WO2013190569A2

WO2013190569A2 - Novel salts of sunitinib and their preparation

Info

Publication number: WO2013190569A2
Application number: PCT/IN2013/000374
Authority: WO
Inventors: Rampalli SRIRAM; Upalla LAVKUMAR; Seshagiri VIJAYA MURALI MOHANRAO; Akshaykant CHATURVEDI
Original assignee: Shilpa Medicare Limited
Priority date: 2012-06-22
Filing date: 2013-06-17
Publication date: 2013-12-27
Also published as: WO2013190569A3

Abstract

The present invention relates to novel pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or its hydrate or solvate thereof. [Formula should be inserted here] The present invention further relates to processes for preparation of the said substituted aryl acrylic acid addition salts of Sunitinib (I). The present application also provides pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or its hydrate or solvate useful as active pharmaceutical ingredient in pharmaceutical composition comprising thereof, possessing anti-cancer activity.

Description

"NOVEL SALTS OF SUNITINIB AND THEIR PREPARATION"

FIELD OF INVENTION

The present invention relates to novel pharmaceutically acceptable substituted aryl acrylic acid addition salts of Suniti

The present invention further relates to processes for preparation of the said substituted aryl acrylic acid addition salts of Sunitinib (I). The present application also provides pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or its hydrate or solvate useful as active pharmaceutical ingredient in pharmaceutical composition comprising thereof, possessing anti-cancer activity.

BACKGROUND OF THE INVENTION

Sunitinib is chemically described as N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2-dihydro- 2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide and is represented by Formula (la).

Formula (la)

The malic acid salt of Sunitinib is a kinase inhibitor and has been approved by USFDA as SUTENT™ for the treatment of Gastrointestinal Stromal Tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced Renal Cell Carcinoma (RCC) and progressive, well-differentiated pancreatic NeuroEndocrine Tumors (pNET) in patients with unresectable locally advanced or metastatic disease.

Tang et al in US 6573293 B2 and WO 01/060814 A2 provided the first disclosure of Sunitinib base and Sunitinib malate salt. This patent application discloses general salts of Sunitinib such as acid addition salts and salts formed when acidic proton present in the parent compound is either replaced by a metal ion or coordinates with an organic base. However, this patent does not describe about the preparation of any salts of Sunitinib and their polymorphic forms.

It has generally been observed that different salts of the base compound have improved physical and chemical properties without affecting the pharmacological action of the drug and hence provide an opportunity to improve the drug performance characteristics of such product.

Besides the malic acid salt of Sunitinib, there are very few disclosures of other salt forms of Sunitinib, viz. - Mangion et al in WO 2010/041134 Al in the entire patent specification describe the process for preparation of only acetic acid salt of Sunitinib. Further, Selic et al in WO 2010/049449 A2 describe the process for preparation of tartaric acid and citric acid salts of Sunitinib.

Besides the aforementioned disclosures, still there appears to be need for new salts of Sunitinib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib, which may further improve the characteristics of drug Sunitinib.

More particularly, salts of Sunitinib with substituted aryl acrylic acid viz. Ferulic acid, Coumaric acid, Caffeic acid and the like have been explored by the inventors of the present application. Substituted aryl acrylic acids are found to occur naturally and may be obtainable by synthetic processes as well. The choice of substituted aryl acrylic acids for salt formation with Sunitinib base has been based on the premise that these salts are pharmaceutically acceptable and have favorable safety profile. For example, Ferulic acid is a known component of 'asafoetida', the dried latex from the giant fennel (Ferula communis). Further, it is found in the seeds of coffee, apple, peanut, and orange, as well as in both seeds and cell walls of plants such as rice, wheat, oats, and pineapple. Ferulic acid is also found in rice bran oil, which is a popular cooking oil.

Coumaric acid, more particularly -Coumaric acid can be found in a wide variety of edible plants such as peanuts, beans, tomatoes, carrots, and garlic. It is also found in wine and vinegar. />-Coumaric acid as glucoside can also be found in commercial breads containing flaxseed. Diesters of /?-Coumaric acid can be found in carnauba wax.

Caffeic acid is found in the bark of Eucalyptus globulus. It can also be found in the fresh water fern Salvinia molesta or in the mushroom Phellinus linteus. Amongst food materials Caffeic acid is found in coffee. It is one of the main natural phenols in argan oil.

Hence, inventors of the present application provide novel pharmaceutically acceptable addition salts of substituted aryl acrylic acid with Sunitinib and process for their preparation: These new salts of Sunitinib as per present application are found to be stable and offer various advantages in terms of storage, shelf life and improved physical and/or chemical properties.

SUMMARY OF THE INVENTION:

Particular aspects of the present specification relate to the novel pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or hydrate or solvate thereof and process for their preparation. Further, the present invention of this application also relates to pharmaceutical compositions comprising of stable pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or hydrate or solvate thereof, which are useful in the treatment of various cancerous disorders.

In one aspect of the present application, the present invention provides stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (I) or a hydrate or solvate thereof,

wherein, R is selected from -H, -OH or -0-C_1-3alkyl.

In another aspect of the present application, stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I), or a hydrate or solvate thereof is optionally in crystalline form or in amorphous form.

In a further aspect of the present application, stable pharmaceutically acceptable substituted aryl acrylic acid addition s Formula (la),

and is characterized by X-ray powder diffraction pattern comprising of at least 5 characteristic 2Θ° peaks selected from the XRPD peak set of 4,2, 8.5, 13.6, 15.4, 17.7, 19.6, 25.9, 26.8 and 27.8 i 0.2 20° and melting range of 165- 180°C.

In another aspect of the present application, stable pharmaceutically acceptable substituted aryl acrylic acid addition Formula (lb),

and is characterized by X-ray powder diffraction pattern comprising of at least 5 characteristic 2Θ° peaks selected from the XRPD peak set of 3.1, 6.9, 8.4, 12.4, 13.8, 20.1, 24.6, 25.6 and 26.1 ± 0.2 26° and melting range of 160-170 °C.

In yet another aspect of the present application, it relates to a process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) comprising the steps of:

a) providing a solution of Sunitinib base in Q-Q alcohol;

b) addition of substituted aryl the reaction mixture;

wherein, R is selected from -H, -OH, or -0-C_1-3 alkyl;

c) extracting the solvent and isolating the substituted aryl acrylic acid addition salt of Sunitinib;

d) Optionally, treating the substituted aryl acrylic acid addition salt of Sunitinib as obtained in step c) with a suitable polar solvent, to obtain the stable pure crystalline pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I).

In another aspect, the present invention also relates to a composition comprising stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof together with one or more pharmaceutically acceptable excipients.

Further particular aspects of the invention are detailed in the description of invention, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Sunitinib Ferulate (la). Fig. 2 is an example of a 1H NMR spectrum of Sunitinib Ferulate (la). Fig. 3 is an example of IR spectral pattern of Sunitinib Ferulate (la).

Fig. 4 is an example of X-ray powder diffraction ("XRPD") pattern of Sunitinib Coumarate (lb).

Fig. 5 is an example of a Ή NMR spectrum of Sunitinib Coumarate (lb). Fig. 6 is an example of IR spectral pattern of Sunitinib Coumarate (lb). DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to stable pharmaceutically acceptable substituted aryl acrylic acid addition salts of Sunitinib (I) or hydrate or solvate thereof and process for their preparation.

In one embodiment of the present application, it provides stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (I) or a hydrate or solvate thereof,

(I)

wherein, R is selected from -H, -OH or -O-C₁.3a.kyl.

In a further embodiment of the present application, it provides that group -R in Formula (I) is selected from -H, -OH or -OCH₃. Substituted aryl acrylic acids used for salt formation with Sunitinib base can be selected from Ferulic acid, o-Coumaric acid, m-Coumaric acid, p- Coumaric acid, Caffeic acid and the like.

In another embodiment of the present application, stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (I) or a hydrate or solvate thereof may be present in crystalline or amorphous form.

In a preferred embodiment of the present invention stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) is represented specifically by Formula (la).

In a further embodiment of the present invention stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (la) i.e. Sunitinib Ferulate is characterized by: a) X-ray powder diffraction pattern substantially according to Fig-1 ;

b) 1H NMR spectrum substantially according to Fig-2;

c) IR spectral pattern substantially according to Fig-3;

d) Melting range of 165-180 °C.

In a still further embodiment of the present application, it provides stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (la) i.e. Sunitinib Ferulate, characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2Θ° peaks selected from the XRPD peak set of 4.2, 8.5, 13.6, 15.4, 17.7, 19.6, 25.9, 26.8 and 27.8 ± 0.2 20°.

The characteristic peaks and their d-spacing values of the stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (la) i.e. Sunitinib Ferulate are tabulated in the Table- 1.

S.No. Angle (2Θ°)±0.20 d Spacing Value (A⁰)

8. 17.71 5.001

9. 18.11 4.893

10. 19.58 4.528

1 1. 25.97 3.427

12. 26.85 3.317

13. 27.46 3.245

14. 27.78 3.208

Table- 1 : Characteristic XRPD Peaks of Crystalline Sunitinib Ferulate (la)

In another preferred embodiment of the present invention stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) is represented specifically by Formula (lb).

In a further embodiment of the present invention stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (lb) i.e. Sunitinib Coumarate is characterized by: a) X-ray powder diffraction pattern substantially according to Fig-4;

b) Ή NMR spectrum substantially according to Fig-5;

c) IR spectral pattern substantially according to Fig-6;

d) Melting range of 160- 170 °C. In a still further embodiment of the present application, it provides stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (lb) i.e. Sunitinib Coumarate, characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2Θ° peaks selected from the XRPD peak set of 3.1, 6.9, 8.4, 12.4, 13.8, 20.1, 24.6, 25.6 and 26.1 ± 0.2 20°.

The characteristic peaks and their d-spacing values of the stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib represented by Formula (lb) i.e. Sunitinib Coumarate are tabulated in the Table-2.

Table-2: Characteristic XRPD Peaks of Crystalline Sunitinib Coumarate (lb)

Minor variations in the observed 2 θ° angles values may be expected based on the analyst person, the specific XRPD diffractometer employed and the sample preparation technique. Further possible variations may also be expected for the relative peak intensities, which may be largely affected by the non-uniformity of the particle size of the sample. Hence, identification of the exact crystalline form of a compound should be based primarily on observed 2 theta angles with lesser importance attributed to relative peak intensities. The 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern, d-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.

The new stable salt forms of Sunitinib as described by the present application have been found to be quite stable and easy to handle and store for longer time without any measurable change in their morphology and physicochemical characteristics, while retaining their characteristics within the defined limits. This offers advantages for large scale manufacturing in terms of handling, storage, shelf life and favorable impurity profile.

In another embodiment of the present application, it provides a process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I),

(I)

comprising the steps of: a) providing a solution of Sunitinib base in Ci-C₄ alcohol;

b) addition of substituted aryl acrylic acid of Formula (A) to the reaction mixture;

wherein, R is selected from -H, -OH, or -0-C_1-3 alkyl;

d) Optionally, treating the substituted aryl acrylic acid addition salt of Sunitinib as obtained in step c) with a suitable polar solvent, to obtain the stable pure crystalline pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I). The individual steps of the process according to the present invention for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) are detailed separately herein below.

Step a) comprises providing a solution of Sunitinib base in Ci-C alcohol;

Sunitinib base from any source is added to solvent Ci-C₄ alcohol which is taken 40-60 times . v (in mL)/w (in g) w.r.t. weight of Sunitinib base. The reaction mass is stirred for 5 to 30 mins at temperature ranging between 20-35 °C depending upon the dissolution of Sunitinib base.

In a preferred embodiment Ci-C₄ alcohol used in this step is selected from methanol, ethanol, «-propanol, z^'so-propanol, w-butanol, sec-butanol or tert-butanol.

Step b) comprises addition of substituted aryl aaylic acid of Formula (A) to the reaction mixture;

(A)

wherein, R is selected from -H, -OH, or -0-C_1-3 alkyl;

To the solution obtained in step a), substituted aryl acrylic acid of Formula (A) is added in the mole ratio of 0.5 to 2.0 w.r.t. to the amount of Sunitinib base. The reaction is carried out by stirring for 20-60 mins at a temperature ranging between 20-35 °C, depending upon the progress of the reaction.

In a preferred embodiment of the present invention, substituted aryl acrylic acid of Formula (A) used in the present reaction is selected from Ferulic acid, o-Coumaric acid, w-Coumaric acid, /?-Coumaric acid, Caf eic acid and the like.

Step c) comprises extracting the solvent and isolating the substituted aryl acrylic acid addition salt of Sunitinib;

The reaction mass obtained from step b) is heated to a temperature ranging from 40-50 °C, optionally under reduced pressure conditions to distill out the solvent. Reduced pressure conditions for distilling out the solvent may be suitably utilized by person skilled in the art in order to isolate the substituted aryl acrylic acid addition salt of Sunitinib.

The Sunitinib salt obtained may have Sunitinib base and substituted aryl acrylic acid in the ratio of 0.5 to 2.0 or any other ratio depending upon the amount of acid used in reaction of step b) and the actual reaction conditions utilized by the person skilled in the art.

Step d) which is optional comprises treating the substituted aryl acrylic acid addition salt of Sunitinib as obtained in step c) with a suitable polar solvent, to obtain the stable pure crystalline pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib CD- Substituted aryl acrylic acid addition salt of Sunitinib as obtained from step c) is provided as a solution in a suitable polar solvent, wherein polar solvent can be selected from Acetonitrile, DMF or DMSO. In this reaction the polar solvent is utilized in amount 20-30 times by volume (in mL) with respect to the amount of Sunitinib base (in g) taken initially for the reaction in step a). The polar solvent may optionally be used in 2-5 batches in this reaction.

After completion of the above step and maintaining the solution for suitable time duration depending on the progress of reaction, the polar solvent is distilled out from the reaction mixture at a temperature ranging between 40-60 °C. If required, reduced pressure conditions may be utilized for distilling out the polar solvent from the reaction mixture. Then, polar solvent is again added to the reaction mixture followed by cooling of the reaction mass to a temperature below 30 °C, wherein a suspension is obtained, which is stirred for 20-60 mins. On completion of the reaction, the reaction mass is filtered and washed again with the suitable polar solvent. The solid material obtained is then dried at a temperature ranging between 45-60 °C thus providing the crystalline substituted aryl acrylic acid addition salt of Sunitinib (I) as end product.

Process of isolating substituted aryl acrylic acid addition salt of Sunitinib (I) comprise processes but not limited to conventional processes including scrapping, if required filtering from slurry and optional drying, which may be carried out at room temperature for the suitable durations.

The substituted aryl acrylic acid addition salt of Sunitinib (I) described herein may be characterized and analyzed by X-ray powder diffraction pattern (XRPD) on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. IR study was performed on Perkin Elmer Spectrum ES Version 10.03.03 instrument. Illustrative examples of analytical data for the Sunitib Ferulate salt (la) and Sunitib Coumarate salt (lb) obtained in the Examples are set forth in the Figs. 1- 6.

In a further embodiment according to the specification, the invention also relates to a composition containing substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof. Substituted aryl acrylic acid addition salt of Sunitinib (I) is preferably selected from Sunitinib Ferulate or Sunitinib Coumarate.

The substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any ether sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof, of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline ceHulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE

Example-01: PROCESS FOR PREPARATION OF SUNITINIB FERULATE (la)

(Ia)

25 ml methanol was charged into 50 ml round bottomed flask at 25-30 °C along with addition of 0.5 g of Sunitinib base. The reaction mass was stirred for 10-15 min at 25-30 °C. At same temperature 0.25 g of Ferulic acid was added to the reaction mixture which was further stirred for 30-45 mins. On completion of the reaction, methanol was completely distilled out under vacuum at 40-45 °C and the solid material was isolated. To the isolated solid material, 1 mL acetonitrile was added, which was later distilled out under vacuum at 40-45°C to remove the traces of left Methanol. Further 10 mL acetonitrile was again added to the reaction mixture and the suspension obtained was cooled to 25-30°C, where it was stirred for 30 mins. On completion of stirring, the solid was filtered and washed with 1 mL acetonitrile. The wet solid was then suck dried and unloaded. The product obtained was further dried under vacuum at 50-55 °C for 48 h, to obtain 0.69 g of crystalline Sunitinib Ferulate (la) having X-ray powder diffraction pattern according to Fig-1, ¹H NMR spectrum according to Fig-2, IR spectral pattern according to Fig-3 and melting range of 165-

180 °C. Yield: 93.2%

Example-02: PROCESS FOR PREPARATION OF SUNITINIB COUMARATE (lb)

(Ib)

25 ml methanol was charged into 50 ml round bottomed flask at 25-30 °C along with addition of 0.5 g of Sunitinib base. The reaction mass was stirred for 10-15 min at 25-30 °C. At same temperature 0.25 g of />-Coumaric acid was added to the reaction mixture which was further stirred for 30-45 mins. On completion of the reaction, methanol was completely distilled out under vacuum at 40-45 °C and the solid material was isolated.

To the isolated solid material, 1 mL acetonitrile was added, which was later distilled out under vacuum at 40-45°C to remove the traces of left Methanol. Further 10 mL acetonitrile was again added to the reaction mixture and the suspension obtained was cooled to 25-30°C, where it was stirred for 30 mins. On completion of stirring, the solid was filtered and washed with 1 mL acetonitrile. The wet solid was then suck dried and unloaded. The product obtained was further dried under vacuum at 50-55 °C for 48 h, to obtain 0.65 g of crystalline Sunitinib Coumarate (lb) having X-ray powder diffraction pattern according to Fig-4, Ή NMR spectrum according to Fig-5, IR spectral pattern according to Fig-6 and melting range of 160-170 °C.

Yield: 91.5%

While the foregoing provides a detailed description of the preferred embodiments of the invention, it is to be understood that the descriptions are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

We Claim

1. Stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of

Sunitinib represented by Formula (I)

(I)

wherein, R is selected from -H, -OH, or -0-Ci-₃alkyl; or

a hydrate or solvate of the said salt.

Stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 1, wherein the said salt form or a hydrate or solvate thereof is optionally in a crystalline form or in amorphous form.

Stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof, according to claim 1 wherein, R is selected from -H, -OH, or -OCH3.

Stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 1 wherein the said salt is represented by Formula (la),

(la) and is characterized by X-ray powder diffraction pattern comprising of at least 5 characteristic 20° peaks selected from the XRPD peak set of 4.2, 8.5, 13.6, 15.4, 17.7, 19.6, 25.9, 26.8 and 27.8 ± 0.2 2Θ° and melting range of 165-180°C.

5. Stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 1 wherein the said salt is represented by Formula (lb),

(lb)

and is characterized by X-ray powder diffraction pattern comprising of at least 5 characteristic 20° peaks selected from the XRPD peak set of 3.1, 6.9, 8.4, 12.4, 13.8, 20.1, 24.6, 25.6 and 26.1 ± 0.2 20° and melting range of 160-170 °C.

6. A process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 1 , comprising the steps of:

a) providing a solution of Sunitinib base in Ci-C₄ alcohol;

wherein, R is selected from -H, -OH, or -0-Ci_-3 alkyl;

7. A process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 6, wherein in step a) C1-C4 alcohol is selected from methanol, ethanol, «-propanol, wo-propanol, «-butanol, sec- butanol or ter/-butanol.

8. A process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 6, wherein step d) further comprises the steps of:

i. Providing a solution of substituted aryl acrylic acid addition salt of Sunitinib with a suitable polar solvent;

ii. Distilling out the polar solvent from the reaction mixture at a temperature ranging between 40-60 °C;

iii. Re-adding the polar solvent to the reaction mixture and cooling it to a temperature below 30 °C;

iv. Filtering the reaction mass and washing the solid material with a suitable polar solvent;

V: Drying the solid material at a temperature ranging between 45-60 °C and obtaining the crystalline substituted aryl acrylic acid addition salt of Sunitinib (I) as end product.

9. A process for preparing stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) according to claim 8, wherein the suitable polar solvent used in step d) is selected from Acetonitrile, DMF or DMSO.

10. A pharmaceutical composition comprising stable pharmaceutically acceptable substituted aryl acrylic acid addition salt of Sunitinib (I) or a hydrate or solvate thereof, according to any of the preceding claims, together with one or more pharmaceutically acceptable excipients.