FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"NOVEL POLYMORPH OF SORAFENIB AND ITS SALT"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


Technical field of the Invention
The present invention relates to an amorphous form of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide or its pharmaceutically acceptable salt, processes for preparation of amorphous form and compositions comprising the same.
Background of the Invention
4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide is commonly known as Sorafenib (I). Sorafenib is prepared as its tosylate salt.

Sorafenib or pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patent applications disclose processes for preparation of Sorafenib.
WO2006034796 discloses process for preparation of sorafenib and its tosylate salt.
WO2006034797 describes various polymorphs of sorafenib tosylate. This patent acknowledges that sorafenib tosylate prepared by general method disclosed in WO0042012 gives polymorph II which is metastable. This patent application describes Form 1, Form III, ethanol solvate and methanol solvate of sorafenib tosylate which are characterized by Melting point, Differential scanning calorimetry & Thermogravimetry, X-ray diffraction, IR spectrum, Raman spectrum, NIR spectrum, FIR spectrum. It also describes various methods for preparation of Form I, Form III, methanol solvate and ethanol solvate. This patent application discloses processes for preparation of Form I from Form II.


The polymorph 1 is claimed in WO2006034797 which involves tedious reaction processes such as long reaction hours, cooling the reaction mixture to very low temperature like -25°C. Also the process for preparation of Form I requires critical conditions like subsequent cooling at a controlled rate to get Form 1.
Thus, processes given for preparation of polymorphs 1 & HI are time consuming. All these reaction conditions are very difficult to achieve at industrial level.
Majority of the drugs exhibit polymorphism and different activity in different polymorphic forms. Polymorphism in general means that the drug exists in different physical forms which may be crystalline or non-crystalline. Different polymorphs will have different free energies and therefore different physical properties like solubility, chemical stability, melting point, density, flow characteristics which affects the ease with which the material is handled during processing into pharmaceutical product. Another important property is rate of dissolution i.e. the rate at which drug gets dissolved in patient's stomach.
Unlike crystalline forms, amorphous solids do not possess a distinguishable crystal lattice. In general, amorphous solids are more stable and hence, they are preferred in formulating pharmaceutical compositions. Further, amorphous solids usually have better bioavailability.
Summary of the Invention
It is the object of the present invention to provide compound of formula (I) or pharmaceutically acceptable salts thereof in an amorphous form.
It is another object of the present invention to provide process for preparation of compound of formula (I) or pharmaceutically acceptable salts thereof in an amorphous form.
Another aspect of the present invention is to provide process for conversion of amorphous form of pharmaceutically acceptable salt of compound of formula (I) to Form 1 thereof.


A further object of the present invention is to provide a complex of Polyvinyl pyrrolidone (PVP) with compound of formula (1) or pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a process for preparation of Polyvinyl pyrrolidone (PVP) complex with compound of formula (I) or pharmaceutically acceptable salt thereof.
In yet another object of the invention there is provided a pharmaceutical composition comprising compound of formula (1) or pharmaceutically acceptable salt thereof in an amorphous form or PVP complex with compound of formula (I) or pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers and/or excipients.
Detailed Description of the Invention
In one aspect, the invention provides compound of formula (1) or a pharmaceutically acceptable salt thereof in an amorphous form.
In another aspect, the invention provides process for preparation of compound of formula (1) or a pharmaceutically acceptable salt thereof in an amorphous form.
The process involves dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitable solvent and recovering the amorphous material by suitable means.
The techniques which used to recover the amorphous form of a compound of formula (I)
or its pharmaceutically acceptable salt include spray drying, freeze drying, preferably
spray drying.
The compound of formula (1) or a pharmaceutically acceptable salt thereof dissolved to
form a clear solution may be in any crystalline or other form, including solvates and
hydrates.
The solvent may be selected according to the technique and conditions used. The solvent
can be any organic solvent or mixture thereof which may be selected from ketones,


ethers, amide, alcohols, hydrocarbons which may or may not be substituted and halogenated solvents.
The solvents can be selected from but not limited to acetone, methyl isobutyl ketone, tetrahydrofuran, N,N-dimethyl formamide, methanol, ethanol, isopropanol, isobutyl alcohol, n-butyl alcohol, dimethyl sulfoxide, N-methyl pyrrolidone, toluene, methylene dichloride.
In another aspect, amorphous form of compound of formula (1) or a pharmaceutically acceptable salt thereof can be micronized and used in suitable formulation.
In yet another aspect of the present invention, amorphous sorafenib tosyiate can be converted to sorafenib tosyiate Form I. The process for conversion of amorphous sorafenib tosyiate to Form I of sorafenib tosyiate comprising the following steps:
a) suspending amorphous sorafenib tosyiate in suitable solvent at suitable temperature followed by stirring the suspension to get crystalline solid and
b) filtering the crystalline solid obtained followed by drying in a vacuum.
The solvent used can be any organic solvent or mixture thereof which may be selected from alcohols, esters, ethers, ketones, amide, hydrocarbons which may or may not be substituted and halogenated solvents.
The solvents can be selected from but not limited to methanol, ethanol, isopropanol, n-butanol, isobutanol, ethyl acetate, diisopropyl ether, acetone, methyl isobutyl ketone, ethyl methyl ketone, N,N-dimethyl formamide, dimethyl sulfoxide, toluene, hexane, methylene dichloride, ethylene dichloride.
The temperature at which amorphous sorafenib tosyiate suspended is in the range between 25 - 40°C, more preferably between 25 - 35°C. The suspension is stirred for the period of 5 - 24 hours, preferably for 12-14 hours.
In yet another aspect of the present invention, there is provided a complex of compound of formula (I) or its pharmaceutically acceptable salt with polyvinyl pyrrolidone (PVP).


In further aspect, the invention provides a process for preparing a complex of compound of formula (1) or its pharmaceutically acceptable salt with polyvinyl pyrrolidone (PVP) which process comprises following steps :
a) dissolving or suspending compound of formula (1) its pharmaceutically acceptable salt in a suitable solvent;
b) dissolving PVP in a suitable solvent;
c) adding the solution of PVP to the solution or suspension prepared in step a), followed by stirring the mixture to obtain a PVP complex of compound of formula (1) or its pharmaceutically acceptable salt; and
d) isolating the PVP complex either by filtering or by concentrating the solution followed by drying the PVP complex.
Optionally, the solution in step a) may be heated.
The solvent used to dissolve compound of formula (1) its pharmaceutically acceptable salt can be any organic solvent selected from ketones, ethers, alcohols, amide, hydrocarbons which may or may not be substituted. These solvents may be used either alone or as a mixture with other solvent.
The solvents can be selected from but not limited to acetone, tetrahydrofuan, dioxane, C\-C4 alcohols like methanol, ethanol, isopropanol, isobutanol, n-butanol, N,N-dimethyl formamide, dimethyl sulfoxide.
Another solvent used to dissolve PVP can be selected from any organic solvent selected from alcohols, ethers. These solvents may be used either alone or as a mixture with other solvent.
The solvents can be selected from but not limited to C1-C4 alcohols like methanol, ethanol, isopropanol, isobutanol, n-butanol, tetrahydrofuran.
The percentage of PVP used is in the range of 5% to 50%. The preferred percentage is
25%.


In yet another aspect, the present invention provides pharmaceutical compositions which contain effective amount of amorphous form of compound of formula (I) its pharmaceutical^ acceptable salt together with pharmaceutically acceptable carriers. The "effective amount" means an amount of a compound of the present invention which is effective for prevention or treatment of the various cancers.
Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally, transdermally or nasally.
Suitable forms of oral administration include tablets, hard or soft gelatin capsules, sublingual tablets, dry syrups, suspensions, sachets. Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion while transdermal administration includes spray, patches and other known forms. Nasal administration includes suitable aerosol delivery systems known in the art.
Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and standard procedures available or known.
Brief Description of accompanying drawings
Figure 1 is an X-ray powder diffractogram (XRD) of compound of formula (I) in
amorphous form.
Figure 11 is an X-ray powder diffractogram (XRD) of tosylate salt of compound of
formula (I) in an amorphous form.
Figure III is an X-ray powder diffractogram (XRD) of Form 1 of tosylate salt of
compound of formula (1).
The present invention will now be further illustrated by the following examples, which do
not limit the scope of the invention in any way.
Examples
Example 1
Sorafenib base (50 g) was dissolved in acetone (2.5 lit, 50 vol) at 25 -30°C under stirring
for 1 hour. It was then fed to spray dryer unit via peristaltic pump and spray dried at 45 -


50°C. The spray dried material thus obtained was collected from the spray dryer chamber and dried in vacuum oven at 45 - 50°C for 12-14 hours under vacuum to obtain amorphous sorafenib (45 g).
Example 2
Sorafenib tosylate (50 g) was dissolved in N,N-Dimethyl formamide (100 ml, 2 vol.) at 25 -30°C under stirring for 10 minutes. It was then fed carefully to spray dryer unit via peristaltic pump and spray dried at 195 - 200°C. The spray dried material thus obtained was collected from the spray dryer chamber and dried in vacuum oven at 80 - 90°C for 3 - 4 days under high capacity vacuum to get sorafenib tosylate (35 g) which is amorphous in nature.
Example 3
Sorafenib tosylate (100 g) was dissolved in N-methyl pyrrolidone (300 ml, 3 vo!25 -30°C
under stirring for 30 minutes. It was then fed carefully to spray dryer unit via peristaltic
pump and spray dried at 220 - 230°C. The spray dried material thus obtained was
collected fr|>m the spray dryer chamber and dried in vacuum oven at 70 - 80°C for 5 - 6
days under high capacity vacuum to get sorafenib tosylate (70 g) which is amorphous in
nature.
Example 4
Amorphous sorafenib tosylate (5 g) was suspended in di-isopropyl ether (50 ml) at 25 -30°C. The suspension was then stirred at ambient temperature for 12 - 14 hours where in the yellowish pale solid turned white crystalline in nature. The obtained white solid was then filtered and vacuum dried for 12-14 hours at 50 - 60°C. The obtained white crystalline product (4.5 g) is Form 1 of sorafenib tosylate.
Example 5
Sorafenib base (25 g) was stirred with acetone (1300 ml) at room temperature and atmospheric pressure. The obtained clear solution was then freeze dried under high vacuum using lypholiser. The obtained solid was then dried in vacuum oven at 40 - 50°C to remove solvent traces. The material obtained is amorphous sorafenib (20 g).


Example 6
Sorafenib tosylate (13 g) was stirred with N.N-Dimethyl Formamide (30 ml) at room temperature and atmospheric pressure. The obtained clear solution was then freeze dried under high vacuum using lypholiser. The obtained solid was then dried in vacuum oven at 80 - 90°C to remove solvent traces which further yields amorphous form of the sorafenib tosylate (9.8 g).
Example 7
Ssorafenib tosylate (5 g) was stirred with (1:1) mixture of N,N-Dimethyl formamide and Methanol (50 ml) at room temperature and atmospheric pressure. The obtained clear solution was then freeze dried under high vacuum using Lypholiser. The obtained solid was then dried in vacuum oven at 80 - 90°C to remove solvent traces to give amorphous sorafenib tosylate (3.8 g).
Example 8
Sorafenib (2 g) was dissolved in tetrahydrofuran (20 ml) in a round bottom flask at 50°C to get clear solution. In another flask, PVP (0.1 g) was dissolved in methanol (2 ml). To the clear solution of sorafenib, solution of PVP was added and the mixture was stirred for half an hour to one hour. After completion of reaction, the solvent was distilled off completely at 50 - 55°C. The material obtained was then dried in an oven at 60°C for 12 hours to get complex of sorafenib with PVP (1.34 g).
Example 9
Sorafenib tosylate (2 g) was suspended in ethanol (50 ml) in a round bottom flask at 25-30°C. In another flask. PVP (0.1 g) was dissolved in ethanol (2 ml). To the suspension of sorafenib tosylate. solution of PVP was added and the mixture was stirred for 16 - 20 hours. After completion of reaction, the product obtained was filtered and then dried in an oven at 60°C for 12 hours to get complex of sorafenib tosylate with PVP (0.7 g).
Example 10
Tablets containing amorphous form of sorafenib or its pharmaceutically acceptable salt
(active ingredient).


Ingredient Quantities
Active ingredient 274 mg
Microcrystalline cellulose I50mg
Crosscarmellose sodium 40 mg
Sodium lauryl sulphate 2 mg
Magnesium stearate 4mg
Total 470 mg
Active ingredient, microcrystalline cellulose, crosscarmellose sodium, sodium lauryl sulphate & magnesium stearate are sifted separately through suitable sieve and then blended together. The lubricated granules are then compressed into tablets using suitable compression machine.
Example 11
Tablets containing amorphous form of sorafenib or its pharmaceutically acceptable salt
(active ingredient).

Ingredient Quantities
Active ingredient 274 mg
Microcrystalline cellulose 140 mg
Crosscarmellose sodium 20 mg
Sodium lauryl sulphate 2 mg
Hydroxypropyl methyicellulose (6 cps) 10 mg
Water q.s.
Crosscarmellose sodium 20 mg
Magnesium stearate 4 mg
Total 470 mg
Active ingredient, microcrystalline cellulose, crosscarmellose sodium, sodium lauryl sulphate, hydroxypropyl methyicellulose & magnesium stearate are sifted separately


through suitable sieve. Active ingredient, microcrystalline cellulose, crosscarmeliose sodium, sodium lauryl sulphate are blended together. The binder is prepared using hydroxypropyl methylcellulose in water. The dry mix is then sprayed with the binder and the blend is then sifted through suitable mesh and lubricated with magnesium stearate. The lubricated granules are then compressed into tablets using suitable compression machine.