Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides

Definitions

• 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.
• 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 amorphous Sorafenib tosylate, to crystalline Sorafenib hydrochloride, to crystalline Sorafenib hydrochloride hydrate, to crystalline Sorafenib mesylate, besylate and maleate, to crystalline Sorafenib monohydrate benzene sulphonic acid co-crystals and to a process for the preparation of amorphous Sorafenib or a salt thereof.
• the present invention relates to a composition comprising amorphous Sorafenib free base and at least one pharmaceutically acceptable excipient.
• the weight ratio of Sorafenib to excipient(s) preferably is in the range of about 1 :2 to about 2:1.
• the excipient is HPMC (hydroxypropylmethyl cellulose).
• the present invention also relates to a composition comprising amorphous Sorafenib tosylate and at least one pharmaceutically acceptable excipient.
• the weight ratio of Sorafenib tosylate to excipient(s) preferably is in the range of about 1 :2 to about 2:1.
• the excipient is crosscarmellose sodium.
• the present invention also relates to a crystalline compound comprising Sorafenib free base and p-toluene sulphonic acid.
• This compound preferably is a co-crystal of Sorafenib free base and p-toluene sulphonic acid.
• This compound may comprise further components, such as solvent molecules.
• the crystalline compound is in particular obtainable by co-crystallisation of Sorafenib and p-toluene sulphonic acid.
• the present invention also relates to a crystalline compound comprising Sorafenib free base and benzene sulphonic acid.
• This compound preferably is a co-crystal of Sorafenib free base and benzene sulphonic acid.
• This compound may comprise further components, such as solvent molecules, especially water.
• the crystalline compound is in particular obtainable by co-crystallisation of Sorafenib and benzene sulphonic acid.
• the present invention further relates to a pharmaceutical composition
• a pharmaceutical composition comprising the above salts, polymorphs or compositions 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 ⁇ m, preferably 5 to 200 ⁇ m, more preferably 10 to 100 ⁇ m.
• 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 conventional excipients known to a person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe f ⁇ r 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.
• a pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity.
• 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.
• Amorphous Sorafenib tosylate can be obtained by milling partially crystalline or substantially crystalline Sorafenib tosylate in a suitable milling device, e.g. as described in Example 1. It can be seen from the X-ray diffraction (XRD) pattern that the obtained product is amorphous (cf. Figure 1c).
• XRD X-ray diffraction
• the differential scanning calorimetry (DSC) thermogram of amorphous Sorafenib tosylate shows an exothermic peak at about 155oC, followed by an endothermic peak at about 231oC.
• the exothermic peak at 155°C indicates that amorphous Sorafenib tosylate undergoes crystallisation at 155°C.
• Amorphous Sorafenib tosylate shows an IR spectrum exhibiting characteristic peaks at 1690 ⁇ 2 cm '1 , 1598 ⁇ 2 cm -1 , 1505 ⁇ 2 cm -1 and 1310 ⁇ 2 cm -1 (cf. Figure 1 b).
• Amorphous Sorafenib free base or salt can be obtained by milling partially crystalline or substantially crystalline Sorafenib free base or salt in a suitable milling device, e.g. as described in Example 2. As it can be seen from the XRD pattern the obtained product is amorphous (cf. Figure 2b).
• Amorphous Sorafenib free base shows an IR spectrum exhibiting characteristic peaks at 1713 ⁇ 2 cm -1 , 1657 ⁇ 2 cm -1 , and 1546 ⁇ 2 cm -1 (cf. Figure 2a).
• Suitable salts are for example the tosylate, mesylate and maleate salts.
• Sorafenib hydrochloride can be obtained from reacting Sorafenib free base with a solution comprising HCI.
• solvent ethanol, methyl ethyl ketone (MEK), isopropyl alcohol (IPA), acetone, acetonitrile (ACN), acetonitrile/water, acetone/acetonitrile or similar solvents or mixtures thereof can be used.
• MEK methyl ethyl ketone
• IPA isopropyl alcohol
• ACN acetonitrile
• acetonitrile/water acetone/acetonitrile or similar solvents or mixtures thereof
• source of HCI a suitable solution of HCI e.g. in IPA, in aqueous media or in dioxane can be used. It was surprisingly found that different polymorphic forms of Sorafenib hydrochloride are obtained depending on the reaction temperature and the solvents used. This is illustrated in the following schemes 1 and 2.
• Sorafenib hydrochloride form Il can also be obtained by reacting Sorafenib free base in isopropyl alcohol with HCI at a temperature of about -5oC.
• the reaction of Sorafenib free base in a mixture of water and acetonitrile as solvent with an aqueous solution of HCI at ambient temperature (about 26°C) also yields Sorafenib hydrochloride form II.
• the DSC thermogram of Sorafenib hydrochloride form Il shows a broad endothermic peak at about 220oC (cf. Figure 3a).
• Sorafenib hydrochloride form Il shows an IR spectrum exhibiting characteristic peaks at 3511 ⁇ 2 cm '1 , 3085 ⁇ 2 crrf 1 , 1695 ⁇ 2 cm -1 , 1636 ⁇ 2 cm -1 , 1604 ⁇ 2 cm -1 , and 1558 ⁇ 2 cm -1 (cf. Figure 3b).
• Sorafenib hydrochloride form Il can further be characterised by an XRD pattern having a characteristic peak at 24.6 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 9.4 ⁇ 0.2, 11.9 ⁇ 0.2, 16.5 ⁇ 0.2, 19.6 ⁇ 0.2 and 24.6 ⁇ 0.2 degrees 2-theta.
• the DSC thermogram of Sorafenib hydrochloride form I shows a broad endothermic peak at about 213oC (cf. Figure 4a).
• Sorafenib hydrochloride form I has a melting point of about 228 - 228°C.
• Sorafenib hydrochloride form I shows an IR spectrum exhibiting characteristic peaks at 3251 ⁇ 2 cm -1 , 3087 ⁇ 2 cm -1 , 1716 ⁇ 2 cm -1 , 1694 ⁇ 2 cm -1 , and 1609 ⁇ 2 cm -1 (cf. Figure 4b).
• Sorafenib hydrochloride form I can further be characterised by an XRD pattern having a characteristic peak at 24.1 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 18.6 ⁇ 0.2, 24.1 ⁇ 0.2, 25.6 ⁇ 0.2, and 26.2 ⁇ 0.2 degrees 2-theta.
• Sorafenib hydrochloride hydrate can be obtained by suspending Sorafenib free base in a suitable solvent, such as a water acetonitrile mixture, and adding a source of HCI, e.g. aqueous HCI solution (about 35 %).
• a source of HCI e.g. aqueous HCI solution (about 35 %).
• the product crystallises from the solution upon cooling, e.g. to between about 0°C and about 5°C.
• the solid product can be filtered off, optionally washed with solvent, e.g. acetonitrile, and dried under vacuum, e.g. at about 8OoC for about 2 to 3 hours.
• Different hydrates of Sorafenib hydrochloride can be obtained by the above method.
• the water content of the hydrate can be influenced by the ratio of acetonitrile to water in the solvent mixture. If the ratio (by volume) of acetonitrile to water is about 6:2, Sorafenib hydrochloride hydrate form I having a water content of about 9 % is obtained, which corresponds to the trihydrate (which has a theoretical water content of 9,72 %).
• the thermo gravimetric analysis of Sorafenib hydrochloride hydrate form I shown in the upper part of Figure 5b confirms the presence of three hydrate water molecules.
• Sorafenib hydrochloride hydrate form I is characterised by a melting range of about 213 - 218°C and shows an IR spectrum exhibiting characteristic peaks at 3502 ⁇ 2 cm -1 , 3420 ⁇ 2 cm -1 , 3249 ⁇ 2 cm -1 , 1708 ⁇ 2 cm -1 , 1687 ⁇ 2 cm -1 , 1610 ⁇ 2 cm -1 , and 1402 ⁇ 2 cm -1 (cf. Figure 5a).
• the DSC thermogram of Sorafenib hydrochloride hydrate form I is shown in the lower part of Figure 5b.
• Sorafenib hydrochloride hydrate form I can further be characterised by an XRD pattern having a characteristic peak at 6.5 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 6.5 ⁇ 0.2, 9.6 ⁇ 0.2, 12.2 ⁇ 0.2, 14.0 ⁇ 0.2, 21.0 ⁇ 0.2, 24.5 ⁇ 0.2, 26.1 ⁇ 0.2 and 29.2 ⁇ 0.2 degrees 2-theta.
• Sorafenib hydrochloride hydrate form Il is obtained, if the ratio (by volume) of acetonitrile to water in the solvent mixture is about 6:1.
• Sorafenib hydrochloride hydrate form Il is characterized by a melting range of about 196 - 199°C and shows an IR spectrum exhibiting characteristic peaks at 3289 ⁇ 2 cm -1 , 3084 ⁇ 2 cm -1 , 1714 ⁇ 2 cm -1 , 1692 ⁇ 2 cm -1 , and 1625 ⁇ 2 cm -1 (cf. Figure 5d).
• Sorafenib hydrochloride hydrate form Il has about three hydrate water molecules (see Figure 5e, upper part showing the thermo gravic analysis).
• the DSC thermogram of form Il shown in the lower part of Figure 5e is, however, different to the DSC thermogram of form I shown in the lower part of Figure 5b.
• Sorafenib hydrochloride hydrate form Il can be characterized by an XRD pattern having a characteristic peak at 24.5 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 9.5 ⁇ 0.2, 12.1 ⁇ 0.2, 13.8 ⁇ 0.2, 21.0 ⁇ 0.2, 24.5 ⁇ 0.2 and 26.0 ⁇ 0.2 degrees 2-theta.
• the two forms of Sorafenib hydrochloride hydrate show differences in IR, DSC and XRD, whereby the weight loss of the two hydrates by TGA shows differences indicating different water contents of the two forms.
• the two forms can in particular be distinguished by the differences in their IR spectra (cf. Figures 5a and d).
• Sorafenib mesylate form I can be obtained by reacting Sorafenib free base with methane sulphonic acid in a suitable solvent, in particular ethanol.
• the crystals can be obtained by filtering and drying, e.g. under vacuum at about 50oC.
• the DSC thermogram of Sorafenib mesylate form I shows a major endothermic peak at about 164oC and a minor endothermic peak at about 233°C.
• the DSC thermogram of Sorafenib mesylate form I is shown in Figure 6a.
• Sorafenib mesylate form I shows an IR spectrum exhibiting characteristic peaks at 1719 ⁇ 2 cm -1 , 1688 ⁇ 2 cm '1 , 1605 ⁇ 2 cm -1 , 1559 ⁇ 2 cm -1 , 1466 ⁇ 2 cm -1 and 1045 ⁇ 2 cm '1 .
• the IR spectrum of Sorafenib mesylate form I is shown in Figure 6b.
• Sorafenib mesylate form Il is characterised by an XRD pattern having a characteristic peak at 20.0 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 12.2 ⁇ 0.2, 15.9 ⁇ 0.2, 17.8 ⁇ 0.2, 18.3 ⁇ 0.2, 19.1 ⁇ 0.2, 20.0 ⁇ 0.2 and 24.2 ⁇ 0.2 degree 2-theta.
• Sorafenib besylate form I is obtained by reacting Sorafenib free base with benzene sulphonic acid in a suitable solvent, e.g. an organic solvent such as anhydrous ethanol.
• a suitable solvent e.g. an organic solvent such as anhydrous ethanol.
• the crystalline product which can be obtained by cooling the reaction solution, can be filtered and dried, e.g. under vacuum at about 50oC.
• the DSC of Sorafenib besylate form I shows an endothermic peak at about 209oC (cf. Figure 8a).
• the melting point is in the range of about 205oC to about 21OoC.
• Sorafenib besylate form I shows an IR spectrum exhibiting characteristic peaks at 1717 ⁇ 2 cm -1 , 1682 ⁇ 2 cm -1 , 1635 ⁇ 2 cm -1 , 1597 ⁇ 2 cm -1 , 1334 ⁇ 2 cm -1 , 1315 ⁇ 2 cm -1 , 1037 ⁇ 2 cm -1 , 1019 ⁇ 2 cm -1 , and 612 ⁇ 2 cm -1 .
• the IR spectrum of Sorafenib besylate form I is shown in Figure 8b.
• Sorafenib besylate form I is characterised by an XRD pattern having a characteristic peak at 25.7 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 7.5 ⁇ 0.2, 8.1 ⁇ 0.2, 12.5 ⁇ 0.2, 15.1 ⁇ 0.2, 15.9 ⁇ 0.2, 17.8 ⁇ 0.2, 18.7 ⁇ 0.2 and 25.7 ⁇ 0.2 degrees 2- theta.
• Sorafenib besylate form Il can be prepared by reacting Sorafenib free base with benzene sulphonic acid in acetonitrile as solvent.
• the crystalline product which can be obtained by cooling the reaction solution, can be filtered off and dried, e.g. under vacuum at about 50oC for about three hours.
• the DSC thermogram of Sorafenib besylate form Il shows an endothermic peak at about 201oC (cf. Figure 9a).
• the melting point is in the range of about 201 °C to about 205°C.
• Sorafenib besylate form Il shows an IR spectrum exhibiting characteristic peaks at 1718 ⁇ 2 cm -1 , 1683 ⁇ 2 cm '1 , 1597 ⁇ 2 cm -1 , 1547 ⁇ 2 cm -1 and 1191 ⁇ 2 cm -1 .
• the IR spectrum of Sorafenib besylate form Il is shown in Figure 9b.
• Sorafenib besylate form Il is characterised by an XRD pattern having a characteristic peak at 25.3 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 7.6 ⁇ 0.2, 8.2 ⁇ 0.2, 11.6 ⁇ 0.2, 15.8 ⁇ 0.2, 18.0 ⁇ 0.2, 18.9 ⁇ 0.2, 25.3 ⁇ 0.2 and 26.2 ⁇ 0.2 degrees 2- theta.
• Crystals (herein also called co-crystals) of Sorafenib, benzene sulfonic acid and water are obtained by combining Sorafenib free base with benzene sulfonic acid in a suitable aqueous solvent, e.g. aqueous ethanol. Crystallisation yields crystals of Sorafenib, benzene sulfonic acid and water in high purity. Since the crystals contain Sorafenib, benzene sulfonic acid and water in a molar ratio of about 1 :0.5:1 , they are also called Sorafenib hemibesylate monohydrate. Alternatively, the crystals of Sorafenib hemibesylate monohydrate can be obtained by slurrying Sorafenib besylate form I in aqueous ethanol.
• Sorafenib hemibesylate monohydrate remains unchanged when dried for several days under forced drying conditions (70oC, 20 mbar).
• Sorafenib hemibesylate monohydrate is advantageous as low cost non-anhydrous ethanol can be used. Further, the presence of water avoids the otherwise existing problem of formation of toxic benzene sulfonic acid alkene esters. Even in the presence of low percentages of water the tendency of formation of these toxic by-products is significantly reduced. Further in the co-crystal the molar amount of active principle Sorafenib is high compared to the 1 :1 salts, such as Sorafenib besylate form I, while solubility is much higher than for pure crystalline base of Sorafenib.
• the DSC thermogram of Sorafenib hemibesylate monohydrate shows an endothermic peak at about 145°C (cf. Figure 9d).
• the melting range is from about 143oC to about 147°C.
• Sorafenib hemibesylate monohydrate shows an IR spectrum exhibiting characteristic peaks at 1541 ⁇ 2 crr ⁇ 1 , 1506 ⁇ 2 crrf 1 , 1420 ⁇ 2 crrT 1 , 1306 ⁇ 2 cm -1 , 1284 ⁇ 2 cm -1 , 1174 ⁇ 2 cm -1 , 1122 ⁇ 2 cm -1 , 1030 ⁇ 2 cm -1 and 825 ⁇ 2 cm -1 .
• the IR spectrum of Sorafenib besylate monohydrate is shown in Figure 9e.
• Sorafenib hemibesylate monohydrate is characterized by an XRD pattern having a characteristic peak at 16.8 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 13.2 ⁇ 0.2, 16.8 ⁇ 0.2, 20.0 ⁇ 0.2, 20.6 ⁇ 0.2, 23.3 ⁇ 0.2, 23.7 ⁇ 0.2 and 25.3 ⁇ 0.2 degrees 2-theta.
• Sorafenib maleate form I can be obtained by reacting Sorafenib free base with maleic acid in a suitable solvent, e.g. acetonitrile (temperature about 75°C).
• a suitable solvent e.g. acetonitrile (temperature about 75°C).
• the solid product can be obtained from the solution by cooling, filtering off and drying, e.g. under high vacuum at about 45oC for about two hours.
• the DSC thermogram of Sorafenib maleate form I shows an endothermic peak at about 162°C and a smaller endothermic peak at about 109oC (cf. Figure 10a).
• the melting range is from about 157°C to about 159oC.
• a composition comprising amorphous Sorafenib free base and a pharmaceutically acceptable excipient according to the present invention can be obtained by mixing Sorafenib free base and the pharmaceutically acceptable excipient in the desired weight ratio, followed by sufficiently milling the mixture in a suitable device.
• the preferred weight ratio of Sorafenib to excipient is about 1 :2 to about 2:1 , in particular about 1 :1.
• the preferred pharmaceutically acceptable excipient is hydroxypropylmethyl cellulose (HPMC).
• Sorafenib free base also a salt of Sorafenib, in particular the tosylate salt of Sorafenib can be used.
• the preferred pharmaceutically acceptable excipient to be mixed with Sorafenib tosylate is crosscarmellose sodium.
• the present invention further relates to co-crystals of Sorafenib and p-toluene sulphonic acid.
• These co-crystals can be obtained by dissolving p-toluene sulphonic acid (p-TSA) and Sorafenib free base in a suitable solvent, preferably an organic solvent, such as acetonitrile, optionally filtering, and drying the obtained solid.
• p-TSA p-toluene sulphonic acid
• a suitable solvent preferably an organic solvent, such as acetonitrile
• the Sorafenib p-TSA co-crystals can be characterised by a DSC thermogram showing an endothermic peak at about 179°C and a minor endothermic peak at about 207oC.
• the melting range is from about 178°C to about 187oC.
• the co-crystal shows an IR spectrum exhibiting characteristic peaks at 3080 ⁇ 2 cm -1 , 1719 ⁇ 2 cm '1 , 1683 ⁇ 2 cm '1 , 1633 ⁇ 2 cm -1 and 1598 ⁇ 2 cm -1 .
• the DSC thermogram and the IR spectrum of the Sorafenib p- toluene sulphonic acid co-crystal are shown in Figures 12a and b, respectively.
• the Sorafenib p-toluene sulphonic acid co-crystal is further characterised by an XRD pattern having characteristic peaks at 18.7 ⁇ 0.2 and 24.9 ⁇ 0.2 degrees 2-theta, in particular having characteristic peaks at 7.3 ⁇ 0.2, 12.0 ⁇ 0.2, 15.7 ⁇ 0.2, 18.7 ⁇ 0.2, 21.8 ⁇ 0.2, 24.9 ⁇ 0.2 and 25.7 ⁇ 0.2 degrees 2-theta.
• Figure 1a is the DSC thermogram of amorphous Sorafenib tosylate.
• Figure 1 b is the IR spectrum of amorphous Sorafenib tosylate.
• Figure 1c is the XRD pattern of amorphous Sorafenib tosylate.
• Figure 2a is the IR spectrum of amorphous Sorafenib free base.
• Figure 2b is the XRD pattern of amorphous Sorafenib free base.
• Figure 3a is the DSC thermogram of Sorafenib hydrochloride form II.
• Figure 3b is the IR spectrum of Sorafenib hydrochloride form II.
• Figure 3c is the XRD pattern of Sorafenib hydrochloride form II.
• Figure 4a is the DSC thermogram of Sorafenib hydrochloride form I.
• Figure 4b is the IR spectrum of Sorafenib hydrochloride form I.
• Figure 4c is the XRD pattern of Sorafenib hydrochloride form I.
• Figure 5a is the IR spectrum of Sorafenib hydrochloride hydrate form I.
• Figure 5b is the thermo gravimetric analysis (TGA) (upper part) and the DSC thermogram (lower part) of Sorafenib hydrochloride hydrate form I.
• Figure 5c is the XRD pattern of Sorafenib hydrochloride hydrate form I.
• Figure 5d is the IR spectrum of Sorafenib hydrochloride hydrate form II.
• Figure 5e is the thermo gravimetric analysis (TGA) (upper part) and the DSC thermogram (lower part) of Sorafenib hydrochloride hydrate form II.
• Figure 5f is the XRD pattern of Sorafenib hydrochloride hydrate form II.
• Figure 6a is the DSC thermogram of Sorafenib mesylate form I.
• Figure 6b is the IR spectrum of Sorafenib mesylate form I.
• Figure 6c is a H 1 NMR spectrum of Sorafenib mesylate form I.
• Figure 7a is the DSC thermogram of Sorafenib mesylate form II.
• Figure 7b is the IR spectrum of Sorafenib mesylate form II.
• Figure 7c is the XRD pattern of Sorafenib mesylate form II.
• Figure 8a is the DSC thermogram of Sorafenib besylate form I.
• Figure 8b is the IR spectrum of Sorafenib besylate form I.
• Figure 8c is the XRD pattern of Sorafenib besylate form I.
• Figure 9a is the DSC thermogram of Sorafenib besylate form II.
• Figure 9b is the IR spectrum of Sorafenib besylate form II.
• Figure 9c is the XRD pattern of Sorafenib besylate form II.
• Figure 9d is the DSC thermogram of Sorafenib hemibesylate monohydrate co-crystals.
• Figure 9e is the IR spectrum of Sorafenib hemibesylate monohydrate co-crystals.
• Figure 9f is the XRD pattern of Sorafenib hemibesylate monohydrate co-crystals.
• Figure 9g is the H 1 NMR spectrum of Sorafenib hemibesylate monohydrate co-crystals.
• Figure 10a is the DSC thermogram of Sorafenib maleate form I.
• Figure 10b is the IR spectrum of Sorafenib maleate form I.
• Figure 11a is the DSC thermogram of Sorafenib maleate form II.
• Figure 11b is the IR spectrum of Sorafenib maleate form II.
• Figure 12a is the DSC thermogram of Sorafenib p-toluene sulphonic acid co-crystals.
• Figure 12b is the IR spectrum of Sorafenib p-toluene sulphonic acid co-crystals.
• Figure 12c is the XRD pattern of Sorafenib p-toluene sulphonic acid co-crystals.
• DSC thermograms were obtained using Mettler Toledo Model DSC 822 e ' Heating range : 3OoC to 300oC, Heating rate : 10°C/min, Purge gas : Nitrogen 50 ml /min, Sample holder: 40 ⁇ l Aluminum crucible.
• TGA were obtained using Mettler Toledo TGA/DSC 1 with the following parameters Heating range :30° to 400°C; Heating rate : 10oC / min; Weight of sample : 5-15 mg.
• the water content was determined using a Mettler Toledo DL31 , Karl Fischer Titrator. High Performance Liquid Chromatography (HPLC)
• Example 1 Preparation of amorphous Sorafenib tosylate
• Sorafenib tosylate was removed from the mill and dried under vacuum at 45°C for 2 hrs.
• DSC shows a sharp endothermic peak at 213°C indicating form I (cf. Figure 4a).
• IR 3251 , 3087, 1716, 1694, 1609 cm -1 .
• IR indicates form I (cf. Figure 4b).
• the XRD pattern is shown in Figure 4c.
• TGA shows 2.89 % loss between 47°C and 79oC, 5.26% loss between 79°C and 113oC,
• Residual solvent 554 ppm acetonitrile
• TGA shows 1.83 % loss between 47oC and 72oC, 4.63 % loss between 37°C and 107oC,
• the XRD pattern is shown in Figure 5f.
• This reaction mixture was heated to reflux (78oC) and stirred at reflux temperature 78°C for
• DSC shows major endothermic peaks at 159°C and 162oC, and a minor exothermic peak at 188°C and a minor endothermic peak at 232°C (cf. Figure 7a).
• HPLC 99.96 %.
• the XRD pattern is shown in Figure 7c.
• DSC shows a sharp endothermic peak at 209°C (cf. Figure 8a).
• DSC shows a sharp endothermic peak at 201 oC (cf. Figure 9a).
• the XRD pattern is shown in Figure 9c.
• Sorafenib free base (20 g, 43 mmol) was suspended in dry ethanol (500 ml) and the suspension was heated to reflux until all solid was dissolved.
• a solution of benzene sulphonic acid (7.5 g, 47.3 mmol, 1.1 eq.) in water (15 ml) was added dropwise to the solution at 75oC.
• the solution (ethanol/H 2 0 96.4:3.6) was stirred at 75°C for 30 min. The heating bath was removed and the solution was allowed to cool to 3OoC, after which it was further cooled using an ice bath. When the internal temperature reached 4°C a light yellow solid precipitated from the solution.
• the suspension was stirred at OoC for 1.5 h after which is was allowed to come to room temperature and stirred 16 h.
• the solid was collected by filtration and the wet filter cake was washed with ethanol (20 ml).
• the solid was dried at 70°C/20 mbar to yield 22.2 g of a fine powder.
• Sorafenib free base (6 g, 12.9 mmol) was suspended in dry ethanol (150 ml) and the suspension was heated to reflux until solid was dissolved.
• a solution of benzene sulphonic acid (2.25 g, 14.2 mmol, 1.1 eq.) in water (150 ml) was added dropwise to the solution at 75oC leading to the formation of a precipitate.
• the suspension (EtOH/H 2 O 44.1 :55.9) was stirred at 75°C for 40 min. After this time the heating bath was replaced by an ice bath. The suspension was stirred at OoC for 2 h and then at room temperature for 16 h.
• the light yellow precipitate was collected by filtration and dried at 50°C/30 mbar for 24 h, then at 60°C/30 mbar for 24 h, and finally at 70°C/30 mbar for 6 days yielding 6.6 g Sorafenib hemibesylate monohydrate co-crystals.
• DSC shows a minor endothermic peak at 109oC and a sharp endothermic peak at 162°C
• DSC shows a sharp endothermic peak at 161 oC (cf. Figure 11a).
• IR 1698, 1678, 1622 cm -1 (cf. Figure 11b).
• Example 7 Amorphous Sorafenib Free Base and HPMC E3 (1:2)
• Example 8 Amorphous Sorafenib Free Base and HPMC E3 (1:1)
• Example 10 Amorphous Sorafenib Tosylate and Crosscarmellose Sodium
• Example 11 Amorphous Sorafenib Tosylate and Crosscarmellose Sodium
• DSC shows a sharp endothermic peak at 179oC and a minor endothermic peak at 207oC
• the XRD pattern is shown in Figure 12c.
• the results are illustrated in the following tables 3 - 6:
• Sorafenib HCI form Il and Sorafenib p-TSA co-crystals show excellent hygroscopy results which renders these substances particularly suitable for pharmaceutical compositions.
• Sorafenib tosylate, Sorafenib p-toluene sulphonic acid co-crystals, and Sorafenib hydrochloride were investigated in respect of stability during storage at 4OoC and 75 % RH (relative humidity) for 4 weeks (4 w), in an open or closed storage container. The results are illustrated in the following table 7:
• All compounds are stable at 40oC / 75 % RH for 4 weeks, and therefore suitable for pharmaceutical compositions.

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