PAZOPANIB HC1 POLYMORPH AND PROCESS FOR PREPARATION THEREOF

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION

The present invention relates to process for preparing crystalline Pazopanib HC1 (I). The crystalline form designated as Form- SP of Pazopanib HC1 (I) obtained by the process/es according to the present invention is useful as an anti-cancer agent.

INTRODUCTION

Pazopanib hydrochloride has the IUPAC name as 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino) pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride and has the following structure- It is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals.

Boloor ,et al. in WO 02/059110 and its equivalent patents-US7105530, US7262203, US 7858626 and US8114885 disclose the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride along with the uses of this compound. In particular, this compound is therapeutically useful as inhibitor of tyrosine kinase enzymes, namely Vascular Endothelial Growth Factor Receptors (VEGFR), and accordingly may be used for the treatment and/or prevention of diseases which are associated with VEGFRs, such as cancer, particularly breast cancer and colon cancer.

Further Boloor ,et al. in WO 03/106416 also disclose other methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methyl amino) pyrimidine-2-yl amino)-2-methyl benzene sulfonamide hydrochloride.

WO 2007/064752 disclosed the use of Pazopanib for the treatment of age related macula degeneration. WO 2007/064753 also discloses Pazopanib for the treatment of various cancer including prostate cancer, brain cancer, glioblastoma multi-forme, neuro-endocrine cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.

Biomedical Analysis, 2009, Vol. 50, pp 144- 150, also describes a process for the preparation of Pazopanib HC1.

RENDELL JACOB et al in WO2011069053Al disclosed various crystalline forms of Pazopanib HC1 and process for preparation thereof. The application also disclosed Pazopanib HC1 essentially free from (2-chloropyrimidin-4yl)-2,3-dimethyl-2H-indazol-6-amine CPMI. It appears to claim form XIII of Pazopanib HC1 characterized by an X-ray powder diffraction pattern having peaks at 15.1, 16.6, 19.9 and 23.8 +/- 0.2 degrees 2-Theta and combinations thereof.

The disclosure of this application includes Form-I, XIV and XV as Pazopanib dihydrochloride salt forms and Form-II,III,IV,V,VI, VIII, IX,X, G, A, XI, XII and XIII as Pazopanib hydrochloride salt forms. It also discloses XRPD of crystalline form of Pazopanib base.

PCT Publication No. WO2007/143483, WO2006/20564 and WO 2005/105094, as well as US publication Nos. US 2006/0252943, US 2008/0293691 and US 7,262,203 (US'203) describe anhydrous and hydrate forms of Pazopanib HC1 and their process for preparation thereof.

Polymorphism is a typical property of some molecules, wherein the occurrence of different crystal forms is noticed. A single molecule may give rise to diverse polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

Identifying new polymorphic forms and solvates of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a

pharmaceutical^ useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For one or more of these reasons, there is an inherent need for identifying new polymorphs of Pazopanib HC1.

Thus, in one aspect the present invention relates to the Pazopanib HC1 crystalline form designated as Form-SP. In another aspect, the present invention also relates to the process for preparation of Pazopanib HC1 Form-SP crystalline form. In still another aspect, the present invention relates to the Crystalline Pazopanib HC1 in the polymorphic form SP (also referred to as "Polymorph SP"). Polymorph SP of Pazopanib HC1 is characterized by an XRPD pattern having atleast 5 characteristic peaks selected from 6.49, 8.16, 10.34, 11.37, 11.74,13.05,17.09,18.09,18.49,20.80,23.62 ± 0.20 2-theta.

Though many processes are known for preparation of Pazopanib HC1, as have been mentioned herein before but most of them suffer from the limitation of very low yields and high amount of impurity formation, which makes isolation of the final API very difficult. Most of the prior art processes are very time consuming with very long reaction times and many times these processes do not even go to completion.

Thus the prior art processes are not industrially or commercially suitable and are non-amenable for up scaling. Inventors of the present invention thus provide a new commercially viable and less time consuming process for the preparation of crystalline Pazopanib HC1, which provides Pazopanib hydrochloride crystalline form designated as Form-SP in good yield and with high purity.

SUMMARY OF INVENTION

Particular aspects of the present application relate to the process for the preparation crystalline Pazopanib HC1 (I) and its polymorphic designated as Form-SP.

The application further relates to processes for preparation of crystalline Pazopanib HC1 (I) designated as polymorphic Form-SP, substantially free from process related impurities. The crystalline polymorphic Form-SP of Pazopanib HC1 (I) obtained by the processes according to the present invention is useful as active pharmaceutical ingredient in pharmaceutical compositions for the treatment of cancer. Different aspects of the present application are summarized herein below individually.

In one aspect of the present application, the present invention provides a process for preparing crystalline Pazopanib hydrochloride (I) comprising the steps of:

a) combining 2,3-dimethyl-2#-indazol-6-amine.HCl (A) with 2,4 dichloropyrimidine (B) in the presence of solvent N-propyl alcohol (IPA) to provide N-(2-chloropyrimidin-4-yl)- 2,3 -dimethyl-2H-indazol-6-amine (C);

b) converting N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C) to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) in the presence of a methylating agent and an alkali metal alkoxide;

c) reacting AL(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) with 5-amino-2-methylbenzenesulfonamide (E) in the presence of aqueous HC1 to provide

d) converting the step c) product to Pazopanib hydrochloride crystalline Form-SP.

In another aspect of the present application, the present invention provides Pazopanib hydrochloride crystalline Form-SP characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 20° peaks selected from the XRPD pattern having atleast 5 characteristic peaks selected from 6.49, 8.16, 10.34, 11.37, 11.74, 13.05, 17.09, 18.09, 18.49, 20.80 , 23.62 ± 0.20 20°. The said crystalline Form-SP is further characterized by DSC isotherm comprising at least two endothermic peaks ranging between-

a. Peak -1 - Between 90 to 120°C

b. Peak -2- Between 285 to 310°C

In yet another aspect of the present application, the present invention provides process for preparing Pazopanib hydrochloride crystalline Form-SP comprising the steps of-

a) Combining the Pazopanib hydrochloride from any source with an organic solvent and water.

c) Raising the temperature up to about 40 - 75 °C.

e) Maintaining the solution under stirring at about 40 - 75 °C for a time duration ranging between 15 to 90 mins.

f) Cooling the solution to a temperature below 35 °C at a rate of not exceeding 1° C/min.

g) Isolating the crystalline Form-SP.

In a further aspect, the Crystalline Form-SP of Pazopanib HC1 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 useful in the treatment of various types of cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is Illustration of X-ray powder diffraction (XRPD) pattern of Pazopanib hydrochloride -Form SP, prepared according to Example-2

Fig. 2 is Illustration of a differential scanning calorimetric ("DSC") curve of Pazopanib hydrochloride, prepared according to Example-2

Fig. 3 is Illustration of a Infra-red ("IR") spectrum of Pazopanib hydrochloride, prepared according to Example-2

Fig. 4 is Illustration of X-ray powder diffraction (XRPD) pattern of Pazopanib hydrochloride -Form SP, prepared according to Example-3

DETAILED DESCRIPTION

As set forth herein, aspects of the present invention relate to the process for preparation of crystalline Pazopanib HC1 polymorphic Form- SP, substantially free from process related impurities.

Individual embodiments of the present invention are detailed herein below separately. In an embodiment of the present application, the present invention provides process for preparing crystalline Pazopanib hydrochloride (I) comprising the steps of:

a) combining 2,3-dimethyl-2H-indazol-6-amine.HCl (A) with dichloropyrimidine (B) in the presence of solvent wo-propyl alcohol (IPA) to provide N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C);

b) converting N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C) to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) in the presence of a methylating agent and an alkali metal alkoxide;

c) reacting N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) with 5-amino-2-methylbenzenesulfonamide (E) in the presence of aqueous HC1 to provide crude Pazopanib hydrochloride (I);

d) converting the step c) product to Pazopanib hydrochloride crystalline Form-SP.

The individual steps of the process according to the present invention for preparing Pazopanib hydrochloride are detailed separately herein below:

Step a) comprises combining 2,3-dimethyl-2i7-indazol-6-amine.HCl (A) with Dichloropyrimidine (B) in the presence of solvent wo-propyl alcohol (IPA), to provide N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C);,3-dimethyl-2H-indazol-6-amine.HCl (A) is combined with 2,4-Dichloropyrimidine (B) in the presence of solvent iso-propyl alcohol (IPA), along with the use of a base and an additional water soluble organic solvent selected from THF, DMF, DMA or DMSO. Amount of IPA used in this reaction is 15-25 times (v/w: mL/g) of 2,3-dimethyl-2H-indazol-6-amine.HCl (A).

Inventors of the present application found that use of IPA in this reaction results in good yield of highly pure end product AL(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C), unlike the prior known methods wherein high amounts of impurities in the end product remains an issue of concern for the further reaction course. Suitable base to be used for this reaction may be selected from NaHCO3, KHCO3, Na2CO3, K2CO3, and the like.

Isopropyl alcohol (IPA), water soluble organic solvent, 2,3-dimethyl-2H-indazol-6-amine.HCl (A), 2,4-dichloropyrimidine (B) and a base like Sodium bicarbonate are reacted at room temperature followed by the heating of reaction mass to a temperature of more than 65 °C which is maintained for a time of about 3-7 hours depending upon the progress of the reaction which can be monitored by HPLC. On completion of the reaction, reaction mass is cooled to 40 - 50 °C. Solvent may be distilled out from the reaction mass under reduced pressure conditions suitably chosen by a person skilled in the art, followed by further cooling of the reaction to 30 -35 °C.

The reaction mass may further be subjected to stirring with purified water initially at temperature of 25 - 35 °C and then at 0-5 °C. The intermediate obtained in this step may optionally be purified by treating with an organic solvent selected from acetone, methyl ethyl ketone or diethyl ketone. This purification step of treatment with an organic solvent may involve heating of the reaction mass to a temperature of around 50-65 °C followed by gradual cooling to a temperature of about 0 °C.

Step b) comprises converting N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C) to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) in the presence of a methylating agent and an alkali metal alkoxide; Conversion of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine(C) to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) is carried out using a methylating agent which is preferably methyl iodide, in the presence of an alkali metal alkoxide base which can be selected from potassium tert-butoxide or sodium tert-butoxide. 2-4 moles of methylating agent and 2-4 moles of the alkali metal alkoxide base are used in this reaction with respect to 1 mole of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C).

It has been observed by the inventors of the present application that prior art known methods of methylation, for e.g. by use of alkali metal carbonates and other bases etc. are very time consuming and reaction generally does not go to completion. Such prior art disclosed methods yielded lower yields along with formation of higher amount of impurities.

Process according to the present invention involving the use of alkali metal alkoxide base, in this reaction advantageously provides highly pure N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) (~ 98% purity by HPLC), with minimal impurities and the reaction reaches completion in 2-4 hrs.

The methylation reaction is performed in the presence of a suitable water soluble organic solvent selected from THF, DMF or DMSO and the end product obtained is optionally purified by treatment with an organic solvent selected from acetone, methyl ethyl ketone or diethyl ketone. Reaction mass may be subjected to quenching with purified water before purification with the mentioned organic solvents.

Methylation reaction may be performed under inert atmosphere for e.g. nitrogen atmosphere and at a temperature ranging between 0-5 °C. Alkali metal alkoxide base is added to the reaction mixture at the temperature ranging between 0-5 °C, while performing stirring for 1-4 hrs depending upon the progress of the reaction. After completion of stirring, temperature of reaction mass may be increased to about 20-30 °C, where again stirring may be performed for 1-4 hrs.

Step c) comprises reacting N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) with 5-amino-2-methylbenzenesulfonamide (E) in the presence of aqueous HC1 to provide crude Pazopanib Hydrochloride (I).

Reaction of N-(2-chloropyrimidin-4-yl)N,2,3-trimethyl-2H-indazol-6-amine (D) with 5-amino-2-methylbenzenesulfonamide (E) is carried out in the presence of IPA and aqueous HC1. In this reaction IPA may be used in amount of about 30-40 times v/w (mL/g) with regard to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D). Reaction is carried out at a temperature ranging between 70-95 °C, followed by cooling to a temperature below 35 °C. The obtained reaction mass may further be subjected to heating in DMF at a temperature of about 60 °C, followed by cooling, filtering, washing with IPA, drying and isolation of Pazopanib Hydrochloride.

Process of isolating crude Pazopanib Hydrochloride 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 process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appear in the impurity profile of the Pazopanib Hydrochloride may be substantially lessened by the process of the present invention resulting in the formation of crude Pazopanib Hydrochloride of HPLC purity -98%. In

view of maintaining the equilibrium to the impurity profile compliance, the process may require in-process quality checks to avoid unnecessary repetitions of the same process steps. Crude Pazopanib Hydrochloride obtained according to the process of the present invention results in the product with purity by HPLC of ~ 98 % w/w; however purity of about -99% may also be achievable at this stage of crude product formation.

Step d) comprises converting the step c) product to Pazopanib hydrochloride crystalline Form-SP.

The product obtained in step c) i.e. crude Pazopanib Hydrochloride with purity by HPLC of ~ 98 % w/w is converted to crystalline Form-SP, by the process of the present invention comprising the steps of:

a) Combining the crude Pazopanib hydrochloride with an organic solvent and water.

b) Heating up to about 40 - 75 °C.

c) Stirring the solution at same temperature for a time duration ranging between 15 to 90 mins.

d) Cooling the solution to a temperature below 35 °C at a rate of not exceeding 1 °C/min.
e) Isolating the crystalline Form-SP.

It is noteworthy that any other form of crude or pure Pazopanib Hydrochloride obtained by known processes may also be used for preparing crystalline Form-SP.

Crystalline Pazopanib hydrochloride designated as Form-SP, prepared by the process of the present invention is characterized by at least 5 characteristic 20° peaks selected from the XRPD pattern having atleast 5 characteristic peaks selected from 6.49, 8.16, 10.34, 11.37, 11.74, 13.05, 17.09, 18.09, 18.49, 20.80 ,23.62 ± 0.20 20°. The said crystalline Form-SP is further characterized by DSC isotherm comprising at least two endothermic peaks ranging between-

a. Peak -1 - Between 90 to 120°C

b. Peak-2-Between 285 to 310°C

Pazopanib hydrochloride crystalline Form-SP characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 20°peaks selected from the XRPD peak set of 6.49, 8.16, 10.34, 11.37, 11.74, 13.05, 17.09, 18.09, 18.49,20.80,23.62 ± 0.20 20° and DSC isotherm comprising at least two endothermic peaks ranging between 90 to 120°C (Peak -1), 285 to 310°C (Peak -2), has X-ray powder diffraction pattern substantially according to Fig-1 and DSC isothermal pattern substantially according to Fig-2. Pazopanib hydrochloride crystalline Form-SP is further characterized by having water content between 3.50 to 3.80 % w/w.

The characteristic peaks and their d spacing values of the new crystalline Form-SP of Pazopanib hydrochloride are tabulated in the Table-1.

Table-1: Characteristic XRPD Peaks of Crystalline Form-SP

Organic solvent used in conjunction with water to providea soluion of Pazopanib hydrochloride (obtained from any source) may be selected from CI to C4 alcohol or water soluble cyclic ether (e.g. THF) or aliphatic lower ketone (e.g. acetone). In one of the particular embodiment, Isopropanol is used as an organic solvent for making crystalline Form-SP.

The combining of an organic solvent with Pazopanib hydrochloride may be carried out at ambient temperature followed by addition of water in ratio ranging between 40:60 to 60:40 v/v (solvent: water). In particular embodiment, water and solvent (isopropanol) is used in ratio 50:50 v/v.

Temperature of the reaction mixture is raised to a temperature of up to 75 °C. The combined mixture may be maintained at the same temperature for about 1-1.5 hrs; however, this time may be more, depending upon achieving the clear solution and equilibration to impurity profile compliance. It was observed by the inventors of the present application that reaction temperature plays an important role in the course of reaction as well as the end product obtained. If temperature is increased to more than 75 °C, greater amount of impurity formation occurs and end product is not obtained in pure form.

Reaction mass is then cooled up to 25-35 °C and subjected to stirring for about 1-2 hrs. Further cooling of the reaction mass along with stirring may also be carried out as per requirement. To obtain crystalline Form-SP of the present invention cooling of the solution shall be carried out gradually and slowly at a rate of not exceeding 1 °C/min. In one particular embodiment of the present invention, the controlled cooling of the reaction mass from 70 °C to 20 ° C was performed in 2 hrs. In case of uncontrolled/abrupt cooling, crystalline Form-SP of the present invention is not obtainable. The final obtained crystalline Pazopanib hydrochloride Form-SP by the process of the present invention is a hydrate form containing about 0.8 to 1.2 moles of water per mole of Pazopanib HC1.

The product may be isolated from the reaction mass by conventional processes including filtering and optional drying, which may be carried out at room temperature or a raised temperature of about 40-50 °C, for the suitable durations to retain the crystalline polymorphic form characteristics. Other conventional processes include but not limited to scrapping, breaking and triturating.

The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appear in the impurity profile of the Pazopanib hydrochloride can be substantially removed by the process of the present invention resulting in the formation of pure crystalline form-SP. A substantially pure product having purity more than 99% (by HPLC) can be obtained by the process of the present invention. In view of maintaining the equilibrium to the impurity profile compliance, the process may require quality checks.

Crystalline form-SP of the present invention may have one or more advantageous and desirable properties compared to the known Pazopanib Base, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution. The Crystalline Form -SP of Pazopanib HC1 described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetric (DSC) Analysis. The samples of Pazopanib HC1 Crystalline Forms -SP were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A, however, DSC analysis were carried out on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of analytical data for the crystalline solids Torm -SP' obtained in the Examples are set forth in the Figs. 1-4.

In further embodiment, the Crystalline Form -SP of Pazopanib HC1 obtained by the processes disclosed in the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment

of cancer and related disorders. 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, glycerine, 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 Crystalline Form - SP of Pazopanib HC1 of the present application include, 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 derived from Crystalline Form - SP of Pazopanib HC1 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 1: Preparation of Pazopanib Hydrochloride

Stage-I: Coupling of 2,3-dimethyl-2H-indazol-6-amine.HCl (A) and 2,4-dichloropyrimidine

7000 ml Isopropyl alcohol (IPA) and 1750 ml THF were charged into a 20 lit reactor. Further 350 gm 2,3-dimethyl-2H-indazol-6-amine.HCl (A) and 630 gm 2,4-dichloropyrimidine (B) were added to the reaction mass at room temperature. At same temperature 600 gm sodium bicarbonate was also added to the reaction mass. The reaction mass was heated to 75 - 80°C and stirred at same temperature till completion of reaction (-5.0 hrs). Progress of the reaction was regularly monitored. On completion of the reaction as confirmed by HPLC reaction mass was cooled to 40 - 50°C. Solvent was distilled out under vacuum from reaction mass to reduce reaction mass volume to 50%. Reaction mass was further cooled to 30 - 35 °C.

14000 ml purified water was charged to reaction mass slowly over period of 15 - 20 mins. The reaction mass was stirred at 25 - 35 °C for 1 - 2 hrs, followed by cooling to 0 - 5 °C and further stirring for 1 - 2 hr. The reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product, which was washed with water (875ml x 2). This was then suck dried under vacuum for 1 - 2 hrs. Filtered solid was unloaded. The obtained wet cake product was charged to 5.0 lit reactor having 3000 ml Acetone and flushed with further 500 ml Acetone. Reaction mass was heated to 55 - 60°C and maintained for 2 - 2.5 hrs. Then gradually, reaction mass was cooled to 25 - 30°. Further cooling of reaction mass to 0 - 5°C was done and reaction mass was maintained at this temp for 60 - 90 mins. Then, reaction mass was filtered on Buchner funnel under vacuum to get wet cake product, which was washed with 350 ml chilled Acetone. The product was unloaded and dried at 40 - 45 °C for 4 - 5 hrs till the moisture content came below 1.0% to obtain the dried product (-310 gm).

Stagc-II: Mcthylation of N-(2-chloropyrimidin-4-yl-2,3-dimethyl-2H-indazol-6-amine (C) 3300 ml DMF was charged to a 10 lit reactor under nitrogen atmosphere. Then 330 gm N-(2-chloropyrimidin-4-yl)-2, 3-dimethyl-2H-indazol-6-amine (C) was added to the reactor. Reaction mass was cooled to 0 - 5 °C followed by addition of Methyl iodide. Potassium tert-butoxide was added lot wise to the reaction mass over a period of 1-2 hrs, maintaining temperature below 5°C. Slowly reaction mass temp was raised to 20 - 25°C followed by stirring for 1.5 - 2.0 hrs. Progress of the reaction was monitored till completion as confirmed by HPLC.

Meanwhile 16500 ml purified water was charged in 20 Lit reactor. Water was cooled to 5-10°C under stirring. The reaction mass from 10 lit reactor was slowly quenched in to water in 20 lit reactor maintaining reaction mass temperature below 10 °C. Reaction mass was stirred for 2- 2.5 hr maintaining reaction mass temperature below 0 to 10°C. Reaction mass was then filtered on Buchner funnel to get a wet cake product, which was washed with 660 mL water. Wet cake product was then suck dried for 30 - 60 min under vacuum and unloaded. 1650 ml Acetone was charged to a 10 lit reactor and wet cake product was added to it. Reaction mass was heated to 55 - 60°C which was maintained for 1.5-2 hrs. Then gradually reaction mass was cooled to 25 - 30° and then further to 0 - 5°C, where it was maintained for 1 - 2 hrs. The reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product which was washed with 330 mL chilled Acetone. Then the product was unloaded and dried at 40 - 45 °C for 3- 4 hrs till moisture content was not more than 1.0% to obtain the dried product (~ 260 gm)

Stage-Ill: Coupling reaction of N-(2-chloropvrimidin-4-yl)-N,2,3-trimethvl-2H-indazol-6-amine (D) and 5-amino-2-methylbenzenesulfonamide (E) to get Pazopanib hydrochloride 8575 ml IP A was charged to a 10 lit reactor. Then 245 gm N-(2-chloropyrimidin-4-yl)-N, 2, 3-trimethyl-2H-indazol-6-amine (D), 166.7gm 5-amino-2-methylbenzenesulfonamide (E) and 24.5 ml cone. Hydrochloric acid were added to it sequentially at RT. Reaction mixture was then heated to 80 - 85°C where stirring was performed for 5 - 6 hrs. Progress of the reaction was monitored till completion as confirmed by HPLC. Then the reaction mass was gradually cooled to 25 - 35 °C, where stirring was done for 60 mins. Reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product, which was washed with 490 ml IPA. The product was then suck dried for 30 - 60 min under vacuum. Then this wet cake product was charged into a 10 lit reactor already having 1960 ml of DMF. The reaction mass was heated to 55 - 60°C, which was maintained for 1.5-2 hrs. Then gradually reaction mass was cooled to 25 - 30° and then further to 10 - 15°C, which was maintained for 60 - 90 min. Reaction mass, was then filtered on Buchner funnel under vacuum to get wet cake product, which was washed with 490 ml IPA. The obtained product was then unloaded and dried at 40 - 45 °C for 3 - 4 hrs, till moisture content was not more than 2.0% to obtain ~ 380 gm crude Pazopanib hydrochloride as end product.

EXAMPLE 2: Preparation of Crystalline Pazopanib Hydrochloride (Form-SPWSolvent IPA and Water 50:50 v/v) 50 gm crude Pazopanib hydrochloride (HPLC purity = 98.94%; SMI = 0.22%) was charged to a 500 mL RBF. 150ml IPA and 150ml purified water was then added to the reaction mixture. The reaction mass was heated under stirring up to 50 - 55 °C, for 30-60 min to get clear solution. Then the reaction mass was slowly cooled to 25 to 35 °C to get the precipitation of product. The reaction mass was further cooled 15 - 20°C and stirring was done for 1 -2 hrs. Reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product. The product cake was washed with a mixture of IPA (25ml) and purified water (25ml). Then it was suck dried for 30-60 mins under vacuum. The product was then unloaded after drying under vacuum at 40 -50 °C for 4 - 6 hrs to obtain Crystalline Pazopanib Hydrochloride (Form-SP) characterized by XRPD as per Fig-1, DSC as per Fig. -2 and IR pattern as per Fig.-3. Yield = 42 gm (84%) HPLC purity = 99.89% (SMI = 0.08%) Mass = 438 [M+1]+ 1H NMR (400 MHz, DMSO-d6) δ: 2.56 (s, 3H), 2.65 (s, 3H), 3.58 (s, 3H), 4.09 (s, 3H), 5.93 (br s, 1H), 6.93 (d,lH), 7.42 (br s, 3H), 7.60 (s, 1H), 7.63 (s, 1H), 7.85 (s, 1H), 7.87 (s, 1H), 8.38 (br s,lH), 11.04 (brs, 1H). Moisture content by KF = 3.75%

EXAMPLE 3: Preparation of Crystalline Pazopanib Hydrochloride (Form-SPUSolvent IPA and Water 50:50 v/v)

1750 ml IPA and 1750ml purified water were charged to a 5 lit RBF. 350.0 gm crude Pazopanib Hydrochloride was then added to the reaction mixture. The reaction mass was then heated under stirring up to 75 °C to get clear solution which was stirred for 60 - 90 mins. The reaction mass was then filtered through the micron filter at 70 °C. The filtrate was collected in a 5 lit reactor and cooled gradually over a period of 120 mins to 20 °C to get the precipitation, of product. Further stirring was done for 1 - 2 hrs and then reaction mass was filtered on Buchner funnel under vacuum to get wet cake product. The product cake was then washed with mixture of IPA (350 mL) and purified water (350 mL), followed by suck drying for 30 - 60 mins under vacuum. The product was further dried under vacuum at 40 - 50 °C for 5 - 6 hrs to obtain -200 gm of final product i.e. Crystalline Pazopanib Hydrochloride Form-SP, characterized by XRPD as per Fig-4.

If required, same procedure may be repeated once or twice to comply with stipulated impurity limits.

EXAMPLE 4: Preparation of Crystalline Pazopanib Hydrochloride (Form-SPWSolvent THF and Water 50:50 Vm 50 gm crude Pazopanib hydrochloride (HPLC purity = 98.84%; SMI = 0.454%) was charged to a 500 mL RBF. 150ml THF and 150ml purified water was then added to the reaction mixture. The reaction mass was heated under stirring up to 50 - 60 °C, for 30 min to get clear solution. Then the reaction mass was slowly cooled to 25 to 35 °C to get the precipitation of product. The reaction mass was further cooled 15 - 20°C and stirring was done for 1 -2 hrs.

Reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product.

The product cake was washed with a mixture of THF (25ml) and purified water (25ml). Then it was suck dried for 30 - 60 mins under vacuum. The product was then unloaded after drying under vacuum at 40 - 50 °C for 4 - 6 hrs to obtain Crystalline Pazopanib Hydrochloride (Form-SP).

Yield - 40 gm (80%)
HPLC purity = 99.86% (SMI - 0.08%)
Moisture content by KF = 3.70%

EXAMPLE 5: Preparation of Crystalline Pazopanib Hydrochloride (Form-SP)-Solvent Acetone and Water 50:50 v/v) 50 gm crude Pazopanib hydrochloride (HPLC purity = 98.84%; SMI = 0.454%) was charged to a 500 mL RBF. 150ml Acetone and 150ml purified water was then added to the reaction mixture. The reaction mass was heated under stirring up to 50 - 60 °C, for 30 min to get clear solution. Then the reaction mass was slowly cooled to 25 to 35 °C to get the precipitation of product. The reaction mass was further cooled 15 - 20°C and stirring was done for 1 -2 hrs. Reaction mass was then filtered on Buchner funnel under vacuum to get wet cake product. The product cake was washed with a mixture of Acetone (25ml) and purified water (25ml). Then it was suck dried for 30 - 60 mins under vacuum. The product was then unloaded after drying under vacuum at 40 - 50 °C for 4 - 6 hrs to obtain Crystalline Pazopanib Hydrochloride (Form-SP).

Yield = 41 gm (82%)
HPLC purity = 99.86% (SMI = 0.09%)
Moisture content by KF = 3.77%

Claims:

1) A process for preparing crystalline Pazopanib hydrochloride (I) comprising the steps of: a) combining 2,3-dimethyl-2H-indazol-6-amine.HCl (A) with 2,4-dichloropyrimidine (B) in the presence of solvent iso-propyl alcohol (IPA) to provide N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C);

b) converting N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (C) to N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) in the presence of a methylating agent and an alkali metal alkoxide;

c) reacting N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (D) with 5-amino-2-methylbenzenesulfonamide (E) in the presence of aqueous HC1 to provide crude Pazopanib hydrochloride (I).

e) converting the step c) product to Pazopanib hydrochloride crystalline Form-SP.

2) A process for preparing crystalline Pazopanib hydrochloride (I) according to claim 1) wherein, step a) is performed in the presence of solvent iso-propyl alcohol (IPA) in the amount between 15-25 times (v/w: mL/g) of 2,3-dimethyl-2H-indazol-6-amine.HCl (A) and in the presence of a base and an additional water soluble organic solvent selected from THF, DMF, DMA or DMSO.

3) A process for preparing crystalline Pazopanib hydrochloride (I) according to claim 1) wherein, in step b) alkali metal alkoxide is selected from potassium tert-butoxide or sodium tert-butoxide.

4) A process for preparing crystalline Pazopanib hydrochloride (I) according to claim 1) wherein, intermediates obtained in step a) or b) are optionally purified by treating with an organic solvent selected from acetone, methyl ethyl ketone or diethyl ketone.

5) A process for preparing crystalline Pazopanib hydrochloride (I) according to claim-1, wherein step d) of converting Pazopanib HC1 to crystalline Form-SP comprises the steps of-

a) Combining the crude Pazopanib hydrochloride with an organic solvent and water.

b) Heating up to about 40 - 75 °C.

c) Stirring the solution at same temperature for a time duration ranging between 15 to 90 mins.

d) Cooling the solution to a temperature below 35 °C at a rate of not exceeding 1 °C/min.

e) Isolating the crystalline Form-SP.

6) Pazopanib hydrochloride crystalline Form-SP characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 29° peaks selected from the XRPD peak set of 6.49,8.16, 10.34, 11.37, 11.74, 13.05, 17.09, 18.09, 18.49, 20.80, 23.62 ± 0.20 20° and DSC isotherm comprising at least two endothermic peaks ranging between 90 to 120°C (Peak -1) and 285 to 310°C(Peak-2)..

7) Pazopanib hydrochloride crystalline Form-SP according to claim -6, characterized by X-ray powder diffraction pattern substantially according to Fig-1, DSC isothermal pattern substantially according to Fig-2 and having water content ranging between 3.50 to 3.80 % w/w.

8) A process for preparing crystalline Pazopanib hydrochloride (I) Form-SP according to claim- 6 or 7, comprising the steps of –

a) Combining Pazopanib hydrochloride from any source with water and an organic solvent selected from C1 to C4 alcohol or water soluble cyclic ether (e.g. THF) or aliphatic lower ketone (e.g. acetone).

b) Raising the temperature up to about 40 - 75 °C.

c) Maintaining the solution under stirring at about 40 - 75 °C for a time duration ranging between 15 to 90 mins.

d) Cooling the solution to a temperature below 35 °C at a rate of not exceeding 1° C/min.

e) Isolating the crystalline Form-SP.

9) A process for preparing Pazopanib hydrochloride crystalline Form-SP according to claim 8, wherein organic solvent and water are in the ratio between 40:60 to 60:40 v/v.

10) A pharmaceutical composition comprising Pazopanib hydrochloride crystalline Form-SP according to any of the preceding claims, together with one or more pharmaceutically acceptable excipients.