16 December 2010 ( ) WO 2010/ A2

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 16 December 2010 ( ) WO 2010/ A2 (51) International Patent Classification: (74) Agents: TEIPEL, Stephan et al; Prinzregentenstr. 16, C07D 213/81 ( ) Munchen (DE). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/EP20 10/ kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) International Filing Date: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 8 June 2010 ( ) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (26) Publication Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 1395/CHE/ June 2009 ( ) IN SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): RATIO- PHARM GMBH [DE/DE]; Graf-Arco-Strasse 3, (84) Designated States (unless otherwise indicated, for every UIm (DE). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (72) Inventors; and ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (75) Inventors/Applicants (for US only): GIDWANI, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Ramesh Matioram [IN/IN]; Coral 702, Nirmal EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lifestyles, L.B.S. Marg, Mulund (West), Mumbai, Maha- LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, rasthra (IN). WAKCHAURE, Vikas S [IN/IN]; SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Ekta Residency A-101, Plot No. 14 Sector -6, Khanda GW, ML, MR, NE, SN, TD, TG). Colony, New Panvel, Maharashtra (IN). STRIEGEL, Hans-Gunter [DE/DE]; Reiherweg 6, Published: Blaubeuren (DE). ALBRECHT, Wolfgang without international search report and to be republished [DE/DE]; Alfred-Mendler-Weg 25/1, UIm (DE). upon receipt of that report (Rule 48.2(gf) (54) Title: POLYMORPHS OF 4-[4-[[4-CHLORO-S-(TRIFLUOROMETHYL)PHENYL]CARBAMOYLAMINO]PHENOXY] N-METHYL-PYRIDINE-2-CARBOXAMIDE (57) Abstract: The present invention relates to polymorphs of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]- carbamoylamino]phenoxy]-n-methyl-pyridine-2-carboxamide and pharmaceutical compositions comprising the same.

2 (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-n-methyl-pyridine-2-carboxamide, polymorphs of salts thereof and pharmaceutical compositions comprising the same. The present invention relates to polymorphs of 4-[4-[[4-chloro-3-4-[4-[[4-Chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2- carboxamide, also known as Sorafenib, has the following chemical structure: Sorafenib is a small molecular inhibitor of several protein kinases, including RAF, VEGFR- 2PK30, and PDGFR kinases. These enzymes are all molecular targets of interest for the treatment of hyper-proliferative diseases, including cancer. ω-carboxylaryl substituted diphenyl ureas including Sorafenib and its synthesis are disclosed in WO 2000/ This document also discloses various pharmaceutically acceptable salts of the compounds. WO 2006/ discloses pharmaceutical compositions comprising a solid dispersion of Sorafenib. WO 2006/ discloses a process for preparing Sorafenib and its tosylate salt. The tosylate salt is obtained in crystalline form.

3 W O 2006/ 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 W O 00/42012 is designated polymorph II. Typically Sorafenib is administered orally, as this route provides comfort and convenience of dosing. Although several salts of Sorafenib and polymorphic forms thereof are known in the art, these known forms are not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known forms of Sorafenib are not optimal in regard to polymorphic and chemical stability, flow properties, compressibility, dissolution rate, and they are at least to some extent hygroscopic and show electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions, such as tablets. It is therefore an object of the present invention to provide further polymorphic forms of Sorafenib, as well as pharmaceutical compositions comprising the same, which do not encounter the above problems. In particular, it is an object to provide polymorphic forms of Sorafenib which show improved bioavailability, reduced inter-patient variability, improved overall therapeutic efficacy, improved polymorphic and/or chemical stability, excellent flow properties, good compressibility, an improved dissolution profile, and which are non-hygroscopic and/or do not electrostatically charge. The polymorphic forms of Sorafenib show advantageous properties in at least one of the mentioned aspects. Thus, the present invention relates to 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. Further, the present invention relates to a composition comprising amorphous Sorafenib free base and at least one pharmaceutically acceptable excipient. In this composition the weight ratio of Sorafenib to excipient(s) preferably is in the range of about 1:2 to about 2:1. In one embodiment the excipient is HPMC (hydroxypropylmethyl cellulose).

4 The present invention also relates to a composition comprising amorphous Sorafenib tosylate and at least one pharmaceutically acceptable excipient. In this composition the weight ratio of Sorafenib tosylate to excipient(s) preferably is in the range of about 1:2 to about 2:1. In one embodiment 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 comprising the above salts, polymorphs or compositions of Sorafenib. Herein the term "polymorphic form" includes amorphous or different crystalline structures of the same compound as well as solvates including hydrates thereof and co-crystals. The term "crystalline" refers to any substantially non-amorphous form of a substance. The term "amorphous form" refers to a form of the substance which has substantially no long-range order like crystalline structures. The atoms or molecules of a material present in amorphous form are arranged in a non-uniform array. It is for example possible to distinguish amorphous forms from crystalline forms of a substance by powder X-ray diffraction. A crystalline compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % amorphous fractions. An amorphous compound should contain not more than 10 %, preferably not more than 5 % or 1 % and more preferably about 0 % crystalline fractions. The term "pharmaceutical composition" refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of

5 single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition is in a single dosage form the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell. The active pharmaceutical ingredient, i.e. the Sorafenib in its forms as described herein, can be present in the pharmaceutical composition in an amount of 10 to 90 % by weight, preferably 20 to 80 % by weight, more preferably 40 to 55 % by weight of the total weight of the composition. Advantageous properties regarding solubility, homogeneity and flowability are achieved if the active ingredient, composition or pharmaceutical composition of the present invention has a mean particle size of 1 to 300 µm, preferably 5 to 200 µm, more preferably 10 to 100 µm. A bulk density of the active ingredient, composition or the pharmaceutical composition ranging from 0.3 to 0.9 g/ml, preferably 0.4 to 0.85 g/ml, more preferably 0.5 to 0.8 g/ml is advantageous. The active ingredient, composition or pharmaceutical composition preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.1 to 1.5. The Hausner factor is the ratio of bulk density to tapped density. The pharmaceutical composition of the present invention can comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers. As pharmaceutically acceptable excipients conventional excipients known to a person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fϋr Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.

6 Preferred examples of fillers are lactose, mannitol, sorbitol and microcrystalline cellulose. The filler is suitably present in an amount of 0 to 90 % by weight, preferably of 30 to 80 % by weight of the total weight of the composition. The binding agent can be microcrystalline cellulose (MCC) or hydroxypropylmethyl cellulose (HPMC). The binding agent is suitably present in an amount of 1 to 25 % by weight, preferably of 2 to 10 % by weight of the total weight of the composition. The lubricant is preferably a stearate, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant is suitably present in an amount of 0.1 to 2 % by weight, preferably of about 1 % by weight of the total weight of the composition. Preferred disintegrating agents are croscarmellose sodium, sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone (crospovidone). The disintegrating agent is suitably present in an amount of 0.1 to 20 % by weight, more preferably of 0.5 to 7 % by weight of the total weight of the composition. The flow enhancer can be colloidal silicon dioxide. The flow enhancer is suitably present in an amount of 0.5 to 8 % by weight, more preferably of 0.5 to 3 % by weight of the total weight of the composition. The antisticking agent is for example talcum and may be present in an amount of 1 to 5 % by weight, preferably of 1.5 to 3 % by weight of the total weight of the composition. If desired, an improvement of the solubility of the active pharmaceutical ingredient can be achieved by the addition of complex forming agents/compounds (e.g. sodium benzoate, sodium salicylate or cyclodextrins), alternation of solvent properties (e.g. by adding PVP or polyethylene glycols) or the addition of solubilizers which form tenside micelles (e.g. surfactants). Suitable solubilizers are for example surfactants such as polyoxyethylene alcohol ethers (e.g. Brij ), polysorbates (e.g. Tween ) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic ) and may be present in amounts of 0.5 to 7 % by weight, preferably of 1 to 5 % by weight of the total weight of the composition.

7 Alternatively, a pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity. However, pseudo-emulsifiers also possess emulsifying properties. Preferred pseudo-emulsifiers are for example cellulose ethers, gum Arabic or tragacanth and may be present in an amount of 1 to 10 % by weight, preferably of 3 to 7 % by weight of the total weight of the composition. The pharmaceutical composition of the present invention can be formulated in any known form, preferably as tablets, capsules, granules, pellets or sachets. A particularly preferred pharmaceutical composition is in the form of tablets or capsules. The pharmaceutical composition may contain dosage amounts of about 100, 200 or 400 mg of the active pharmaceutical ingredient. Thus the administered amount can be readily varied according to individual tolerance and safety. The pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art. Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants, and can be compressed into tablets or filled into sachets or capsules of suitable size. Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients. Suitable powder or granulate mixtures according to the invention are further obtainable by spray drying, lyophilization, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method. The so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules. The above mentioned methods known in the art also include grinding and sieving techniques permitting the adjustment of desired particle size distributions. The following polymorphic forms of Sorafenib and salts thereof have been found to have advantageous properties over the known polymorphic forms.

8 I) Amorphous Sorafenib tosylate 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). The differential scanning calorimetry (DSC) thermogram of amorphous Sorafenib tosylate (cf. Figure 1a) 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. The hereby obtained crystals melt at about 23OºC. Amorphous Sorafenib tosylate shows an IR spectrum exhibiting characteristic peaks at 1690 ± 2 cm 1, 1598 ± 2 c m - 1, 1505 ± 2 c m - 1 and 1310 ± 2 c m - 1 (cf. Figure 1b). II) Amorphous Sorafenib 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 c m - 1, 1657 ± 2 c m - 1, and 1546 ± 2 c m - 1 (cf. Figure 2a). Suitable salts are for example the tosylate, mesylate and maleate salts. III) Sorafenib hydrochloride and Sorafenib hydrochloride hydrate Sorafenib hydrochloride can be obtained from reacting Sorafenib free base with a solution comprising HCI. As 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. As 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

9 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. Scheme 1: Sorafenib HCI Form I Sorafenib HCI Form Il Scheme 2: Sorafenib HCI Form I Sorafenib HCI Form Il Thus, the reaction of Sorafenib free base in ethanol with HCI in isopropyl alcohol results in Sorafenib hydrochloride form I, when the reaction is conducted at 26 C (indicated in the schemes as "26 deg C"), while form Il is obtained when the reaction is conducted at -2ºC. According to scheme 2, when methyl ethyl ketone is used as solvent and 35 wt.-% of aqueous HCI solution is applied, form I is obtained when the reaction is conducted at -5ºC while form Il is obtained when the reaction is conducted at 26ºC. Sorafenib hydrochloride form Il can also be obtained by reacting Sorafenib free base in isopropyl alcohol with HCI at a temperature of about -5ºC.

10 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 ± 2 cm 1, 3085 ± 2 crrf 1, 1695 ± 2 c m - 1, 1636 ± 2 c m - 1, 1604 ± 2 c m - 1, and 1558 ± 2 c m - 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 XRD pattern of Sorafenib hydrochloride form Il is shown in Figure 3c. 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 C. Sorafenib hydrochloride form I shows an IR spectrum exhibiting characteristic peaks at 3251 ± 2 c m - 1, 3087 ± 2 c m - 1, 1716 ± 2 c m - 1, 1694 ± 2 c m - 1, and 1609 ± 2 c m - 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. The XRD pattern of Sorafenib hydrochloride form I is shown in Figure 4c. 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.

11 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 C and shows an IR spectrum exhibiting characteristic peaks at 3502 ± 2 c m - 1, 3420 ± 2 c m - 1, 3249 ± 2 c m - 1, 1708 ± 2 c m - 1, 1687 ± 2 c m - 1, 1610 ± 2 c m - 1, and 1402 ± 2 c m - 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. The XRD pattern of Sorafenib hydrochloride hydrate form I is shown in Figure 5c. 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 C and shows an IR spectrum exhibiting characteristic peaks at 3289 ± 2 c m - 1, 3084 ± 2 c m - 1, 1714 ± 2 c m - 1, 1692 ± 2 c m - 1, and 1625 ± 2 c m - 1 (cf. Figure 5d). Also 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.

12 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 XRD pattern of Sorafenib hydrochloride hydrate form Il is shown in Figure 5f. Thus, 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). IV), Sorafenib mesylate 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 c m - 1, 1688 ± 2 cm 1, 1605 ± 2 c m - 1, 1559 ± 2 c m - 1, 1466 ± 2 c m - 1 and 1045 ± 2 cm ' 1. The IR spectrum of Sorafenib mesylate form I is shown in Figure 6b. The H 1 NMR spectrum of Sorafenib mesylate form I is shown in Figure 6c. The spectrum shows that Sorafenib mesylate form I is a 1:1 ethanol solvate. Increasing the reaction temperature of the reaction of Sorafenib free base with methane sulphonic acid increases the yield and results in a product with different properties, namely Sorafenib mesylate form II. The DSC thermogram of form Il shows an additional exothermic peak at about 188ºC (cf. Figure 7a), whereas the characteristic IR peaks remain unchanged (cf. Figure 7b).

13 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. The XRD pattern of Sorafenib mesylate form Il is shown in Figure 7c. V) Sorafenib besylate 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. 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 c m - 1, 1682 ± 2 c m - 1, 1635 ± 2 c m - 1, 1597 ± 2 c m - 1, 1334 ± 2 c m - 1, 1315 ± 2 c m - 1, 1037 ± 2 c m - 1, 1019 ± 2 c m - 1, and 612 ± 2 c m - 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. The XRD pattern of Sorafenib besylate form I is shown in Figure 8c. 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.

14 Sorafenib besylate form Il shows an IR spectrum exhibiting characteristic peaks at 1718 ± 2 c m - 1, 1683 ± 2 cm 1, 1597 ± 2 c m - 1, 1547 ± 2 c m - 1 and 1191 ± 2 c m - 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. The XRD pattern of Sorafenib besylate form Il is shown in Figure 9c. 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). The preparation of 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.

15 Sorafenib hemibesylate monohydrate shows an IR spectrum exhibiting characteristic peaks at 1541 ± 2 crrϊ 1, 1506 ± 2 crrf 1, 1420 ± 2 crrt 1, 1306 ± 2 c m - 1, 1284 ± 2 c m - 1, 1174 ± 2 c m - 1, 1122 ± 2 c m - 1, 1030 ± 2 c m - 1 and 825 ± 2 c m - 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. The XRD pattern of Sorafenib hemibesylate monohydrate is shown in Figure 9f. The H 1 NMR spectrum of Sorafenib hemibesylate monohydrate dissolved in dmso-d7 is shown in Figure 9g. It shows that the stoichiometry for Sorafenib : benzene sulfonic acid is 1 : 0.5. Vl) Sorafenib maleate 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). 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. When ethanol is used as solvent at a slightly decreased temperature (e.g. about 55ºC) Sorafenib maleate form Il is obtained, which does not show the DSC peak at 109ºC (cf. Figure 11a). Both forms of Sorafenib maleate show an IR spectrum exhibiting characteristic peaks at 1698 ± 2 c m - 1, 1678 ± 2 c m - 1, 1622 ± 2 c m - 1 (cf. Figures 10b and 11b).

16 VII) Amorphous Sorafenib free base or salt with excipient 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). Instead of 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. VIII) Sorafenib p-toluene sulphonic acid co-crystal 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. 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 c m - 1, 1719 ± 2 cm 1, 1683 ± 2 cm 1, 1633 ± 2 c m - 1 and 1598 ± 2 c m - 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, ± 0.2, 24.9 ± 0.2 and 25.7 ± 0.2 degrees 2-theta. The XRD pattern of the Sorafenib p-toluene sulphonic acid co-crystal is shown in Figure 12c.

17 The attached Figures show: Figure 1a is the DSC thermogram of amorphous Sorafenib tosylate. Figure 1b 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.

18 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.

19 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 µl Aluminum crucible. XRD samples were analysed on a Bruker-AXS D8 Advance powder X-Ray diffractometer. The measurement conditions were as follows : Measurement in Bragg-Brentano-Geometry on vertical goniometer (reflection, theta/theta, 435 mm measurement circle diameter) with sample rotation (30 rpm) on 9 position sample stage Radiation: Cu Kα1( A), Tube (Siemens FLCu2K), power 40kV/40mA Detector: position sensitive detector VANTEC-1 3 capture angle (2theta), Anti scatter slit 6.17 mm Detector slit mm 4 soller slit, primary beam stop (<2 2theta) Monochromator: None Second β filter: Ni filter 0.1 mm (0.5%) Start angle: 2 End Angle: 55 Measurement time: 11 min

20 Step: Software: Theta EVA (Bruker-AXS, Karlsruhe). NMR spectra were obtained on Bruker 300 MHz NMR instrument using d6-dmso as solvent. IR spectra were obtained using a Perkin Elmer, Model "Spectrum one", DFR mode 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)

21 The invention is further illustrated by the following examples which are not intended to be limiting.

22 Example 1: Preparation of amorphous Sorafenib tosylate 500 mg of Sorafenib tosylate was milled for 40 min at 20 Hz frequency in a 5 ml capacity agate jar having two 10 mm size agate balls. After 40 min milling, the material was reshuffled, and milling was continued for additional 1.5 hours. The process of reshuffling the powder and milling for 1.5 hours was repeated twice. Total milling time = 5 hrs 10 min. Sorafenib tosylate was removed from the mill and dried under vacuum at 45 C for 2 hrs. Yield = 350mg (70.0 %) XRD confirms that the product obtained is amorphous (cf. Figure 1c). DSC shows an exothermic peak at 155 C followed by an endothermic peak at 231 ºC (cf. Figure 1a). The exothermic peak at 155ºC indicates that Sorafenib tosylate undergoes crystallization at 155ºC. The thereby obtained crystals melt at 231ºC. IR = 1690, 1598, 1505, 1310 c m - 1 (cf. Figure 1b). Example 2: Preparation of Amorphous Sorafenib 300 mg of Sorafenib free base was milled in a 5 ml agate jar having two 10 mm agate balls for 20 hrs at 20 Hz. The milled product was removed and dried under vacuum at 55ºC for 2 hrs. Yield = 250mg (83.3 %). XRD confirms that the product obtained is amorphous (cf. Figure 2b). IR = 1713, 1657, 1546 crrf 1 (cf. Figure 2a). HPLC purity = % Example 3a: Preparation of Sorafenib Hydrochloride Form Il 120 ml of ethanol was added to 3.0 g of Sorafenib (6.454 mmol) in a 250 ml round bottom flask resulting in a suspension. A solution of g (2.0 eq.) of 35 % aq. HCI in 30 ml ethanol was prepared. The HCI solution was added to the suspension of Sorafenib free base at 26 C in 15 min. The reaction mass was stirred for 4 hrs at 26ºC. The product crystallized out as pale yellow slurry. The crystals were filtered off, washed with 6 ml ethanol and dried at 45ºC for 2 1 hr. Yield = 2.5 g (77.27 %). DSC shows a broad endothermic peak at 220ºC (cf. Figure 3a). IR = 351 1, 3085, 1695, 1636, 1604, 1558 c m - 1 (cf. Figure 3b). The XRD pattern is shown in Figure 3c.

23 Example 3b: Preparation of Sorafenib Hydrochloride Form I 160 ml of MEK (methyl ethyl ketone) was added to 4.0 g of Sorafenib (8.605 mmol) resulting in an almost clear solution, which was cooled to -10 C g (8.605 mmol) of 35 % aq. HCI was added. The reaction mass was a clear pale yellow colored liquid. The product crystallized out within 10 mins after HCI addition. The reaction mass was stirred for 3 hr at -5 C to -10ºC, the solid was filtered off, washed with 32 ml of MEK and dried under vacuum at 45 C for 9 hr. Yield = 3.7 g (85.84 %). DSC shows a sharp endothermic peak at 213 C indicating form I (cf. Figure 4a). Melting point = C. IR = 3251, 3087, 1716, 1694, 1609 cm - 1. IR indicates form I (cf. Figure 4b). Residual solvent: 3823 ppm MEK The XRD pattern is shown in Figure 4c. Example 3c: Preparation of Sorafenib Hydrochloride Hydrate Form I 1.0 g (2.151 mmol) of Sorafenib free base was suspended in a mixture of 20 ml water and 60 ml acetonitrile, and g (4.302 mmol) of 35 % aq HCI was added. The reaction mixture was a clear solution at 26ºC. The clear solution was cooled to 5ºC. The product crystallized out at 5 C. The reaction mass was stirred for 1 hr at 5ºC to 8 C, the solid was filtered off and dried under vacuum at 80ºC for 3 hr. Yield = 0.77 g (69.4 %). Melting point = C. IR = 3502, 3420, 3249, 1708, 1687, 1610, 1402 cm - 1 (cf. Figure 5a). TGA shows 2.89 % loss between 47 C and 79ºC, 5.26% loss between 79 C and 113ºC, 2.60 % loss between 123 C and 164ºC, % loss between 186 C and 294ºC (cf. Figure 5b), Residual solvent: 554 ppm acetonitrile Water content = %. Theoretical water content of Sorafenib hydrochloride trihydrate is 9.72 %. Hence the product obtained is a trihydrate. The XRD pattern is shown in Figure 5c.

24 Example 3d: Preparation of Sorafenib Hydrochloride Hydrate Form Il 100 mg ( mmol) of Sorafenib free base was suspended in a mixture of 1 ml water and 6 ml acetonitrile, and 44.9 mg ( mmol) of 35% aq HCI was added. The reaction mixture was a clear solution at 26ºC. The solution was cooled to OºC. The product crystallized out at 0ºC within five minutes. The reaction mass was stirred at OºC to 5ºC for two hours, the solid was filtered off, washed with 2 ml acetonitrile and dried under vacuum at 80ºC for two hours. Yield = 65 mg (58.18 %). Melting point = 196 to 199 C. IR = 3289, 3084, 1714, 1692, 1625 crτv 1 (cf. Figure 5d). HPLC: Sorafenib = %. TGA shows 1.83 % loss between 47ºC and 72ºC, 4.63 % loss between 37 C and 107ºC, 2.96 % loss between 118 C and 164 C, % loss between 198 C and 294 C (cf. Figure 5e). The XRD pattern is shown in Figure 5f. Example 4: Preparation of Sorafenib Mesylate Table 1: Summary of experiments on the preparation of Sorafenib mesylate Example 4a: Sorafenib Mesylate Form I 1 ml of ethanol was added to 100 mg ( mmol) of Sorafenib in the free base form. A freshly prepared solution of mg ( mmol) methane sulphonic acid (MSA) in 1 ml ethanol was added drop wise and a clear solution was obtained. This reaction mixture was stirred at 26 C for 3 hrs. The product crystallized out as white crystals and the crystals were filtered off and dried under vacuum at 50ºC for 3 hrs. Yield = 75 mg (62.50 %). DSC shows a major endothermic peak at 164 C and a minor endothermic peak at 233ºC (cf. Figure 6a).

25 IR = 1719, 1688, 1605, 1559, 1466, 1045 cm ' 1 (cf. Figure 6b). HPLC = %. H 1 NMR shows that the product obtained is the 1:1 ethanol solvate of Sorafenib mesylate (cf. Figure 6c). Example 4b: Sorafenib Mesylate Form Il 6 ml of ethanol (20 vol) was added to 300 mg ( mmol) of Sorafenib free base mg ( mmol) methane sulphonic acid was added dropwise to obtain a clear solution. This reaction mixture was heated to reflux (78ºC) and stirred at reflux temperature 78 C for 3 hrs. The reaction mixture was cooled to 26ºC and stirred for 8 hrs. The solid was filtered off, and dried at 50ºC for 7 hrs under high vacuum. Yield = 308 mg, (85.08 %). 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 = %. IR = 1718, 1688, 1553, 1045 c m - 1 (cf. Figure 7b). The XRD pattern is shown in Figure 7c. Example 5a: Sorafenib Besylate Form I To a round bottom flask containing 4 ml of ethanol and 200 mg (0.430 mmol) of Sorafenib free base mg ( mmol) of benzene sulphonic acid were added resulting in a clear solution. The reaction mixture was warmed to 40 C for 20 min, cooled to 26 C and kept stirring at room temperature for 3 hrs. The product crystallized out, was filtered off and dried under vacuum at 50ºC for 3 hrs. Yield = 216 mg (80.59 %). DSC shows a sharp endothermic peak at 209 C (cf. Figure 8a). Melting range = 205 to 21OºC. IR= 1717, 1682, 1635, 1597, 1334, 1315, 1292, 1194, 1037, 1019, 612 crτϊ 1 (cf. Figure 8b). HPLC = %. The XRD pattern is shown in Figure 8c.

26 Example 5b: Sorafenib Besylate Form Il In a round bottom flask containing 2.55 ml of a saturated solution of benzene sulphonic acid in acetonitrile, 150 mg (0.322 mmol) of Sorafenib free base were added resulting in a clear solution. The product crystallized immediately. The pale yellow colored reaction mass was kept as such for 3 days. The reaction mass was filtered off and dried at 50ºC for 2 hrs under high vacuum. Yield = 145mg (72.1 %). DSC shows a sharp endothermic peak at 201ºC (cf. Figure 9a). Melting range = 201 to 205ºC. IR= 1718, 1683, 1597, 1548, 1191 c m - 1 (cf. Figure 9b). HPLC = %. The XRD pattern is shown in Figure 9c. Example 5c: Sorafenib Hemibesylate Monohydrate Co-crystals Procedure 1: 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 :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. The stable co-crystals of Sorafenib hemibesylate monohydrate melted between 142ºC and 146 C, showing a peak maximum at C in the DSC thermogram (cf. Figure 9d). IR= 1541, 1506, 1420, 1306, 1284, 1173, 1122, 1030 Cm 1 (cf. Figure 9e) The XRD pattern is shown in Figure 9f. The H 1 NMR spectrum is shown in Figure 9g.

27 Procedure 2 : 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. After complete addition of benzene sulphonic acid 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. The stable co-crystals of Sorafenib hemibesylate monohydrate melted between 143ºC and 147ºC, showing a peak maximum at ºC in the DSC thermogram. Procedure 3 : In a 50 ml three-neck flask a suspension of Sorafenib besylate form I ( 1.0 g) in ethanol (96 v/v%, 20 ml) was inoculated with a small sample of Sorafenib hemibesylate monohydrate co-crystals (0.05 g). The suspension was stirred at room temperature over night. The solid was filtered off and washed with ethanol (96 v/v%, twice 5 ml each). After drying at 70 C/30 mbar 0.83 g Sorafenib hemibesylate monohydrate co-crystals were isolated. Example 6: Preparation of Sorafenib Maleate Table 2: Summary of experiments on the preparation of Sorafenib Maleate

28 Example 6a: Sorafenib Maleate Form I To a round bottom flask containing 2 ml of a saturated solution of maleic acid in acetonitrile, 100 mg ( mmol) of Sorafenib free base were added. The partly clear solution was warmed to 75ºC for 10 min to obtain a clear solution. The reaction mass was cooled to 26ºC and stirred for 1 hr, filtered off and dried under high vacuum at 45 C for 2 hrs. Yield = 72 mg (57.6 %). DSC shows a minor endothermic peak at 109ºC and a sharp endothermic peak at 162 C (cf. Figure 10a). Melting range = 157 to 159 C. IR = 1698, 1678, 1622 crrt 1 (cf. Figure 10b). HPLC : Maleic acid = 1.89 %; Sorafenib = %. Example 6b: Sorafenib Maleate Form Il In a round bottom flask containing 2 ml of a saturated solution of maleic acid in ethanol, 100 mg ( mmol) of Sorafenib free base were added. The partly clear solution was warmed to 55 C for 10 min to obtain a clear solution. The reaction mass was cooled to 26 C and stirred for 3 hrs, filtered off and dried under high vacuum at 50ºC for 2 hrs. Yield = 78.0 mg (62.4 %). DSC shows a sharp endothermic peak at 161ºC (cf. Figure 11a). IR = 1698, 1678, 1622 c m - 1 (cf. Figure 11b). HPLC: Maleic acid = 1.97 % ; Sorafenib = %. Example 7: Amorphous Sorafenib Free Base and HPMC E3 (1:2) A mixture of 100 mg of Sorafenib free base and 200 mg of hydroxypropylmethyl cellulose (HPMC E3) was milled for 1 hr at 20 Hz using a 5 ml agate jar with two 10 mm agate ball in a Retsch mill. The material was reshuffled well and again milled for 1 hr at 20 Hz. The obtained product is amorphous. Example 8: Amorphous Sorafenib Free Base and HPMC E3 (1:1) A mixture of 100 mg of Sorafenib free base and 100 mg of hydroxypropylmethyl cellulose (HPMC E3) was milled for 1 hr at 20 Hz on Retsch mill in a 5 ml agate jar having two 10

29 mm agate ball. The material was reshuffled well and again milled for 1 hr at 20 Hz. The obtained product is amorphous. Example 9: Amorphous Sorafenib Free Base and HPMC E3 (2:1) A mixture of 100 mg of Sorafenib free base and 50 mg of hydroxypropylmethyl cellulose (HPMC E3) was milled for 1 hr at 20 Hz in a Retsch mill using 5 ml agate jar having two 10 mm agate ball. The material was reshuffled well and again milled for 1 hr at 20 Hz. The obtained product is amorphous. Example 10: Amorphous Sorafenib Tosylate and Crosscarmellose Sodium A mixture of 100 mg of Sorafenib tosylate and 200 mg of Crosscarmellose sodium was milled for 1 hr at 20 Hz in a Retsch mill using 5 ml agate jar having two 10 mm agate ball. The material was reshuffled well and again milled for 1 hr at 20 Hz. The obtained product is amorphous. Example 11: Amorphous Sorafenib Tosylate and Crosscarmellose Sodium A mixture of 100 mg of Sorafenib tosylate and 100 mg of Crosscarmellose sodium was milled for 1 hr at 20 Hz in a Retsch mill using 5 ml agate jar having two 10 mm agate ball. The material was reshuffled well and again milled for 1 hr at 20 Hz. The obtained product is amorphous. Example 12: Preparation of Sorafenib p-toluene Sulphonic Acid Co-Crystal A saturated solution of p-toluene sulphonic acid was prepared by dissolving 10 g p-toluene sulphonic acid in 50 ml acetonitrile. 3.0 g Sorafenib free base was added to the solution and the resulting reaction mixture was stirred for 2 hrs at 26 C. The obtained solid was filtered off and dried under vacuum at 7OºC for 6 hrs. Yield = 3.3 g (78.2 %). DSC shows a sharp endothermic peak at 179ºC and a minor endothermic peak at 207ºC (cf. Figure 12a). Melting range = C. IR = 3080, 1719, 1682, 1633, 1598 c m - 1 (cf. Figure 12b). HPLC: p-tsa = 0.72 % ; Sorafenib = %.

30 Residual solvent: Acetonitrile 869 ppm. Water content = 0.57 %. The XRD pattern is shown in Figure 12c. Example 13: Hygroscopicity Data Sorafenib tosylate, Sorafenib p-toluene sulphonic acid (p-tsa) co-crystals, and Sorafenib hydrochloride form I and form Il where investigated in respect of hygroscopicity at 43 %, 75 % and 93 % relative humidity, respectively. The results are illustrated in the following tables 3-6 :