FIELD OF INVENTION

The present invention relates to novel pharmaceutically acceptable glucuronic acid addition salt of Sunitinib (I) or its solvate thereof. The present invention further relates to the processes for preparation of the said glucuronic acid addition salt of Sunitinib. The glucuronic acid addition salt of Sunitinib or its solvate thereof may be useful as an anti-cancer agent.

BACKGROUND OF THE INVENTION

Sunitinib is chemically described as Ar-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro- 1,2-dihydro-2-oxo-3//-indol-3-ylidine)methyl]-2,4-dimethyl-li/-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 a need for new salt forms of Sunitinib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore novel pharmaceutically acceptable salts of Sunitinib, which may further improve the characteristics of drug Sunitinib.
Hence, inventors of the present application report glucuronic acid addition salt of Sunitinib. The choice of glucuronic acid for salt formation with Sunitinib base has been based on the premise that this salt is pharmaceutically acceptable and has favorable safety profile. Therefore, inventors of the present application provide novel pharmaceutically acceptable salt of glucuronic acid with Sunitinib and processes for its preparation. This new salt of Sunitinib as per present application is found to be stable and offers various advantages in terms of storage, shelf life, solubility, safety profile and improved physical and/or chemical properties.

SUMMARY OF THE INVENTION:

Particular aspects of the present specification relate to the novel pharmaceutically acceptable glucuronic acid addition salt of Sunitinib (I) or solvate thereof and processes for its preparation. Further, the invention of this application also relates to pharmaceutical compositions comprising of glucuronic acid addition salt of Sunitinib (I) or solvate thereof, which may be useful in the treatment of various cancerous disorders. In one aspect of the present application, the present invention provides glucuronic acid addition salt of Sunitinib represented by Formula (I) or a solvate thereof. In a further aspect of the present application, glucuronic acid addition salt of Sunitinib contains Sunitinib base and glucuronic acid in about 1:1 proportion. In another aspect of the present application, glucuronic acid addition salt of Sunitinib, or solvate thereof exists in a crystalline form or as an amorphous solid. In yet another aspect of the present application, it relates to a process for preparing glucuronic acid addition salt of Sunitinib comprising the steps of:

a) providing a solution of Sunitinib base in a water-miscible organic solvent;

b) addition of glucuronic acid of Formula (A) to the reaction mixture; HOOC H0 OH (A)

c) stirring the reaction mass for time duration ranging from 2-20 hrs;

d) optionally adding another solvent selected from water, C2-C5 ether, C2-C5 ester or a C3-C6 ketonic solvent to the reaction mixture of step c) during the stirring process;

e) filtering the solid material from the reaction mass;

f) washing the solid material obtained in step e) with an organic solvent;

g) drying the solid material obtained in step f) to obtain the glucuronic acid addition salt of Sunitinib.

In another aspect of the present application, glucuronic acid addition salt of Sunitinib obtained by the process of the present invention is crystalline in nature and is characterized by X-ray powder diffraction pattern comprising of at least 4 characteristic 20° peaks selected from the XRPD peak set of 10.1, 11.3, 13.7, 15.1, 18.6, 19.7 and 24.9 ± 0.2 20°, IR absorption characteristic peaks at approximately 3403.88 cm"1, 3241.21 cm"1, 1669.29 cm"1, 1631.22 cm"1, 1615 cm"1, 1297.45 cm"1 and 1151 cm"1 and DSC isotherm comprising of at least one endothermic peak ranging between 160 to 185 °C or between 210 to 230 °C. In another aspect, the present invention also relates to a composition comprising glucuronic acid addition salt of Sunitinib or a hydrate or solvate thereof together with one or more pharmaceutically acceptable excipients. Further particular aspects of the present invention are detailed in the description of the invention, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of Sunitinib Glucuronate
(I).

Fig. 2 is an example of a lK NMR spectrum of Sunitinib Glucuronate (I).

Fig. 3 is an example of IR spectral pattern of Sunitinib Glucuronate (I).

Fig. 4 is an example of Differential Scanning Calorimetry ("DSC") curve of Sunitinib Glucuronate (I).

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to novel glucuronic acid addition salt of Sunitinib (I) or solvate thereof and processes for its preparation. In one embodiment of the present application, it provides glucuronic acid addition salt of Sunitinib represented by Formula (I), or solvate thereof. In another embodiment of the present application, glucuronic acid addition salt of Sunitinib contains Sunitinib base and glucuronic acid in a ratio of about 1:1. Ratio of about 1:1 means that the glucuronic acid addition salt of the present application has Sunitinib base and glucuronic acid in stoichiometric ratio of 1:1. This composition may vary up to range of ± 5% (mole ratios) i.e. stoichiometric ratio may range from 1: 0.95 to 1: 1.05, without deviating from the spirit of the invention. Said compositions of about 1:1 stoichiometric ratio were found to retain the characteristic XRPD diffraction pattern along with other solid state parameters. In a further embodiment of the present application, glucuronic acid addition salt of Sunitinib represented by Formula (I) or solvate thereof may be present in crystalline solid form or as an amorphous material. In a preferred embodiment of the present invention glucuronic acid addition salt of Sunitinib, prepared according to the process of this invention, is present in a crystalline form and is characterized by:

a) X-ray powder diffraction pattern substantially according to Fig-1;

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

c) IR spectral pattern substantially according to Fig-3, and

d) Differential Scanning Calorimetry ("DSC") curve substantially according to Fig-4. In a still further embodiment of the present application, it provides stable crystalline glucuronic acid addition salt of Sunitinib, characterized by XRPD peak set of 10.1, 11.3, 13.7, 15.1, 18.6, 19.7 and 24.9 ± 0.2 20°, IR absorption characteristic peaks at approximately 3403.88 cm"1, 3241.21 cm"1, 1669.29 cm"1, 1631.22 cm"1, 1615 cm"1, 1297.45 cm"1 and 1151 cm"1 and DSC isotherm comprising of at least one endothermic peak ranging between 160 to 185 °C or between 210 to 230 °C. The characteristic peaks and the corresponding d-spacing values of the crystalline glucuronic acid addition salt of Sunitinib obtained by the process of the present invention are tabulated in the Table-1. Table-1: Characteristic XRPD Peaks of Crystalline Sunitinib Glucuronate
Minor variations in the observed 2 9° 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. The crystalline form of glucuronic 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. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the Sunitib glucuronate obtained in the examples are set forth in the Figs. 1-4.

The novel salt form of Sunitinib i.e. Sunitinib glucuronate as described by the present application has been found to be quite stable and easy to handle and store for longer time without any measurable changes in its morphology and physicochemical characteristics, while retaining its properties within the defined limits. This may offer advantages for large scale manufacturing in terms of handling, storage, shelf life and favorable impurity profile. Besides the physical/chemical properties, the novel salt form of the current application further provides advantage in terms of solubility of the drug and hence provides possibility of better bioavailability and pharmacological profile. In another embodiment of the present application, it provides a process for preparing glucuronic acid addition salt of Sunitinib (I), comprising the steps of:

a) providing a solution of Sunitinib base in a water-miscible organic solvent;

b) addition of glucuronic acid of Formula (A) to the reaction mixture; HOOC H0 OH (A)

c) stirring the reaction mass for time duration ranging from 2-20 hrs;

d) optionally adding another solvent selected from water, C2-C5 ether, C2-C5 ester or a C3 C6 ketonic solvent to the reaction mixture of step c) during the stirring process;

e) filtering the solid material from the reaction mass;

f) washing the solid material obtained in step e) with an organic solvent;

g) drying the solid material obtained in step f) to obtain the glucuronic acid addition salt of Sunitinib.

The individual steps of the process according to the present invention for preparing glucuronic acid addition salt of Sunitinib (I) are detailed separately herein below. Step a) comprises providing a solution of Sunitinib base in a water-miscible organic solvent; Sunitinib base from any source is added to the water-miscible organic solvent, selected from C1-C4 alcohol, DMSO (dimetylsulfoxide), DMF (dimethylformamide), NMP (N-methylpyrrolidone) and THF (tetrahydrofuran). In one of the preferred embodiment C1-C4 alcohol is used 15-50 times v/w (mL/g) w.r.t. weight of Sunitinib base. The reaction mass is stirred for 5 to 30 mins at temperature ranging between 20-80 °C depending upon the dissolution of Sunitinib base. C1-C4 alcohol used in this step may be selected from methanol, ethanol, H-propanol or wo-propanol. Step b) comprises addition of glucuronic acid of Formula (A) to the reaction mixture; To the solution obtained from step a), glucuronic acid of Formula (A) is added in the mole ratio of 1.0 to 1.5 w.r.t. amount of Sunitinib base. Addition of glucuronic acid to the reaction mixture is done at a temperature ranging between 20-80 °C. Glucuronic acid may optionally be added to the reaction mixture in the form of a solution in water or a suitable organic solvent. When glucuronic acid is added to the reaction mixture in solution form, addition is performed slowly over time duration of 10-20 mins. On addition of glucuronic acid the reaction mass turns into a clear solution.
Step c) comprises stirring the reaction mass for time duration ranging from 2-20 hrs;

The reaction mass obtained in step b) is stirred for time duration ranging between 2-20 hrs. After initial stirring for 30-45 mins, solid material slowly starts emitting from the earlier obtained clear reaction mixture. After emission of the solid material, the reaction mass is further subjected to stirring for time duration of 2-20 hrs. Optionally during the stirring process, an antisolvent like water or other organic solvents like C2-C5 ether (Eg. Diethylether, THF etc.), C2-C5 ester (Eg. ethylacetate) or a C3-C6 ketonic solvent (Eg. acetone, methylisobutyl ketone etc.) may be added to the reaction mixture (Step d)). In a preferred embodiment, the amount of C3-C6 ketonic solvent (preferably acetone) added to the reaction mixture may range from 40-70 times in volume (mL) w.r.t. the amount of Sunitinib base (in g) initially taken for the reaction. Temperature of the reaction mixture is maintained at a temperature below 30 °C during this stirring process. Cooling of the reaction mixture may be performed if required. Step e) comprises filtering the solid material from the reaction mass; The solid material obtained from step c) or d) is filtered from the reaction mass by conventional methods well known in the prior art. Step f) comprises washing the solid material obtained in step e) with an organic solvent; The solid material obtained from filtration performed in step e) is given washing with an organic solvent selected from a C1-C4 alcohol like methanol and ethanol or a C3-C6 ketonic solvent like acetone. The organic solvents used for washing the said solid material may be utilized in a low temperature state and in amount 2-5 times in volume (mL) w.r.t. the amount of Sunitinib base (in g) initially taken for the reaction.
Step g) comprises drying the solid material obtained in step f) to obtain the glucuronic acid addition salt of Sunitinib.

The solid material obtained in step f) is then dried at a temperature above 45 °C for a time duration ranging between 36-84 hrs, thus providing the pure glucuronic acid addition salt of Sunitinib as end product. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to isolate the glucuronic acid addition salt of Sunitinib. The moisture content of the final API obtained by the process of the present invention is about 1%, however it may be a bit more or less than 1% without deviating from the scope of the invention. By suitable modifications of the above mentioned process of this invention the end product may be obtained as a crystalline solid or in an amorphous form. Process of isolating glucuronic acid addition salt of Sunitinib may also comprise other processes but not limited to conventional processes including scrapping, if required filtering from slurry and drying, which may be carried out at room temperature or a bit raised temperature for the suitable durations. It is worth mentioning that glucuronic acid used in the present invention is found to occur naturally and may be obtainable by synthetic processes as well. Glucuronic acid is a naturally occurring carboxylic acid and is reported to be present in food articles like Kombucha, which is an effervescent fermentation of sweetened tea that is used as a functional food. Otherwise, glucuronic acid is commonly found in carbohydrate chains of proteoglycans and is part of mucous animal secretions (such as saliva), cell glycocalyx and intercellular matrix. In the animal body, glucuronic acid is involved in the xenobiotic metabolism of substances such as bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids.

The formation of glucuronic acid takes place in the liver of animals, including humans and other primates, and is derived from glucose. In most of the plants and mammals glucuronic acid is also a precursor of ascorbic acid, which is also known as Vitamin C. Moreover, glucuronic acid is part of the natural detoxification process in the body. Hence it has also been looked at as a treatment for certain diseases, most notably prostate cancer. In addition to removing harmful toxins in the body it also appears to regulate testosterone levels, which can help with this type of cancer. In a further embodiment according to this patent's specification, the invention also relates to a composition containing glucuronic acid addition salt of Sunitinib (I) or solvate thereof. The glucuronic acid addition salt of Sunitinib (I) 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 other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising glucuronic 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 cellulose, 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 glucuronic acid addition salt of Sunitinib or solvate thereof of the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

EXAMPLE

Example-01: PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 35 mL methanol was charged into a 250 mL round bottomed flask at 25-30°C and 1.0 g Sunitinib base was added to it. The reaction mass was stirred for 15 mins followed by addition of 0.534 g D (-)-Glucuronic acid to the reaction mixture, wherein the reaction mass turned into a clear solution. The reaction mass was further stirred for 30 mins till the solid material slowly started emitting from the solution. After the emission of solid material, the reaction mass was further stirred for 5 hrs. Then the solid material was filtered and washed with 2.0 mL chilled methanol. The wet solid material obtained was suck dried and unloaded. Still further drying of the solid material was performed under vacuum for -48 hrs at 50-55 °C, to obtain ~ 1.3 g Sunitinib glucuronate. Yield: 87.42 %

Example-02: PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 35 mL methanol was charged into a 250 mL round bottomed flask at 25-30°C and 1.0 g Sunitinib base was added to it. The reaction mass was stirred for 15 mins followed by addition of 0.534 g D (-)-Glucuronic acid to the reaction mixture, wherein the reaction mass turned into a clear solution. The reaction mass was further stirred for 30 mins till the solid material slowly started emitting from the solution. Then 60.0 mL acetone was added to the reaction mass and stirring was further continued for 17 hrs. The solid material obtained was filtered and washed with 2.0 mL acetone. Then the wet solid material was suck dried and unloaded. Still further drying of this solid material was performed under vacuum for -48 hrs at 50-55 °C, to obtain - 1.25 g Sunitinib glucuronate, characterized by XRPD pattern according to Fig-1; !H NMR spectrum according to Fig-2; IR spectral pattern according to Fig-3 and "DSC" curve according to Fig-4. Yield: 84.17%

Example-03: PROCESS FOR PREPARATION OF SUNITINIB GLUCURONATE 20 mL ethanol was charged into a 100 mL round bottomed flask at 25-30°C and 1 g Sunitinib base was added to it. The reaction mass was stirred for 15 mins and then its temperature was increased to ~ 50-55 °C. After this, 0.536 g of D (-)-Glucuronic acid (dissolved in 2.5 mL DM water) was slowly added to the reaction mixture over a time duration of ~ 15 mins, wherein the reaction mass initially turned into a clear solution and then slowly a solid material started emitting. The reaction mass was further stirred for 30 mins followed by cooling to a temperature of- 25-30 °C. Stirring was further continued for 5 hrs. The solid material obtained was then filtered and washed with 2.0 mL chilled ethanol. The wet solid obtained was then suck dried and unloaded. Still further drying of the solid material was performed under vacuum for ~48 hrs at 50-55 °C, to obtain ~ 1.4 g Sunitinib glucuronate. Yield: 94 % 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.

We Claim:

1. Glucuronic acid addition salt of Sunitinib represented by Formula (I) or its solvate thereof.

2. Glucuronic acid addition salt of Sunitinib according to claim 1, wherein the said salt form or its solvate thereof is in a crystalline form or in amorphous form.

3. Glucuronic acid addition salt of Sunitinib according to claim 1, wherein the said salt form contains Sunitinib base and glucuronic acid in about 1:1 proportion.

4. A process for preparing glucuronic acid addition salt of Sunitinib according to any of the preceding claims, comprising the steps of:

a) providing a solution of Sunitinib base in a water-miscible organic solvent;

b) addition of glucuronic acid of Formula (A) to the reaction mixture;

c) stirring the reaction mass for time duration ranging from 2-20 hrs;

d) optionally adding another solvent selected from water, C2-C5 ether, C2-C5 ester or a C3-C6 ketonic solvent to the reaction mixture of step c) during the stirring process;

e) filtering the solid material from the reaction mass;

f) washing the solid material obtained in step e) with an organic solvent;

g) drying the solid material obtained in step f) to obtain the glucuronic acid addition salt of Sunitinib.

5. A process for preparing glucuronic acid addition salt of Sunitinib according to claim
4, wherein water-miscible organic solvent is selected from C1-C4 alcohol, DMSO, DMF, NMP and THF.

6. A process for preparing glucuronic acid addition salt of Sunitinib according to claim 4, wherein organic solvent used in step f) is selected from a C1-C4 alcohol or a C3-C6 ketonic solvent.

7. Crystalline glucuronic acid addition salt of Sunitinib obtained according to process of claim 4, wherein the said crystalline salt is characterized by X-ray powder diffraction pattern comprising of at least 4 characteristic 29° peaks selected from the XRPD peak set of 10.1, 11.3, 13.7, 15.1, 18.6,19.7 and 24.9 ± 0.2 29°.

8. Crystalline glucuronic acid addition salt of Sunitinib obtained according to process of claim 4, wherein the said crystalline salt is characterized by DSC isotherm comprising at least one endothermic peak ranging between

a. Peak -1 - Between 160 to 185 °C; or

b. Peak-2-Between 210 to 230 °C

9. Crystalline glucuronic acid addition salt of Sunitinib obtained according to process of claim 4, wherein the said crystalline salt is characterized by IR absorption characteristic peaks at approximately 3403.88 cm"1, 3241.21 cm"1, 1669.29 cm"1, 1631.22 cm"1, 1615 cm"1, 1297.45 cm"1 and 1151 cm"1.

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