"NOVEL POLYMORPHS OF VEMURAFENIB, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION THEREOF"

PRIORITY This application claims the benefit under Indian Complete Application No. 6890/CHE/2015 filed on 11 Dec, 2015 entitled "Novel polymorphs of vemurafenib, process for its preparation and pharmaceutical composition thereof, the contents of each of which are incorporated by reference herein. FIELD OF THE INVENTION

The present invention generally relates to novel polymorphs of Vemurafenib, process for its preparation and pharmaceutical composition containing the same. BACKGROUND OF THE INVENTION

Vemurafenib, also known as propane- 1 -sulfonic acid {3-[5-(4-chlorophenyl)-lH- pyrrolo [2,3-b]pyridine-3-carbonyl]-2,4difluoro-phenyl}-amide, is represented by the following structure of Formula I:

Formula I

Vemurafenib is marketed by Hoffmann La Roche under the trade name ZELBORAF and indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF ^V600E mutation as detected by an FDA-approved test. Vemurafenib tablets contain 240mg of vemurafenib as a co-precipitate of vemurafenib and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

U.S. Patent No. 7,504,509 ("the '509 patent"), 7,863,288 ("the '288 patent") and 8,143,271 ("the '271 patent") discloses a variety of pyrrolo-pyridine and their derivatives such as vemurafenib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. PCT Publication No. WO 2010/114928 ("the '928 publication) discloses crystalline Form 1 and Form 2 of vemurafenib and its characterization data by XRD, DSC and TGA. The '928 publication also discloses vemurafenib mesylate, tosylate, maleate, oxalate, dichloroacetate salts, as well as solid dispersion that include vemurafenib and a ionic polymer such as hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, hydroxypropyl methyl cellulose phthalate and methacrylic acid copolymer in a ratio of vemurafenib and the ionic polymer of about t 3:7 by weight.

PCT Publication No. WO 2010/129570 ("the '570 publication) discloses non- crystalline complexes of vemurafenib L-arginine and L-lysine salts.

PCT Publication No. WO 2011/057974 ("the '974 publication) discloses process for preparation of solid dispersion containing amorphous Form of vemurafenib and HPMCAS. The '974 publication describes that the amorphous form of vemurafenib has improved solubility in water as compared to the crystalline Forms, but is unstable as it has tendency to crystallize.

PCT Publication No. WO 2012/161776 ("the '776 publication) discloses solid Forms of vemurafenib solvates such as Form III (acetonitrile solvate), Form IV (THF 0.75 solvate), Form V (Dioxane mono solvate), Form VI (DMF mono solvate), Form VII (THF hemi solvate), Form IX (Acetone hemi solvate), Form X (Pyridine mono solvate), Form XI (2-methyl pyridine mono solvate), Form XII (Diisopropylamine mono solvate), Form XIII (Morpholine mono solvate), Form XIV (DMSO mono solvate), Form XV (DMSO mono solvate); crystalline form such as Form VIII, Form XVI and molecularly dispersed amorphous forms of vemurafenib such as Form XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI. The '776 publication also discloses vemurafenib salts such as sulfuric acid salt, hydrobromic acid salt and hydrochloric acid salt. The solid Forms reported in the '776 publication are characterized by XRD, DSC and TGA.

PCT Publication No. WO 2014/008270 ("the '270 publication) discloses crystalline vemurafenib tetrahydrofuran solvate Form Tl, salts of vemurafenib such as choline salt Form El and esylate salt Form CI, its characterization data by XRD, DSC and TGA and its process for preparation thereof.

PCT Publication No. WO 2015/078424("the '424 publication) discloses crystalline Form A and Form B of Vemurafenib, its characterization data by XRD, DSC and TGA and its process for preparation thereof. According to USFDA and EMEA review report, vemurafenib exists in several polymorphic forms and solvates, of which crystalline Form II is thermodynamically the most stable. Even though the Form II is thermodynamically most stable but it has low bioavailability (BC Class IV drug) as its solubility in water is very low (<0.0001 mg/ml) and it is not appreciably soluble in many common organic solvents either. To overcome the difficulties associated with the crystalline Form II, another formulation was developed with amorphous form. The amorphous form was found to be more soluble and bioavailable than the crystalline form and it was subsequently processed with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and was used for the commercial tablet. However, as per the '974 publication amorphous form of vemurafenib is unstable as it has tendency to crystallize.

Based on the drawbacks mentioned above, there is a vital need to discover novel polymorphic forms of vemurafenib, which can be overcome the stability, dissolution, and formulation and bioavailability problems associated in the art.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC), thermal gravimetric analysis (TGA) and Infrared spectrometry (IR).

The discovery of new polymorphic forms of a pharmaceutically useful compound, like vemurafenib, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product like solubility and bioavailability. It also adds to the material that a formulation scientist has available for designing, for example, a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic Forms of the vemurafenib have now been discovered and have been designated as crystalline Form-Ll, Form-L2 and Form-L3.

It is another objective to provide pharmaceutical composition of novel polymorphic forms of vemurafenib prepared by the processes of the present invention.

SUMMARY OF THE INVENTION:

The present invention provides novel crystalline forms of vemurafenib in substantially pure form, processes for preparation thereof, and pharmaceutical composition comprising one or more of the novel polymorphic Forms of vemurafenib.

In accordance with one embodiment, the present invention provides novel crystalline forms of vemurafenib in substantially pure form; wherein the crystalline forms have been designated as Form-Ll, Form-L2 and Form-L3.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-Ll. In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-Ll characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-Ll characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-Ll characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1 ; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3 and any combination thereof.

In accordance with another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-Ll, comprising:

a) suspending vemurafenib in a mixture of ethanol and water, b) treating step a) suspension with a base at a temperature of about 40°C to about reflux temperature,

c) cooling the solution to less than about 30°C,

d) optionally adding a suitable alkali metal halide to step b) solution,

e) adjusting pH of step c) solution to less than 8 with a suitable acid, and f) isolating the vemurafenib Form-Ll.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L2. In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L2 characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L2 characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 6.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L2 characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 6 and any combination thereof.

In accordance with another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-L2, the process comprising: drying vemurafenib Form-Ll at a temperature of about 35°C to about 60°C, wherein the vemurafenib Form-Ll characterized by an XRPD pattern substantially in accordance with Fig. 1.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L3.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L3 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7. In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L3 characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L3 characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 9.

In accordance with another embodiment, the present invention provides crystalline vemurafenib Form-L3 characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 9 and any combination thereof.

In accordance with another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-L3, the process comprising: drying vemurafenib Form-Ll at about 60°C to about 80°C, wherein the vemurafenib Form- Ll characterized by an XRPD pattern substantially in accordance with Fig. 1.

In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising novel crystalline forms of vemurafenib and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of Vemurafenib Form-Ll.

Figure 2 is the characteristic differential scanning calorimetric (DSC) thermogram of Vemurafenib Form-Ll. Figure 3 is the characteristic thermo gravimetric analysis (TGA) of Vemurafenib Form-Ll.

Figure 4 is the characteristic powder X-ray diffraction (PXRD) pattern of Vemurafenib Form-L2. Figure 5 is the characteristic differential scanning calorimetric (DSC) thermogram Vemurafenib Form-L2.

Figure 6 is the characteristic thermo gravimetric analysis (TGA) of Vemurafenib Form-L2.

Figure 7 is the characteristic powder X-ray diffraction (PXRD) pattern of Vemurafenib Form-L3.

Figure 8 is the characteristic differential scanning calorimetric (DSC) thermogram of Vemurafenib Form-L3.

Figure 9 is the characteristic thermo gravimetric analysis (TGA) of Vemurafenib Form-L3. DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides novel polymorphic Forms of Vemurafenib, processes for preparation thereof, and pharmaceutical compositions comprising one or more of such polymorphic Forms.

The polymorphic forms of vemurafenib of the present invention obtained by process of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) curves and thermo gravimetric analysis (TGA).

The X-Ray powder diffraction can be measured by an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3- 45°2Θ; step width=0.020°; and scan speed=5°C/minute.

All DSC data reported herein were analyzed in hermitically sealed aluminium pan, with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute with an Indium standard.

All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of about 30°C to about 250°C. In accordance with one embodiment, the present invention provides novel crystalline forms of vemurafenib in substantially pure form; wherein the crystalline forms have been designated as Form-Ll, Form-L2 and Form-L3.

In another embodiment, the present invention provides crystalline vemurafenib Form- LI.

In another embodiment, the crystalline vemurafenib Form-Ll can be an ethanol solvate. In another embodiment, the present invention provides crystalline vemurafenib Form- Ll characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides crystalline vemurafenib Form- LI, characterized by one or more X-Ray diffraction (XRD) peaks at about 4.7, 8.5, 9.5, 9.9, 11.0, 11.6, 12.6, 13.0, 14.1, 15.1, 15.9, 16.6, 17.3, 17.8, 18.1, 18.6, 19.8, 20.7, 21.1, 21.5, 22.5, 23.8, 24.4, 25.5, 26.2, 26.6, 28.2, 28.7, 30.4, 31.2 and 33.8 ± 0.2° 2Θ. In another embodiment, the present invention provides crystalline vemurafenib Form- Ll characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2.

In another embodiment, the present invention provides crystalline vemurafenib Form- LI characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 3.

In another embodiment, the present invention provides crystalline vemurafenib Form- Ll characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 3 and any combination thereof.

In another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-Ll, comprising:

a) suspending vemurafenib in a mixture of ethanol and water,

b) treating step a) suspension with a base at a temperature of about 40°C to about reflux temperature,

c) cooling the solution to less than about 30°C,

d) optionally adding a suitable alkali metal halide to step c) solution, e) adjusting pH of step c) solution to less than 8 with a suitable acid, and f) isolating the vemurafenib Form-Ll.

The starting material vemurafenib is known in the art and can be prepared by any known method. The vemurafenib in the suspension may be any crystalline or other form of vemurafenib, including various solvates and hydrates, as long as polymorph Form-Ll of vemurafenib is produced during the process of the invention or vemurafenib obtaining an existing suspension from a previous processing step.

The step a) process involves providing a suspension of vemurafenib in a mixture of ethanol and water at a temperature of about 25°C to about reflux temperature; preferably at about 25°C to 35°C.

In another embodiment, mixture of ethanol to water used in the ratio of 1 : 1 to about 5: 1; preferably 1: 1 to about 3: 1.

The step b) process involves treating the step a) suspension with a base and heating to a temperature of about 40°C to about reflux temperature to obtain a clear solution; preferably at about 45 °C to 60°C. The base used herein step b) includes, but are not limited to ammonia, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; organic bases such as triethyl amine, diisopropyl ethyl amine and the like; preferably sodium hydroxide.

The step c) process involves cooling the obtained clear solution from step b) to a temperature of about less than 30°C. Then suitable alkali metal halide may be optionally added in to the step c) solution. The alkali metal halide includes, but is not limited to sodium chloride, potassium chloride, calcium chloride and the like; preferably sodium chloride.

Then the vemurafenib form LI can be precipitated by adding a suitable acid to the step c) or d) solution at a temperature of less than 30°C. The suitable acid can be selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, formic acid and the like; preferably hydrochloric acid.

The resultant crystalline vemurafenib form LI can be isolated by conventional techniques known in the art for example filtration. Typically, if stirring is involved, the temperature during stirring can be less than 10°C. The resultant product may optionally be further dried at suitable temperatures i.e. about 25°C to about 45°C for a period of 5 to 45 hours; preferably at about 25°C to 35°C for a period of 10 to 40 hours.

In another embodiment, the present invention provides crystalline vemurafenib Form- L2.

In another embodiment, the present invention provides crystalline vemurafenib Form- L2 characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4. In another embodiment, the present invention provides crystalline vemurafenib form- L2, characterized by one or more powder X-Ray diffraction (PXRD) peaks at about 4.7, 8.5, 9.5, 9.9, 11.0, 11.6, 12.6, 13.0, 14.1, 15.1, 15.9, 16.6, 17.3, 17.8, 18.1, 18.6, 19.8, 20.7, 21.1, 21.5, 22.5, 23.8, 24.4, 25.5, 26.2, 26.6, 28.2, 28.7,30.4, 31.2 and 33.8 ± 0.2° 2Θ.

In another embodiment, the present invention provides crystalline vemurafenib Form- L2 characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5. In another embodiment, the present invention provides crystalline vemurafenib Form- L2 characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 6.

In another embodiment, the present invention provides crystalline vemurafenib Form- L2 characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 4; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 6 and any combination thereof. In another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-L2, the process comprising: drying vemurafenib Form- Ll at a temperature of about 35°C to about 60°C, wherein the vemurafenib Form-Ll characterized by an XRPD pattern substantially in accordance with Fig. 1. Vemurafenib Form-L2 can be prepared by drying the vemurafenib form LI obtained by the process described as above. Preferably the drying is carried out at a temperature of about 50°C for a period of about 4 hours to about 30 hours under vacuum; preferably at about 40°C to 45°C for a period of about 8 to 24 hours. In another embodiment, the present invention provides crystalline vemurafenib Form- L3.

In another embodiment, the present invention provides crystalline vemurafenib Form- L3 characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7.

In another embodiment, the present invention provides crystalline vemurafenib Form- L3, characterized by one or more powder X-Ray diffraction (PXRD) peaks at about 4.6, 9.3, 10.8, 12.3, 14.0, 15.2, 15.9, 16.6, 17.2, 18.4, 18.8, 19.8, 21.0, 21.5, 22.1, 23.7, 23.9, 25.9, 26.6, 28.5, 29.0, 31.4 and 32.3± 0.2° 2Θ.

In another embodiment, the present invention provides crystalline vemurafenib Form- L3 characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8.

In another embodiment, the present invention provides crystalline vemurafenib Form- L3 characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure 9. In another embodiment, the present invention provides crystalline vemurafenib Form- L3 characterized by powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7; a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8; a thermo gravimetric analysis (TGA) substantially in accordance with Figure 9 and any combination thereof.

In another embodiment, the present invention provides a process for preparing crystalline vemurafenib Form-L3, the process comprising: drying vemurafenib Form- Ll at about 60°C to about 80°C, wherein the vemurafenib Form-Ll characterized by an XRPD pattern substantially in accordance with Fig. 1.

Vemurafenib Form-L3 can be prepared by drying the vemurafenib Form-Ll obtained by the process described as above. Preferably the drying is carried out at a temperature of about 70°C for a period of about 2 hours to about 30 hours under vacuum; preferably at about 60°C to 65°C for a period of about 5 to 25 hours.

In another embodiment, the present invention provides novel polymorphic forms of Vemurafenib, having a chemical purity of 96% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more. In another embodiment, the present invention provides novel polymorphic forms of Vemurafenib, wherein the polymorphic forms having less than 5% by weight of any other polymorphic forms including amorphous form, preferably less than 2% by weight, more preferably less than 1% by weight, still more preferably less than 0.5% by weight.

The novel polymorphic forms of Vemurafenib such as Form LI, Form L2 and Form L3 described above are believed to be stable under ambient conditions; further novel polymorphic Form LI, Form L2 and Form L3 of Vemurafenib described above having higher dissolution rate compared to known forms of vemurafenib.

Other embodiments of the invention include composition containing one or more polymorphic forms of Vemurafenib such as Form LI, Form L2 and Form L3 described above, such as pharmaceutical dosage forms. Such pharmaceutical dosage forms may include one or more excipients, including, without limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents, and other conventional excipients and additives. The compositions of the invention can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art. These additional formulation additives and agents will often be biologically inactive and can be administered to humans without causing deleterious side effects or interactions. In another embodiment, the present invention provides a pharmaceutical composition comprising novel polymorphic forms of vemurafenib prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way. EXAMPLE 1:

Preparation of Form-Ll of Vemurafenib

To a 1000 ml round bottom flask fitted with a mechanical stirrer, thermometer was suspended vemurafenib (20 gms), ethanol and water (1 : 1, 500 ml) at 25°C to 30°C. To the reaction mass 20% aqueous sodium hydroxide (13 ml) was added and reaction mass heated to 55°C to obtain clear solution. Cooled the reaction mass temperature to 25°C to 30°C and was added sodium chloride (8.5 gms) and stirred to obtain clear solution. Cooled the reaction mass temperature to 0°C to 5°C and adjusted pH of the solution with diluted HC1 to 7-8 with vigorous stirring and stirred for 45 min at 0°C to 5°C. To the reaction mass cold water (250 ml) was added and stirred for 15 min at 0°C to 5°C. The solid was filtered and washed with ethanol and water (1: 1, 250 ml) to obtain 26.8 gms of wet material. The 1.5 gms of wet product was dried at about 25°C to about 30°C for 12 hr to 36 hrs under vacuum to yield Vemurafenib Form-Ll (0.93 gms). HPLC purity: 99.9%; The XRPD is set forth in Figure-1; The DSC is set forth in Figure-2; The TGA is set forth in Figure-3.

EXAMPLE 2:

Preparation of Form-L2 of Vemurafenib

About 1.5 gms of wet material obtained in example- 1 was dried under vacuum at 25 °C to 30°C for 2 hr and then dried under vacuum at 40°C for 8 hr to 24 hr to yield Vemurafenib Form-L2 (0.9 gms). HPLC purity: 99.8%; The XRPD is set forth in Figure-4; The DSC is set forth in Figure-5; The TGA is set forth in Figure-6.

EXAMPLE 3:

Preparation of Form-L3 of Vemurafenib To a 50 ml round bottom flask fitted with a mechanical stirrer, thermometer was suspended vemurafenib (400 mg), ethanol and water (1 : 1, 10 ml) at 25°C to 30°C. To the reaction mass 20% aqueous sodium hydroxide (0.4 ml) was added and reaction mass stirred at 25°C to 30°C. Cooled the reaction mass temperature to 0°C to 5°C and adjusted pH of the solution with diluted HC1 to 7-8 and stirred for 1 hr at 0°C to 5°C. The solid was filtered and was dried at about 60°C to about 65°C under vacuum to yield Vemurafenib Form-L3 (325 mg). HPLC purity: 99.8%; The XRPD is set forth in Figure-7; The DSC is set forth in Figure-8; The TGA is set forth in Figure-9.

EXAMPLE 4:

Preparation of Form-L3 of Vemurafenib

To a 500 ml round bottom flask fitted with a mechanical stirrer, thermometer was suspended vemurafenib (8.5 gms), ethanol and water (2: 1, 213 ml) at 25°C to 30°C. To the reaction mass 20% aqueous sodium hydroxide (5.5 ml) was added and reaction mass heated to 55°C for complete dissolution. Then cooled the reaction mass temperature to 0°C to 5°C and adjusted pH of the solution with diluted HCl (3.3%) to 7-8 and stirred for 45 min at 0°C to 5°C. To the reaction mass chilled water (106 ml) was added and stirred for 15 min at 0° to 5°C. The solid was filtered and washed with 1: 1 mixture of ethanol: water (85 ml) and dried at about 60 °C under vacuum for 24 hrs to yield Vemurafenib Form-L3 (7.8 gms). HPLC purity: 99.72%

EXAMPLE 5:

Preparation of Form-L3 of Vemurafenib

To a 250 ml round bottom flask fitted with a mechanical stirrer, thermometer was suspended vemurafenib (3.5 gms), ethanol and water (2: 1, 87 ml) at 25°C to 30°C. To the reaction mass 20% aqueous sodium hydroxide (2.7 ml) was added for complete dissolution. Then cooled the reaction mass temperature to 0°C to 5°C and adjusted pH of the solution with diluted HCl (3.3%) to 7-8 and stirred for 45 min at 0°C to 5°C. To the reaction mass chilled water (44 ml) was added and stirred for 15 min at 0° to 5°C. The solid was filtered and washed with 1: 1 mixture of ethanol: water (35 ml) and dried at about 60°C under vacuum for 24 hrs to yield Vemurafenib Form-L3 (3.4 gms). HPLC purity: 99.7%

EXAMPLE 6:

Preparation of Form-L3 of Vemurafenib To a 1000 ml round bottom flask fitted with a mechanical stirrer, thermometer was suspended vemurafenib (10 gms), ethanol and water (3: 1, 267 ml) at 25°C to 30°C. To the reaction mass 20% aqueous sodium hydroxide (6.5 ml) was added and reaction mass was heated to 55°C for complete dissolution. Then cooled the reaction mass temperature to 25 °C to 30°C and was added sodium chloride (4.3 gms) and stirred for clear solution. Cooled the reaction mass temperature to 0°C to 5°C and adjusted pH of the solution with diluted HCl (3.3%) to 7-8 and stirred for 45 min at 0°C to 5°C. To the reaction mass chilled water (125 ml) was added and stirred for 15 min at 0° to 5°C. The solid was filtered and washed with 1: 1 mixture of ethanol: water (100 ml) and dried at about 60°C under vacuum for 24 hrs to yield Vemurafenib Form-L3 (4.8 gms). HPLC purity: 99.71 %

While the invention has been described with reference to above detailed description and the preferred examples, it is not intended to be limited thereto. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.