 related impurities during production. The sorafenib salts according to the invention fulfill those criteria which is essential relating to minimalization of the harmful effects of pharmaceuticals exerted in the human body.
It has been surprisingly found that sorafenib hydrobromide exists in crystalline form(s) not described in the state of the art. Furthermore, the state of the art is silent about the L5 preparation or characterization of sorafenib naphthalene-2-sulfonic acid salts.
According to a further aspect of the present invention there are provided pharmaceutical compositions comprising a therapeutically effective amount of a sorafenib salt of the present invention and if desired, a pharmaceutically acceptable auxiliary agent. According to a further aspect of the present invention there is provided the use of the 10 sorafenib salts of the present invention as pharmaceuticals and the use thereof for the preparation of pharmaceutical compositions.
The pharmaceutical compositions of the present invention may be administered preferably orally. Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
15 The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents. As carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc. can be used. In case of capsules the carrier often serves as the capsule wall material so that no
30 additional carrier is required. Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration solid forms are the tablets, powders, capsules, pirules, chartula and lozenges.
The tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed. The powders are prepared by admixing the finely powdered active ingredient with the finely powdered carriers. The liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions. Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous. Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
The pharmaceutical compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient. The dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder. The term "dosage unit" relates to the capsules, tablets, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
According to a further aspect of the present invention there is provided a process for the preparation of the above pharmaceutical compositions which comprises admixing a sorafenib salt according to the invention or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture into a pharmaceutical dosage form.
The pharmaceutical compositions of the present invention can be prepared by conventional methods of pharmaceutical industry. The pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new sorafenib salts according to the invention or mixtures thereof.
According to a further aspect of the present invention there is provided the use of the sorafenib salts as pharmaceutically active ingredient. According to a further aspect of the present invention there is provided the use of any of the sorafenib salts for the preparation of pharmaceutical compositions for the treatment of cancer.
According to a further aspect of the present invention there is provided the use of any of the sorafenib salts for the treatment of cancer such as cancerous disorder of the kidney (renal cell carcinoma RCC), cancerous disorder of the liver (hepatocellular carcinoma HCC) or other types of cancer including gastric and thyroid carcinoma.
According to a further aspect of the present invention there is provided the use of any of the sorafenib salts for preparing high-purity sorafenib base, additionally the use of any of the sorafenib salts as an intermediate in preparing sorafenib base, their salts or solvates.
The advantage of the present invention is that the new sorafenib salt compounds of the present invention are substances of uniform morphology and have an advantageous crystal form. For this reason the salts of the present invention possess preferable and reproducible properties, such as dissolution rate, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
The active ingredients of the present invention may be prepared by procedures readily suitable for industrial scale manufacture.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples which serve the purpose of illustration only.
EXAMPLES
The sorafenib base used in the following examples was prepared from sorafenib tosylate by general methods well known for the person skilled in the art. Substances: sorafenib hydrogen-bromide (1 : 1) monoacetonitrile solvate salt, sorafenib hydrogen-bromide (1 : 1) hemihydrate salt, anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form I, anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form II, anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form III, sorafenib naphthalene-2- sulfonic acid (1 : 1) monoethanol solvate salt.
All of the new salts of the invention were analyzed by X-ray powder diffraction measurements using the same conditions.
Apparatus: Rigaku Corporation, Miniflex II. powder diffractometer
Radiation: CuKa! (λ=1.54060 A), CuKa2 (λ=1.54439 A)
Accelerating voltage: 30 kV
Anode current: 15 mA
Arrangement: Bragg-Brentano parafocusing geometry, 6-position sample
changer, reflexive measurement setup
Detector: D/teX Ultra
Soller: source side: 2.5°; detector side: 5°
Orifices: source side: automatic and 1.25 ° divergence
detector side: 8 mm scattering slit
Measuring range: continuous Θ/2Θ scan, 3 - 35 °2Θ
Sample holder: zero background, Si single crystal
Uptake velocity: 1 ° /minute
Step interval: 0.02 °2Θ
Sample preparation: the powdered sample was levelled on a zero background Si single crystal sample holder
Rotation speed of the sample holder: 1 rotation/sec
Measurement cycles: 1
Measurement time: 32 minutes The conditions of the thermogravimetric measurements were the following:
Apparatus: Perkin Elmer Pyris 1 TGA thermogravimetric analyser
Heating speed: 10°C /minute
Atmosphere: N2 stream 40 ml/minute
Pan: open Pt pan Example 1
Preparation of sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt
(sorafenib hydrobromide acetonitrile solvate)
Into an apparatus, 5 cm of acetonitrile is weighed in, whereupon 0.200 g (0.43 mmol) sorafenib base is suspended under intensive stirring. To the reaction mixture, 0.100 cm of 47 % hydrogen-bromide dissolved in 1 cm3 of acetonitrile (0.86 mmol) is added. The clear solution is stirred for 30 hours at room temperature, if desired, seed crystals are added. The precipitated crystalline product is filtered and washed with a little amount of acetonitrile. The crude product is dried at 30 °C under vacuum to constant weight. Yield: 0.239 g (94.7 %)
The loss of weight of the product measured by thermogravimetry was 6.8 w/w% (calculated 7.0 w/w%)
Mp.: 205-218 °C
Example 2
Preparation of sorafenib hydrogen-bromide (1 :1) hemihvdrate salt
(sorafenib hydrobromide hemihydrate)
Into an apparatus, 10 cm3 of acetonitrile is weighed in, whereupon 0.500 g (1.07 mmol) sorafenib base is suspended under intensive stirring. To the reaction mixture, 0.250 cm3 of 47 % hydrogen-bromide dissolved in 1 cm3 of acetonitrile (2.20 mmol) is added. The clear solution is stirred for 22 hours at room temperature, if desired, seed crystals are added. The precipitated crystalline product is filtered and washed with a little amount of acetonitrile. The crude product is dried at 100 °C in vacuum to constant weight.
Yield: 0.563 g (94.4 %)
The loss of weight of the product measured by thermogravimetry was 1.3 w/w% (calculated 1.6 w/w%)
Mp.: 210-223 °C Example 3
Preparation of anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form I
(sorafenib napsylate) Into an apparatus, 5 cm3 of acetonitrile is weighed in, whereupon 0.100 g (0.22 mmol) sorafenib base is suspended under intensive stirring. To the reaction mixture 0.045 g (0.22 mmol) of naphthalene-2-sulfonic acid dissolved in 1 cm3 of acetonitrile is added. The reaction mixture is stirred for one day at room temperature, if desired, seed crystals are added. The precipitated crystalline product is filtered and washed with acetonitrile. It is dried in air at room temperature till constant weight.
Yield: 0.103 g (71.1 %)
Mp.: 197-209 °C
Example 4 Preparation of anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form II
(sorafenib napsylate)
Into a heat-proof container, 0.100 g (0.15 mmol) of naphthalene -2-sulfonic acidic (1 :1) anhydrous (form I) salt is weighed. The container is placed into an exsiccator at 100 °C for one hour and after that period, it is allowed to cool to room temperature.
Yield: 0.100 g (100.0 %)
Mp.: 195-205 °C
Example 5
Preparation of anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form HI
(sorafenib napsylate) Into an apparatus equipped with thermostat, 10 cm3 of acetonitrile is weighed in, whereupon 0.200 g (0.43 mmol) sorafenib base is suspended under intensive stirring. The suspension is cooled to (-10) °C and 0.090 g (0.43 mmol) of naphthalene-2-sulfonic acid dissolved in 1 cm3 of acetonitrile is added at this temperature. The reaction mixture is stirred for one hour at (-10) °C and subsequently for 24 hours at room temperature. The precipitated crystalline product is filtered, washed with a little amount of acetonitrile and dried at 45 °C under vacuum to constant weight.
Yield: 0.225 g (77.7 %)
Mp.: 198-206 °C
Example 6
Preparation of sorafenib naphthalene-2-sulfonic acid (1 :1) monoethanol solvate salt
(sorafenib napsylate monoethanolate)
Into an apparatus, 3 cm3 of ethanol is weighed in, whereupon 0.100 g (0.22 mmol) of sorafenib base is suspended under intensive stirring. To the reaction mixture, 0.045 g (0.22 mmol) of naphthalene-2 -sulfonic acid dissolved in 1 cm3 of ethanol is added. The reaction mixture is stirred for 6 days at room temperature, if desired, seed crystals or propane-2-ol are added. The precipitated crystalline product is filtered and washed with a little amount of ethanol. It is dried in air at room temperature.
Yield: 0.80 g (51.7 %)
The loss of weight of the product measured by thermogravimetry was 7.1 w/w% (calculated
6.4 w/w%)
Mp.: 199-205 °C

Claims

Claims:
1. Sorafenib salts selected from the group consisting of hydrogen bromide salts or naphthalene-2-sulfonic acid salts amorphous and crystalline forms, hydrates and solvates thereof. 2. The sorafenib hydrogen-bromide (1 :1) monoacetonitrile solvate salt according to claim 1 having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.
2 °2Θ):
20.409; 23.367; 24.082; 24.825; 25.152; 25.842.
3. The sorafenib hydrogen-bromide (1 : 1) hemihydrate salt according to claim 1 having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ): 13.338; 18.409; 23.178; 23.799; 25.531.
4. Anhydrous sorafenib naphthalene-2-sulfonic acid (1 : 1) salt form I according to claim 1 having the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °2Θ): 17.609; 19.481 ; 20.785; 21.570; 23.368.
5. Anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form II according to claim 1 having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ):
16.174; 19.772; 20.188; 22.314.
6. Anhydrous sorafenib naphthalene-2-sulfonic acid (1 :1) salt form III according to claim 1 having the following characteristic X-ray powder diffraction peaks: °2Θ (±0.2 °2Θ):
10.749; 19.509; 20.033; 22.983; 23.169.
7. Monoethanol solvate of sorafenib naphthalene-2-sulfonic acid (1 : 1) salt according to
claim 1 having the following characteristic X-ray powder diffraction peaks: °20 (±0.2 °20): 8.510; 18.453; 21.848; 25.210.
8. Process for the preparation of a sorafenib salt according to any of Claims 1 to 7, which comprises reacting sorafenib base in an organic solvent or in a mixture of an organic solvent and water with an organic or inorganic acid, preferably hydrogen-bromide or naphthalene-2-sulfonic acid and separating the sorafenib salt formed and if desired, drying.
9. Process according to Claim 8, characterized in that the acid is used in a 0.5-2.5 molar equivalent amount, preferably in a 0.9-2.0 molar equivalent amount.
10. Process according to Claim 8 or 9, characterized in that the organic solvent used is a ϋμ aliphatic alcohol, a C1-5 linear or ring ether, C1-6 ester, acetonitrile or a mixture thereof,
5 optionally in admixture with water.
11. Process according to Claim 10, characterized in that solvent used is tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol, 2-propanol or a mixture thereof, optionally in admixture with water.
12. Process according to any of Claims 8 to 1 1 characterized in that the reaction is carried out LO at a temperature between (-20)°C and the boiling point of the solvent, preferably between
(-15)°C and 30°C.
13. Pharmaceutical composition comprising a sorafenib salt according to any of Claims 1 to 7 in an admixture with conventional pharmaceutical auxiliary agents.
14. Process for the preparation of pharmaceutical compositions according to Claim 13 which L5 comprises admixing a therapeutically effective amount of a sorafenib salt according to any of Claims 1 to 7 with a pharmaceutically acceptable carrier and optionally with further pharmaceutically acceptable auxiliary agents and bringing the mixture into a pharmaceutical dosage form.
15. Sorafenib salts according to any of claims 1 to 7 for use as medicaments.
20 16. Sorafenib salts according to any of Claims 1 to 7 for the preparation of pharmaceutical compositions for the treatment of cancer.
17. Sorafenib salts according to any of claims 1 to 7 for use in the treatment of cancer.
18. Sorafenib salt according to claim 17 wherein the cancer is cancerous disorder of the kidney (renal cell carcinoma RCC), cancerous disorder of the liver (hepatocellular 5 carcinoma HCC) or other types of cancer including gastric and thyroid carcinoma
19. The use of sorafenib salts according to any of Claims 1 to 7 salts for the treatment of cancer.
20. Use of sorafenib salts according to claim 19 wherein the cancer is cancerous disorder of the kidney (renal cell carcinoma RCC), cancerous disorder of the liver (hepatocellular carcinoma HCC) or other types of cancer including gastric and thyroid carcinoma.
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