SORAFENIB ETHYSULFONATE SALT, PROCESS FOR PREPARATION AND USE
Field of the Invention
The present invention provides sorafenib ethane sulphonate, process for its preparation, pharmaceutical composition comprising sorafenib ethane sulphonate and its use for the treatment of cancer.
Background of the Invention
Sorafenib is an inhibitor of the enzyme raf kinase known from WO 00/42012. It is chemically described as 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N^-methylpyridine-2-carboxamide, having structure as represented by Formula I.
CF3 O
I II
Y^l o fi ^Y"^ Nr^^l NH
^^^ ^NH ^NH ^-^ ^-^
Formula I
Sorafenib is marketed in the United States as a tosylate salt as shown in Formula II under the brand name Nexavar®.
CF, O
I II
^-^^ ^NH ^NH ^-^^ ^^ \=/
Formula II
Several acid addition salts of sorafenib are disclosed in WO 00/42012. Sorafenib ethane sulphonate salt of the present invention is not disclosed in the literature.
Summary of the Invention
In one general aspect, the present invention provides for sorafenib ethane sulphonate of Formula III,
CF3 O
I II
^YT^^ O fi ^T II ^'^ "^"^ • II
U J, / S OH
^^^^^NH ^NH \^ \^ H3C I
Formula III
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solvates, hydrates and polymorphs thereof.
Embodiments of this aspect may include one or more of the following features. For example, the sorafenib ethane sulphonate of Formula III may be characterized by X-ray diffraction peaks at d-spacing at about 10.84, 5.59, 5.22, 3.80, and 3.75 A. The sorafenib ethane sulphonate of Formula III may be further characterized by X-ray diffraction peaks at d-spacing at about 5.41, 4.33, 3.47, 3.12, and 3.05 A. The sorafenib ethane sulphonate of Formula III may also be characterized by a DSC thermogram having endotherm at about 208.10°C.
The sorafenib ethane sulphonate of Formula III may also be characterized by the X-ray diffraction pattern as depicted in Figure-1, by the DSC as depicted in Figure-2, the TGA as depicted in Figure-3, and/or the IR spectrum as depicted in Figure-4.
The sorafenib ethane sulphonate of Formula III may have a purity greater than 99% HPLC.
In another general aspect, the present invention provides for a process for the preparation of sorafenib ethane sulphonate of Formula III.
CF3 O
J, / S—OH
^-^^NH ""NH \^ \^ H3C [J
Formula III
The process includes contacting sorafenib free base of Formula I,
CF, O
I II
^^^ ^NH ^NH ^^^ ^^^
Formula I
with ethane sulphonic acid.
Embodiments of this aspect may include one or more of the following features. For example, the process utilizes isolated sorafenib free base of Formula I or the sorafenib free base of Formula I, which is obtained as a solution directly from a reaction in which sorafenib free base is formed.
The sorafenib free base of Formula I is contacted with ethane sulphonic acid in a suitable
solvent selected from water, polar organic solvents, dipolar aprotic organic solvents, and mixtures
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thereof. The polar organic solvent is selected from organic solvents containing at least one hydroxyl group, cyclic ethers, alkyl acetates and mixtures thereof The organic solvent containing at least one hydroxyl group is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol or ethylene glycol. The dipolar aprotic organic solvent is selected from the group comprising of ketones, amides, nitriles, sulphoxides, or mixtures thereof
The sorafenib free base is contacted with ethane sulphonic acid at about 0°C to the reflux temperature of the suitable solvent.
In another general aspect, the present invention provides for the use of sorafenib ethane sulphonate of Formula III,
CF3 O
L i / S OH
\^^NH ^NH ^^ ^^ H3C {J
Formula III
for the preparation of sorafenib acid addition salts of Formula IV.
CF3 O
I II
^^^ ^NH ^NH ^^^ ^<^
Formula IV
The process includes contacting sorafenib ethane sulphonate with an acid of Formula HX.
In yet another general aspect, the present invention provides for a pharmaceutical composition which includes sorafenib ethane sulphonate of Formula III and one or more pharmaceutically acceptable excipients.
Brief Description of the Drawings
Figure 1: X-ray Diffraction pattern (XRD) of sorafenib ethane sulphonate.
Figure 2: Differential Scanning Thermogram (DSC) of sorafenib ethane sulphonate.
Figure 3: Thermo Gravimetric analysis (TGA) of sorafenib ethane sulphonate.
Figure 4: Infra Red Spectrum (IR) of sorafenib ethane sulphonate.
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Detailed Description of the Invention
In one embodiment, the present invention provides for sorafenib ethane sulphonate of Formula III as characterized by XRD peaks at about 8.15 (d-spacing at 10.84 A), 15.83 (5.59 A), 16.97 (5.22 A), 23.40 (3.80 A), and 23.66 (3.75 A) ± 0.2° 26.
In another embodiment, the present invention provides for sorafenib ethane sulphonate of Formula III as further characterized by XRD peaks at about 16.36 (5.41 A), 20.49 (4.33 A), 25.63 (3.47 A), 28.56 (3.12 A), and 29.23 (3.05 A) ± 0.2° 29.
Sorafenib ethane sulphonate of Formula III may also be characterized by DSC thermogram having endotherms at about 208.10°C. It may also be characterized by XRD spectrum, DSC thermogram, TGA and IR spectra as depicted in Figures 1, 2, 3 and 4, respectively. Table 1 provides the d-spacing in A and the corresponding 20 values.
Table 1: XRD Peaks of Sorafenib Ethane Sulphonate
Position ("20) d-spacing (A) Relative Intensity (%)
8.15 10.84 ~ 47.21
8.44 1048 22.55
10.14 8J3 26,93
11.67 7,58 6,60
12.19 726 17.22
12.37 7,15 15,67
13.67 6^8 21.66
14.20 624 29.39
14.64 6,05 19,95
15.83 5,59 53.63
16.36 141 44.79
16.97 522 56.44
17.37 5JJ 22.84
18.38 4,83 29.38
18.63 4J6 1521
18.84 4J1 24.12
19.09 4,65 6,80
19.35 4J9 7,08
19.96 4^5 33.92
20.35 436 29.92
20.49 4J3 39.85
21.38 4A5 14,45
21.65 4AI 14.47
22.35 3,98 13.36
22.56 3,94 16,01
23.15 3,84 31.98
23.40 3,80 100.00
23.66 3J5 92.08
24.14 I 3.69 I 8.49
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Position C'2e) d-spacing (A) Relative Intensity (%)
24.66 3.61 ~ 11.56
24.89 3^58 12,41
25.63 147 36.67
25.85 145 1431
26.39 138 18,65
27.23 127 11.94
28.56 112 45.78
29.23 105 38.90
30.05 Z97 8,51
30.69 Z91 17JJ
31.05 2M 8,92
31.74 2,82 15,05
31.98 Z80 11.18
32.71 2J4 7/n
33.44 2,68 154
34.40 Z61 6J1
34.87 2,57 5,85
36.07 2A9 10J8
37.19 2,42 7,02
38.64 I 2.33 | 7.74
The sorafenib free base of Formula I which is used for the preparation of sorafenib ethane sulphonate of Formula III, may be obtained by any of the methods known in the literature, such as those described in PCT applications WO 00/42012; WO 2006/034796; WO 2006/034797; WO 2009/034308; WO 2009/054004; WO 2009/106825; and WO 2009/092070, which are herein incorporated by reference.
In general, the sorafenib free base of Formula I may be prepared by the reaction of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline with 4-chloro-3-(trifluoromethyl)phenyl isocyanate. The starting sorafenib free base of Formula I may be obtained as a solution directly from a reaction in which sorafenib free base is formed and used as such without isolation.
The term "contacting" may include dissolving, slurrying, stirring, or a combination thereof
The reaction of the sorafenib free base of Formula I with ethane sulphonic acid may be carried out by directly contacting sorafenib free base with ethane sulphonic acid. The reaction may also be carried out in the presence of a suitable solvent. A solution of ethane sulphonic acid in a suitable solvent may also be used. Preferably, ethane sulphonic acid may be added to a reaction mixture containing sorafenib free base and a suitable solvent.
The suitable solvent may be selected from water, polar organic solvents, dipolar aprotic organic solvents, and mixtures thereof
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The polar organic solvents may be selected from organic solvents containing at least one hydroxyl group, cyclic ethers, alkyl acetates, and mixtures thereof. Examples of organic solvents containing at least one hydroxyl group may include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol or ethylene glycol. Examples of cyclic ethers may include tetrahydrofuran or 1, 4-dioxane. Examples of alkyl acetates may include methyl acetate, ethyl acetate, propyl acetate, or butyl acetate.
The dipolar aprotic organic solvents may be selected from the group comprising of ketones, amides, nitriles, sulphoxides, or mixtures thereof Examples of ketones may include acetone, methyl ethyl ketone, or methyl isobutyl ketone. Examples of amides may include N, N-dimethylformamide, or N, N-dimethylacetamide. Examples of nitriles may include acetonitrile, or propionitrile. Examples of sulphoxides may include dimethyl sulfoxide, or diethyl sulphoxide.
In the preferred embodiments of the present invention, the reaction of sorafenib free base with ethane sulphonic acid may be carried out in polar organic solvents selected from organic solvents containing at least one hydroxyl group, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol, or ethylene glycol.
Ethane sulphonic acid may be added slowly to the reaction mixture containing sorafenib free base and the suitable solvent.
In the preferred embodiment of the present invention ethane sulphonic acid may be added to the reaction mixture containing sorafenib free base and the suitable solvent over a period of about 20 minutes, preferably, about 10 minutes.
The reaction of sorafenib free base with ethane sulphonic acid may be carried out at a temperature of about 0°C to the reflux temperature of the suitable solvent, preferably, at about 15°C to about 80°C, most preferably, at about 15°C to about 35°C.
The solution may be stirred for about 30 minutes to about 8 hours, preferably, for about 4 hours.
The reaction mixture containing sorafenib free base, ethane sulphonic acid and solvent(s) may be treated with a decolorizing agent such as activated charcoal before precipitation.
Generally, an ethane sulphonate salt of sorafenib precipitates out of the reaction mixture. The precipitation may be spontaneous depending upon the solvent used and the reaction conditions. The precipitation may also be facilitated by seeding or by reducing the temperature.
Isolation of the ethane sulphonate salt of sorafenib may be accomplished by concentration, precipitation, cooling, filtration or centrifiigation, or a combination thereof, followed by drying
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under reduced pressure. The sorafenib ethane sulphonate may be further purified by recrystallization for better purity.
The process of the present invention provides sorafenib ethane sulphonate of high purity.
The sorafenib ethane sulphonate of Formula III may be converted into a sorafenib free base of Formula I of high purity by hydrolysis in a neutral medium or in the presence of a base. The base may be selected from hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals, ammonia, alkyl amines, hydrazine, and the like. Examples of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals may include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Examples of alkyl amines may include diethyl amine, triethyl amine or methyl diethyl amine.
The processes of the present invention provides sorafenib free base of high purity.
The conversion of the sorafenib ethane sulphonate of Formula III to sorafenib acid addition salts of Formula IV may be carried out by directly contacting sorafenib with an acid of Formula HX.
The acid of Formula HX may be selected from the group comprising hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, /?ara-toluene sulphonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, flimaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid or mandelic acid.
The conversion of the sorafenib ethane sulphonate of Formula III to the sorafenib acid addition salts of Formula IV may also be carried out by a process comprising conversion of sorafenib ethane sulphonate to sorafenib free base in the first step followed by the reaction of sorafenib free base with the acid of Formula HX.
In a preferred embodiment of the present invention, sorafenib ethane sulphonate may be converted to sorafenib tosylate by heating a reaction mixture containing sorafenib ethane sulphonate, ethyl acetate and water to a temperature of about 70°C; slowly adding a solution of /7ara-toluene sulphonic acid monohydrate in ethyl acetate-water mixture to the above reaction mixture over a period of about 30 minutes; cooling the reaction mixture to about 32°C; stirring overnight; further cooling to about 0°C to about 5°C; and stirring for about 3 hours. Sorafenib tosylate may be obtained from the above reaction mixture by slowly raising the temperature to
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about 32°C, and filtering and drying under reduced pressure. Drying may be carried out at about 55°C for about 5 hours.
Solvates, hydrates and polymorphs of sorafenib ethane sulphonate of Formula III are also included within the scope of the present invention. Polymorphs of sorafenib ethane sulphonate may include both amorphous and crystalline forms.
The amorphous form may be obtained by conventional methods such as spray drying, lyophilization and evaporation of the solvent under reduced pressure.
Sorafenib ethane sulphonate is usually administered as part of a pharmaceutical composition. Accordingly, in a further aspect, there is provided a pharmaceutical composition that comprises ethane sulphonate salt of sorafenib and one or more pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. Pharmaceutical compositions comprising the sorafenib ethane sulphonate of Formula III may be administered orally, topically, parenterally, by inhalation or spray, rectally or in the form of injectables. Injectables include intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art, which are within the scope of the present invention.
Methods
The XRD pattern was recorded using Panalytical Expert PRO with Xcelerator as detector, 3-40 as scan range, 0.02 as step size and 3-40° 26 as range.
DSC and TGA were recorded using Mettler Toledo DSC 82 le and TA instrument- Q 500, respectively.
HPLC was performed using a Zorbax SB AQ, 250 mm x 4.6 mm, 5fam column having the following parameters:
Flow rate: 1.0 mL/ minute
Detector: UVat260nm
Injection volume: 10|JL
Column oven Temperature: 30°C
Run time: 50 minutes
Buffer: Orthophosphoric acid in water
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Mobile Phase: Buffer and Methanol
EXAMPLES
Example 1: Preparation of Sorafenib Ethane Sulphonate
Ethanol (20 mL) was added to a reaction vessel containing sorafenib free base (4.0 g). Ethane sulphonic acid (1.62 mL) was added drop wise to the above reaction mixture. The reaction mixture was stirred at about 25°C to 35°C for about 4 hours. The solid was filtered, washed with ethanol (2x10 mL) and dried under reduced pressure at about 60°C for about 5 hours to obtain sorafenib ethane sulphonate.
Yield: 91%
HPLC Purity: 99.46%
Example 2: Preparation of Sorafenib Tosylate
A reaction mixture containing sorafenib ethane sulphonate (5.0 g), ethyl acetate (50 mL) and water (1 mL) was heated to about 70°C. A solution of para-toluene sulphonic acid monohydrate (3.3 g) in ethyl acetate: water:: 1.0 mL: 0.2 mL was slowly added over a period of about 30 minutes to the above reaction mixture. The reaction mixture was cooled to about 32°C and stirred overnight. The reaction mixture was further cooled to about 0°C to about 5°C and stirred for about 3 hours. Temperature of the reaction mixture was slowly raised to about 32°C. The solid material was filtered and dried under reduced pressure at about 55°C for about 5 hours to obtain sorafenib tosylate.
Yield: 36.1%
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WE CLAIM:
1. Sorafenib ethane sulphonate of Formula III
CF, O
I II
^^^^NH ^NH ^^^ ^-^ H3C U
Formula III solvates, hydrates and polymorphs thereof.
2. The sorafenib ethane sulphonate of claim 1 characterized by X-ray diffraction peaks at d-spacing at about 10.84, 5.59, 5.22, 3.80, and 3.75 A.
3. The sorafenib ethane sulphonate of claim 1 further characterized by X-ray diffraction peaks at d-spacing at about 5.41,4.33, 3.47, 3.12, and 3.05 A.
4. The sorafenib ethane sulphonate of claim 1, characterized by DSC thermogram having endotherm at about 208.10°C.
5. The sorafenib ethane sulphonate of claim 1, characterized by X-ray diffraction pattern as depicted in Figure 1.
6. The sorafenib ethane sulphonate of claim 1, characterized by DSC as depicted in Figure 2.
7. The sorafenib ethane sulphonate of claim 1, characterized by TGA as depicted in Figure 3.
8. The sorafenib ethane sulphonate of claim 1, characterized by IR spectrum as depicted in Figure 4.
9. The sorafenib ethane sulphonate of claim I, having greater than 99% HPLC purity.
10. A process for the preparation of sorafenib ethane sulphonate of Formula III,
CF3 O
"^ o ^^V°V^AN"'"' II
II * ''
J, / S—OH
^^^NH ^NH ^-^ ^^ H3C U
Formula III
the process comprising contacting sorafenib free base of Formula I
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CFg O
Nr^^ 0 fi ^1 II ^'^ ^^
— ^NH NH ^-^ ^-^^^
Formula I
with ethane sulphonic acid.
11. The process according to claim 10, wherein the process utilizes isolated sorafenib free base of Formula I or the sorafenib free base of Formula I, which is obtained as a solution directly from a reaction in which sorafenib free base is formed, is used without isolation.
12. The process according to claim 10, wherein the sorafenib free base of Formula I is contacted with ethane sulphonic acid in a suitable solvent selected from water, polar organic solvents, dipolar aprotic organic solvents, and mixtures thereof
13. The process according to claim 12, wherein the polar organic solvent is selected from organic solvents containing at least one hydroxyl group, cyclic ethers, alkyl acetates and mixtures thereof
14. The process according to claim 13, wherein the organic solvent containing at least one hydroxyl group is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol or ethylene glycol.
15. The process according to claim 12, the dipolar aprotic organic solvent is selected from the group comprising of ketones, amides, nitriles, sulphoxides, or mixtures thereof
16. The process according to claim 10, wherein the sorafenib free base is contacted with ethane sulphonic acid at about 0°C to the reflux temperature of the suitable solvent.
17. Use of sorafenib ethane sulphonate of Formula III
CF3 O
\^^NH ^NH \^ \^ H3C iJ
Formula III
for the preparation of sorafenib acid addition salts of Formula IV,
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CF, O
I II
^^^ ^NH ^NH ^<^ ^<^
Formula IV
the process comprising contacting sorafenib ethane sulphonate with an acid of Formula HX.
18. A pharmaceutical composition comprising sorafenib ethane sulphonate of Formula III and one or more pharmaceutically acceptable excipients.
19. Sorafenib ethane sulphonate of Formula III as claimed in claims 1-9 for use in the treatment of cancer.

20. A process for the preparation of sorafenib ethane sulphonate of Formula III as described herein with reference to the example provided herein.
21. A process for the preparation of sorafenib tosylate of Formula II as described herein with
reference to the example provided herein.
Dated this the 30™ day of April, 2012.
For Ranbaxy Laboratories Limited
/^-^^^ (Dr. Santanu De) Associate Director - Intellectual Property
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