WO2021116901A1

WO2021116901A1 - Forms of binimetinib and process for preparation thereof

Info

Publication number: WO2021116901A1
Application number: PCT/IB2020/061628
Authority: WO
Inventors: Venkata Raghavendra Charyulu Palle; Ramakrishna Parameshwar Bhat; Pratik Rameshchandra Patel; Narasimman KUMAR; Thilak GREGORY
Original assignee: Biocon Limited
Priority date: 2019-12-09
Filing date: 2020-12-08
Publication date: 2021-06-17

Abstract

Amorphous forms of Binimetinib and processes for the preparation thereof.

Description

FORMS OF BINIMETINIB AND PROCESS FOR PREPARATION THEREOF RELATED APPLICATION: This application claims the benefit of priority of our Indian patent application IN201941050795 filed on December 09, 2019 which is incorporated herein by reference. TECHNICAL FIELD The present invention refers to a novel amorphous form of binimetinib, a process for the preparation thereof. BACKGROUND AND PRIOR ART OF THE DISCLOSURE MEKTOVI® is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. The chemical name for Binimetinib is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N- (2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide which is having molecular weight 441.2 daltons and its structural formula is as follows,

Binimetinib was disclosed in U.S. Pat. No.7,777,050 B2. US 9,238,627 B2 discloses process for the preparation of Binimetinib, the process comprising the steps of: a) reacting a compound of Formula (I):

with a suitable base to form an intermediate; and b) reacting said intermediate with a compound of Formula (II):

to provide a compound of Formula (III):

or a hydrate thereof, wherein P1 is a protecting group; c) dissolving said compound of Formula (III) or a hydrate thereof in a suitable solvent or solvent system; and d) deprotecting said compound of Formula (III) or a hydrate thereof with a suitable deprotecting reagent, wherein P1 in each occurrence may be the same or different, and is a suitable protecting group, to provide Compound A. US 9,562,016 B2 discloses a pharmaceutical composition comprising crystallized Binimetinib and a pharmaceutically acceptable carrier or excipient. WO 2016131406 (A1) discloses crystalline form A having characteristic peaks at 20.3 ° ± 0.2 °, 28.3 ° ± 0.2 °, 11.1 ° ± 0.2 ° 2 theta and crystalline form B having characteristic peaks at 25.3 ° ± 0.2 °, 18.7 ° ± 0.2 °, and 16.8 ° ± 0.2 ° 2 theta. WO2020165565 (A1) discloses crystalline binimetinib DMSO solvate comprising peaks at about 5.8, 8.9, 14.5, 17.6, 18.8, 20.1, 23.5, and 25.8 degrees two-theta ± 0.2° 2 theta and a crystalline molecular complex of binimetinib and citric acid comprising peaks at about 7.3, 11.4, 12.3, 13.6, 14.2, 14.5, 17.9, 18.2, 20.1 , 21.8, and 24.9 degrees two- theta ± 0.2° 2 theta. An organic compound may give rise to a variety of solid forms either crystalline or amorphous having distinct physical properties. The variation in the physical properties frequently results in differences in bioavailability, stability, etc. Some polymorphic forms of drug substances suffer from the drawbacks of spontaneous conversion to other crystalline forms during storage, resulting in concomitant change, not only in the physical form and shape of the drug crystals, but also associated changes in distinct physical properties. Generally, the forms will revert to a more thermodynamically stable form, often a form with lower solubility. Such a thermodynamically stable form may sometimes result in a reduced or suboptimal bioavailability, especially for oral administration. There remains a continuing need, not only for a pure or substantially pure amorphous form of Binimetinib or its solid dispersions that are stable, but also for processes to produce Binimetinib, which are convenient to scale-up for commercial production quantities and yield both formulation and therapeutic benefits. SUMMARY OF THE INVENTION One aspect of the specification discloses Amorphous Binimetinib. Another aspect of the specification discloses a solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier. Another aspect of the specification discloses a solid dispersion, wherein the Binimetinib is in an amorphous form. Another aspect of the specification discloses a solid dispersion, wherein the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidone, cellulose derivative, colloidal silicon dioxide, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyethylene derivative, polyvinyl alcohol, or propylene glycol derivative. Another aspect of the specification discloses a solid dispersion, wherein the cellulose derivative is selected from microcrystalline cellulose, hydroxy propyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like. Another aspect of the specification discloses a process for preparing an amorphous Binimetinib comprising: a. dissolving Binimetinib in a solvent, b. removal of solvent, and c. isolating amorphous Binimetinb. Another aspect of the specification discloses, a process for preparing a solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier, comprising: a. dissolving Binimetinib in a solvent, b. adding a pharmaceutically acceptable carrier, c. removal of solvent, and d. isolating solid dispersion of Binimetinib. Another aspect of the specification discloses the process for preparation of solid dispersion comprising Binimetinib, wherein the solvent is selected from alcohol having 1- 4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. Another aspect of the specification discloses, a process for preparing Binimetinib, comprising: i) reacting a 6,7-difluoro-3H-benzoimidazole-5-carboxylic acid ester of Formula –VIII-G, wherein R is an alkyl group

with a methylating agent to obtain 6,7-difluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid ester of Formula-VII-G

ii) hydrolysing 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid ester of Formula-VII-G to 6,7-difluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid of Formula-VI

iii) reacting 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid of Formula-VI with a compound of Formula-V-G, wherein P is a protecting group

to obtain a compound of Formula-IV-G

iv) reacting a compound of Formula-IV-G with 2-Fluoro-4-Bromo Aniline of Formula-III

to obtain a compound of Formula-II-G

v) converting a compound of Formula-II-G to Binimetinib. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein R is an alkyl group having 1 to 4 carbon atoms. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein the methylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, or tetramethylammonium chloride. Another aspect of the specification discloses a process for the preparation of Binimetinib as above, wherein in hydrolysis is performed using an inorganic base selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein the protecting group P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups and silyl groups. Another aspect of the specification discloses a process for the preparation of Binimetinib, comprising: i) brominating a compound of Formula-XVIII-G to obtain a compound of Formula-II-G, wherein P is a protecting group

to obtain a compound of Formula-II

ii) converting a compound of Formula-II-G to Binimetinib. Another aspect of the specification discloses a process for the preparation of Binimetinib wherein bromination is carried out using a brominating agent selected from N-bromo succinimide or aluminium tribromide in presence of bromine or bromine in acetic acid. Another aspect of the specification discloses a process for the preparation of Binimetinib wherein the protecting group P is selected from alkyl group, alkenyl group, tertiary aryl- alkyl groups or silyl groups. DESCRIPTION OF THE CURRENT EMBODIMENTS: One aspect of the specification discloses Amorphous Binimetinib. Another aspect of the specification discloses a solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier. Another aspect of the specification discloses a solid dispersion, wherein the Binimetinib is in an amorphous form. Another aspect of the specification discloses a solid dispersion, wherein the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidone, cellulose derivative, colloidal silicon dioxide, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyethylene derivative, polyvinyl alcohol, or propylene glycol derivative. Another aspect of the specification discloses a solid dispersion, wherein the cellulose derivative is selected from microcrystalline cellulose, hydroxy propyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like. Another aspect of the specification discloses a process for preparing an amorphous Binimetinib comprising: d. dissolving Binimetinib in a solvent, e. removal of solvent, and f. isolating amorphous Binimetinb. Another aspect of the specification discloses, a process for preparing a solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier, comprising: e. dissolving Binimetinib in a solvent, f. adding a pharmaceutically acceptable carrier, g. removal of solvent, and h. isolating solid dispersion of Binimetinib. Another aspect of the specification discloses the process for preparation of solid dispersion comprising Binimetinib, wherein the solvent is selected from alcohol having 1- 4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. Another aspect of the specification discloses, a process for preparing Binimetinib, comprising: vi) reacting a 6,7-difluoro-3H-benzoimidazole-5-carboxylic acid ester of Formula –VIII-G, wherein R is an alkyl group

vii) hydrolysing 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid ester of Formula-VII-G to 6,7-difluoro-3-methyl-3H-benzoimidazole-5- carboxylic acid of Formula-VI

viii) reacting 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid of Formula-VI with a compound of Formula-V-G, wherein P is a protecting group

to obtain a compound of Formula-IV-G

ix) reacting a compound of Formula-IV-G with 2-Fluoro-4-Bromo Aniline of Formula-III

to obtain a compound of Formula-II-G

x) converting a compound of Formula-II-G to Binimetinib. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein R is an alkyl group having 1 to 4 carbon atoms. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein the methylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, or tetramethylammonium chloride. Another aspect of the specification discloses a process for the preparation of Binimetinib as above, wherein in hydrolysis is performed using an inorganic base selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide. Another aspect of the specification discloses a process for the preparation of Binimetinib, wherein the protecting group P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups and silyl groups. Another aspect of the specification discloses a process for the preparation of Binimetinib, comprising: iii) brominating a compound of Formula-XVIII-G to obtain a compound of Formula-II-G, wherein P is a protecting group

to obtain a compound of Formula-II

iv) converting a compound of Formula-II-G to Binimetinib. Another aspect of the specification discloses a process for the preparation of Binimetinib wherein bromination is carried out using a brominating agent selected from N-bromo succinimide or aluminium tribromide in presence of bromine or bromine in acetic acid. Another aspect of the specification discloses a process for the preparation of Binimetinib wherein the protecting group P is selected from alkyl group, alkenyl group, tertiary aryl- alkyl groups or silyl groups. Characterization methods: PXRD was used for characterising amorphous Binimetinib and amorphous solid dispersion of Binimetinib. The Powder X-ray diffraction is one of the most used techniques to determine different crystalline and amorphous structures. Instrumental parameters: The powder X-ray powder diffractogram (XRPD) was obtained by using the instrument XRD BRUKER D8 ADVANCE, equipped with LYNXEYE detector with 40mA current intensity and 40kV voltage. The sample was arranged on a Si-Zero Background Sample holder and analysed using the following parameters: - Scanning range (°): 3.000 to 60.000 - Step size (°): 0.03 - Scan type: Locked coupled - Scanning mode: continuous - Count time per step (s): 0.5 - Delay time (s): 0 - Divergent slit: 0.300 - Antiscatter slit: 0.300 BRIEF DESCRIPTION OF THE FIGURES In order that the disclosure may be readily understood and put into practical effect, reference will now be made to exemplary embodiments as illustrated with reference to the accompanying figures. The figures together with a detailed description below, are incorporated in and form part of the specification, and serve to further illustrate the embodiments and explain various principles and advantages, in accordance with the present disclosure wherein: Figure-1: Illustrates the XRD pattern of a solid dispersion of Binimetinib, prepared according to Example 1. Figure-2: Illustrates the XRD pattern of a solid dispersion of Binimetinib, prepared according to Example 2b. DETAILED DESCRIPTION OF THE INVENTION The embodiments of the present invention are further described using specific examples herein after. The examples are provided for better understanding of certain embodiments of the invention and not, in any manner, to limit the scope thereof. Possible modifications and equivalents apparent to those skilled in the art using the teachings of the present description and the general art in the field of the invention shall also form the part of this specification and are intended to be included within the scope of it. General Procedure: General Procedure -1: Preparation of amorphous Binimetinib To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added Binimetinib in solvent. The reaction mixture was stirred. The solvent was removed to isolate Amorphous Binimetinib. Solvent is selected from alcohol having 1-4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. General Procedure -2: Preparation of amorphous solid dispersion of Binimetinib To a glass vessel equipped with a stirrer, condenser and a thermometer probe were added Binimetinib, a pharmaceutically acceptable carrier in solvent. The reaction mixture was stirred. The solvents were removed to isolate amorphous solid dispersion of Binimetinib with a pharmaceutically acceptable carrier. Solvent is selected from alcohol having 1-4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. General Procedure -3: Preparation of Binimetinib:

R is an alkyl group having 1 to 4 carbon atoms and P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups and silyl groups. Stage-1: Preparation of Formula-XI: Formula-XII was added to a stirred solution of concentrated sulphuric acid and fuming nitric acid. The resulting slurry was poured to ice: water mixture. The product was extracted with a organic solvent and organic layer was dried and concentrated under reduced pressure to obtain Formula-XI. Stage-2: Preparation of Formula-X: Aqueous ammonia solution was added to the mixture of Formula-XI and water at 0 °C with stirring. After addition of aqueous ammonia solution, the reaction mixture was warmed to room temperature and stirred. The reaction mixture was cooled to 0 °C and acidified using concentrated Hydrochloric acid. The reaction mixture was filtered and the solid was washed with mixture of water and ether. The solid was dissolved in a solvent or mixture of solvents and the solution was concentrated under reduced pressure to obtain Formula-X. Stage-3: Preparation of Formula-IX-G: TMS diazomethane was added to the solution of Formula-X in a solvent or mixture of organic solvents under stirring. The reaction mixture was stirred at room temperature for 2 to 3 hours. After completion of reaction, the reaction mixture was concentrated. The concentrated mass was crystallised with a solvent to obtain Formula-IX-G. Stage-4: Preparation of Formula-VIII-G: Formula-IX-G, Formic acid and 20% Palladium hydroxide in carbon and Ethanol were heated to 95 °C. The reaction mixture is heated to 95 °C with stirring. After completion of reaction, the reaction mixture was cooled to room temperature and filtered through Celite and washed with Ethanol. The filtrate was concentrated under reduced pressure up to minimum volume for the product precipitation. The concentrated mass was cooled, filtered and the solid washed with chilled Ethanol to obtain Formula-VIII-G. Stage-5: Preparation of Formula-VII-G: Formula-VIII-G, an inorganic base and a methylating agent in a solvent were stirred. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-VII-G. The inorganic base used herein is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and the like. The methylating agent used herein is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, tetramethylammonium chloride and the like. Stage-6: Preparation of Formula-VI Formula-VII-G, THF, water and an alkali solution were stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with water and acidified using 1.0 M Hydrochloric acid. The product was extracted with mixture of Ethyl acetate/THF and washed with water. The organic Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-VI. The alkali solution used herein is selected from sodium hydroxide solution, potassium hydroxide solution, or lithium hydroxide solution and the like. Stage-7: Preparation of Formula-IV-G Formula-VI, Formula-V-G, HOBt, Triethylamine, EDCI and N,N-dimethylformamide were stirred at room temperature under a Nitrogen atmosphere at room temperature. After completion of the reaction, the reaction mixture was diluted with Ethyl acetate/water. The organic Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-IV-G. Stage-8: Preparation of Formula-II-G Formula-III was added the Formula-IV-G suspended in xylenes. The reaction mixture was stirred at 125 to 140 °C. After completion of the reaction, the reaction mixture was cooled to room temperature. The mass was filtered and the solids was washed with xylenes. The wet solid was dried under reduced pressure to obtain Formula-II-G. Stage-9: Preparation of Formula-Ia Formula-II-G was added into the mixture of solvent and a de-protecting agent. The reaction mixture was stirred for 30 min. The reaction mixture was heated to 50 to 55 °C and stirred for 6 to 8 hours. After completion of the reaction, the reaction mixture was cooled to 20 to 25 °C and filtered. Adjusted the pH of the mass using Aqueous Potassium hydroxide solution over a period of 120 minutes to obtain Formula-Ia which was taken to next step without isolation. De-protecting agents used herein is selected from phosphoric acid, hydrochloric acid and the like. Stage-10: Preparation of Amorphous Binimetinib Formula Ia was mixed insolvent. The reaction mixture was stirred. Amorphous Binimetinib was isolated by removal of solvent. Stage-10a: Preparation of Amorphous solid dispersion of Binimetinib Formula Ia and a pharmaceutically acceptable carrier were mixed insolvent. The reaction mixture was stirred. Amorphous Binimetinib was isolated by removal of solvent. Stage-10b: Preparation of Binimetinib salt To a solution of Formula-Ia in solvent was added an acid and stirred. After the completion of the reaction the solvent was removed to afford a Binimetinib pharmaceutically acceptable salt. Solvent is selected from alcohol having 1-4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. Acid used herein is selected form inorganic acids such as Hydrochloric acid, Nitric acid, Sulfuric acid, phosphoric acid and the like; organic acids such as citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, acetic acid, propanoic acid and the like. General Procedure -4: Preparation of Binimetinib:

R is an alkyl group having 1 to 4 carbon atoms and P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups and silyl groups. Stage-1: Preparation of Formula-XI: Formula-XII was added to a stirred solution of concentrated sulphuric acid and fuming nitric acid. The resulting slurry was poured to ice: water mixture. The product was extracted, and organic layer was dried and concentrated under reduced pressure to obtain Formula-XI. Stage-2: Preparation of Formula-X: Aqueous ammonia solution was added to the mixture of Formula-XI and water at 0 °C with stirring. After addition of addition aqueous ammonia solution, the reaction mixture was warmed to room temperature and stirred. The reaction mixture was cooled to 0 °C and acidified using concentrated Hydrochloric acid. The reaction mixture was filtered and the solid was washed with mixture of water and ether. The solid was dissolved in a solvent or mixture of solvents and the solution was concentrated under reduced pressure to obtain Formula-X. Stage-3: Preparation of Formula-IX-G: TMS diazomethane was added to the solution of Formula-X in a solvent or mixture of solvents under stirring. The reaction mixture was stirred at room temperature for 2 to 3 hours. After completion of reaction, the reaction mixture was concentrated. The concentrated mass was crystallised with a solvent to obtain Formula-IX-G. Stage-4: Preparation of Formula-XIV-G Formula-XIII was added to the mixture of Formula-IX-G and xylenes. The reaction mixture was stirred at 125 to 140 °C. After completion of the reaction, the reaction mixture was cooled to room temperature. The mass was filtered and the solids was washed with xylenes. The wet solid was dried under reduced pressure to obtain Formula- XIV-G. Stage-5: Preparation of Formula-XV-G Formula-XIV-G, Formic acid and Palladium hydroxide in carbon (0.80 equiv.) and Ethanol (16.0 vol.) were heated to 95 °C. After completion of reaction, the reaction mixture was cooled to room temperature and filtered through Celite and washed with Ethanol. The filtrate was concentrated under reduced pressure up to minimum volume for the product precipitation. The concentrate mass was cooled, filtered and the solid washed with chilled Ethanol to obtain Formula-XV-G. Stage-6: Preparation of Formula-XVI-G Formula-XV-G, an inorganic base and a methylating agent and a solvent were stirred at room temperature. After completion of the reaction, the reaction mass was diluted with Ethyl acetate and water. Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-XVI-G. Stage-7: Preparation of Formula-XVII Formula-XVI-G, THF, water and an alkali solution were stirred at room temperature. After completion of the reaction, the reaction mass was diluted with water and acidified using 1.0 M Hydrochloric acid. The product was extracted with mixture of Ethyl acetate/THF and washed with water. The layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-XVII. Stage-8: Preparation of Formula-XVIII-G Formula-XVII, Formula-V-G, HOBt, Triethylamine, EDCI and N,N- dimethylformamide were stirred at room temperature. After completion of the reaction, the reaction mass was diluted with Ethyl acetate/water. The organic Layers were separated and the organic layer was concentrated to obtain Formula-XVIII-G. Stage-9: Preparation of Formula-II-G Formula-XVIII-G solution in a solvent or a mixture of solvents were cooled to -75±2 °C under a nitrogen atmosphere. A solution of N- Bromo Succinimdein solvent or a mixture of solvents was added to the reaction mixture, followed by the addition of p- Toluene sulfonic acid. After completion of the reaction, the mass was quenched with Na₂S₂O₄ solution. The reaction mass was diluted with water and ethyl acetate. The layers were separated, and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-II-G. Stage-10: Preparation of Formula-Ia Formula-II-G was added into the mixture of a solvent and a de-protecting agent. The reaction mixture was stirred for 30 min. The reaction mixture was heated to 50 to 55 °C and stirred for 6 to 8 hours. After completion of the reaction, the reaction mixture was cooled to 20 to 25 °C and filtered. Adjusted the pH of the mass using Aqueous Potassium hydroxide solution over a period of 120 minutes to obtain Formula-Ia which was taken to next step without isolation. De-protecting agents used herein is selected from phosphoric acid, hydrochloric acid and the like. Stage-11: Preparation of Amorphous Binimetinib Formula Ia was mixed insolvent. The reaction mixture was stirred. Amorphous Binimetinib was isolated by removal of solvent. Stage-11a: Preparation of Amorphous solid dispersion of Binimetinib Formula Ia and a pharmaceutically acceptable carrier were mixed insolvent. The reaction mixture was stirred. Amorphous Binimetinib was isolated by removal of solvent. Stage-11b: Preparation of Binimetinib salt To a solution of Formula-Ia in solvent was added an acid and stirred. After the completion of the reaction the solvent was removed to afford a Binimetinib pharmaceutically acceptable salt. Solvent is selected from alcohol having 1-4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3-5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. Acid used herein is selected form inorganic acids such as Hydrochloric acid, Nitric acid, Sulfuric acid, phosphoric acid and the like; organic acids such as citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, acetic acid, propanoic acid and the like. Examples: Example 1: Preparation of amorphous solid dispersion of Binimetinib with Aerosil To a 100 mL round bottom flask were added Binimetinib (0.200 g), Aerosil (SYLOID 244 FP, 0.400 g) and N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred at 25±5 °C for 10 to 15 mins. The reaction mixture was concentrated at 70±2 °C under reduced pressure to obtain Amorphous solid dispersion of Binimetinib with Aerosil. Example 2a: Preparation of amorphous solid dispersion of Binimetinib with PVP To a 100 mL round bottom flask were added Binimetinib (2.00 g, 1.00 equiv.), PVP (Povidone K30, 4.00 g) and N,N-dimethylformamide (40.0 mL, 20.0 vol.). The reaction mixture was stirred at 25±5 °C for 30±5 mins. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure at 70±2 °C. The concentrated mass was dissolved in Ethanol (60.0 mL, 30.0 vol.) at 70±2 °C and concentrated at 70±2 °C under reduced pressure to obtain foamy solid. The foamy solid was powdered and dried at 70±2 °C under reduced pressure to obtain amorphous solid dispersion of Binimetinib with PVP. Example 2b: Preparation of amorphous solid dispersion of Binimetinib with PVP To a 250 mL round bottom flask were added Binimetinib(0.10 g), PVP (Povidone K30, 0.25 g) and THF: Water (1:1, 50.0 mL). The reaction mixture was stirred at 25±5 °C for 10 to 15 minutes. The reaction mixture was frozen at -45±5 °C followed by freeze drying for 12 to 15 h to obtain the amorphous solid dispersion of Binimetinib with PVP. Example 3: Process for the preparation of Binimetinib Scheme 1:

Stage-1: Preparation of Formula-XI: Formula-XII(1.00 equiv.) was added to a stirred solution of concentrated sulphuric acid (5.33 vol.) and fuming nitric acid (1.30 equiv.) for 3 to 5 h. The resulting slurry was poured to ice: water mixture (35.0 vol.). The product was extracted with ether. The organic layer was dried with anhydrous sodium sulphate and concentrated under reduced pressure to obtain Formula-XI. Stage-2: Preparation of Formula-X: Aqueous ammonia solution (4 equiv.) was added to the mixture of Formula-XI(1.00 equiv.) and water (5.00 vol.) at 0 °C with stirring. After addition of addition aqueous ammonia solution, the reaction mass was warmed to room temperature and the mass was maintained for 5 hours. The mass was cooled to 0 °C and acidify of the mass to using conc. Hydrochloric acid. The mass was filtered and the solid was washed with mixture of water and ether. The solid was dissolved with Methanol and Ethyl acetate and the solution was concentrated under reduced pressure to obtain Formula-X. Stage-3: Preparation of Formula-IX: TMS diazomethane (2.0 M solution in hexanes, 1.20 equiv.) was added to the solution of Formula-X (1.00 equiv.) in THF (10.0 vol.) and Methanol (3.00 vol.) under stirring. The mass was stirred at room temperature for 2 to 3 hours. After completion of reaction, the reaction mixture was concentrated. The concentrated mass was crystallised with ether to obtain Formula-IX. Stage-4: Preparation of Formula-VIII: Formula-IX (1.00 equiv.), Formic acid (5.50 equiv.) and 20% Palladium hydroxide in carbon (0.80 equiv.) and Ethanol (16.0 vol.) were heated to 95 °C. The reaction mass was acid added. The reaction mixture is heated to 95 °C with stirring. After completion of reaction, the mass was cooled to room temperature and filtered through Celite and washed with Ethanol. The filtrate was concentrated under reduced pressure up to minimum volume for the product precipitation. The concentrate mass was cooled, filtered and the solid washed with chilled Ethanol to obtain Formula-VIII. Stage-5: Preparation of Formula-VII: Formula-VIII (1.00 equiv.), potassium carbonate (1.05 equiv.) and iodomethane (1.05 equiv.) and N,N-dimethylformamide (20.0 vol.) were stirred at room temperature for 15 to 20 h. After completion of the reaction, the reaction mass was diluted with Ethyl acetate and water. Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-VII. Stage-6: Preparation of Formula-VI Formula-VII (1.00 equiv.), THF (10.0 vol.), water (10.0 vol.) and 1.0 M aq. sodium hydroxide solution (9.00 vol., 3.95 equiv.) were stirred at room temperature. After completion of the reaction, the reaction mass was diluted with water and acidified using 1.0 M Hydrochloric acid. The produce was extracted with mixture of Ethyl acetate/THF and washed with water. The organic Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-VI. Stage-7: Preparation of Formula-IV Formula-VI (1.00 equiv.), Formula-V (1.20 equiv.), HOBt (1.20 equiv.), Triethylamine (1.00 equiv.), EDCI (1.30 equiv.) and N,N-dimethylformamide (25.0 vol.) were stirred at room temperature under a Nitrogen atmosphere at room temperature for 20 to 24 hours. After completion of the reaction, the reaction mass was diluted with Ethyl acetate/water. The organic Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-IV. Stage-8: Preparation of Formula-II Formula-III (10.0 equiv.) was added the mixture of Formula-IV (1.00 equiv.) was suspended in xylenes (5.00 vol.) and was added. The reaction mixture was stirred at 125 to 140 °C. After completion of the reaction, the reaction mass was cooled to room temperature. The mass was filtered and the solid was washed with xylenes. The wet solid was dried under reduced pressure to obtain Formula-II. Stage-9: Preparation of Formula-Ia Formula-II was added in to the mixture of Acetonitrile and Phosphoric acid (85 % aqueous solution) in lot wise at 20 to 25 °C. The reaction mixture was stirred at 20 to 25± for 30 min. The reaction mixture was heated to 50 to 55 °C and maintained at the same temperature under stirring for 6 to 8 hours. After completion of the reaction, the reaction mixture was cooled to 20 to 25 °C and filtered. The filtrate was diluted with the mixture of Ethanol/ Water. Adjusted the pH of the mass using Aqueous Potassium hydroxide solution over a period of 120 minutes to obtain Formula-Ia which was taken to next step without isolation. Stage-10: Preparation of Formula-I To a 100 mL round bottom flask were added Formula Ia (0.200 g), Aerosil (SYLOID 244 FP, 0.400 g) and N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred at 25±5 °C for 10 to 15 mins. The reaction mixture was concentrated at 70±2 °C under reduced pressure to obtain the Formula I (Amorphous Binimetinib). Formula I was characterized by XRD. Alternate procedure for the Preparation of Formula-I: To a 100 mL round bottom flask were added Formula Ia (2.00 g, 1.00 equiv.), PVP (Povidone K30, 4.00 g) and N,N-dimethylformamide (40.0 mL, 20.0 vol.). The reaction mixture was stirred at 25±5 °C for 30±5 mins. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure at 70±2 °C. The concentrated mass was dissolved in Ethanol (60.0 mL, 30.0 vol.) at 70±2 °C and concentrated at 70±2 °C under reduced pressure to obtain foamy solid. The foamy solid was powdered and dried at 70±2 °C under reduced pressure to obtain Formula I (Amorphous Binimetinib). Example 4: Process for the preparation of Binimetinib Scheme 2:

Stage-1: Preparation of Formula-XI: Formula-XII(1.00 equiv.) was added to a stirred solution of concentrated sulphuric acid (5.33 vol.) and fuming nitric acid (1.30 equiv.) for 3 to 5 h. The resulting slurry was poured to ice: water mixture (35.0 vol.). The product was extracted with ether. The organic layer was dried with anhydrous sodium sulphate and concentrated under reduced pressure to obtain Formula-XI. Stage-2: Preparation of Formula-X: Aqueous ammonia solution (4 equiv.) was added to the mixture of Formula-XI(1.00 equiv.) and water (5.00 vol.) at 0 °C with stirring. After addition of addition aqueous ammonia solution, the reaction mass was warmed to room temperature and the mass was maintained for 5 hours. The mass was cooled to 0 °C and acidify of the mass to using concentrated Hydrochloric acid. The mass was filtered and the solid was washed with mixture of water and ether. The solid was dissolved with Methanol and Ethyl acetate and the solution was concentrated under reduced pressure to obtain Formula-X. Stage-3: Preparation of Formula-IX: TMS diazomethane (2.0 M solution in hexanes, 1.20 equiv.) was added to the solution of Formula-X (1.00 equiv.) in Tetrahydrofuran (10.0 vol.) and Methanol (3.00 vol.) under stirring. The mass was stirred at room temperature for 2 to 3 hours. After completion of reaction, the reaction mixture was concentrated. The concentrated mass was crystallised with ether to obtain Formula-IX. Stage-4: Preparation of Formula-XIV Formula-XIII (10.0 equiv.) was added to the mixture of Formula-IX (1.00 equiv.) and xylenes (5.00 vol.). The reaction mixture was stirred at 125 to 140 °C. After completion of the reaction, the reaction mass was cooled to room temperature. The mass was filtered and the solids was washed with xylenes. The wet solid was dried under reduced pressure to obtain Formula-XIV. Stage-5: Preparation of Formula-XV Formula-XIV (1.00 equiv.), Formic acid (5.50 equiv.) and 20% Palladium hydroxide in carbon (0.80 equiv.) and Ethanol (16.0 vol.) were heated to 95 °C. The reaction mass was acid added. The reaction mixture is heated to 95 °C with stirring. After completion of reaction, the mass was cooled to room temperature and filtered through Celite and washed with Ethanol. The filtrate was concentrated under reduced pressure up to minimum volume for the product precipitation. The concentrate mass was cooled, filtered and the solid washed with chilled Ethanol to obtain Formula-XV. Stage-6: Preparation of Formula-XVI Formula-XV (1.00 equiv.), potassium carbonate (1.05 equiv.) and iodomethane (1.05 equiv.) and N,N-dimethylformamide (20.0 vol.) were stirred at room temperature for 15 to 20 h. After completion of the reaction, the reaction mass was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-XVI. Stage-7: Preparation of Formula-XVII Formula-XVI (1.00 equiv.), THF (10.0 vol.), water (10.0 vol.) and 1.0 M aq. sodium hydroxide solution (9.00 vol., 3.95 equiv.) were stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with water and acidified using 1.0 M HCl. The produce was extracted with mixture of Ethyl acetate/THF and washed with water. The layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-XVII. Stage-8: Preparation of Formula-XVIII Formula-XVII (1.00 equiv.), Formula-V (1.20 equiv.), HOBt (1.20 equiv.), Triethylamine (1.00 equiv.), EDCI (1.30 equiv.) and N,N-dimethylformamide (25.0 vol.) were stirred at room temperature under a Nitrogen atmosphere at room temperature for 20 to 24 hours. After completion of the reaction, the reaction mixture was diluted with Ethyl acetate/water. The organic Layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and the organic layer was concentrated to obtain Formula-XVIII. Stage-9: Preparation of Formula-II Formula-XVIII (1.00 equiv.), THF (15.0 vol.) and Methanol (15.0 vol) were cooled to - 75±2 °C under a nitrogen atmosphere. A solution of NBS (1.02 equiv.) in the mixture of 1:1 THF/Methanol (2.50 vol.) was added to the mass and followed by the addition of p- Toluene sulphonic acid (1.50 equiv.) solution in Methanol (2.50 vol). There action mixture was stirred at the same temperature for 30 minutes. The reaction mixture was warmed to 0 °C and stirred for 1 h at the same temperature. The reaction mixture was further warmed to room temperature and stirred at same temperature for 15 to 17 hours. After completion of the reaction, the reaction mixture was quenched with Na2S2O4 solution. The reaction mass was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with water. The organic layer was dried with sodium sulphate and concentrated to obtain Formula-II. Stage-10: Preparation of Formula-Ia Formula-II was added in to the mixture of Acetonitrile and Phosphoric acid (85 % aqueous solution) in lot wise at 20 to 25 °C. The reaction mixture was stirred at 20 to 25± for 30 min. The reaction mixture was heated to 50 to 55 °C and maintained at the same temperature under stirring for 6 to 8 hours. After completion of the reaction, the reaction mixture was cooled to 20 to 25 °C and filtered. The filtrate was diluted with the mixture of Ethanol/ Water. Adjusted the pH of the mass using Aqueous Potassium hydroxide solution over a period of 120 minutes to obtain Formula-Iawhich was taken to next step without isolation. Stage-11: Preparation of Formula-I To a 100 mL round bottom flask were added Formula Ia (0.200 g), Aerosil (SYLOID 244 FP, 0.400 g) and N,N-dimethylformamide (10.0 mL). The reaction mixture was stirred at 25±5 °C for 10 to 15 mins. The reaction mixture was concentrated at 70±2 °C under reduced pressure to obtain the Formula I (Amorphous Binimetinib). Formula I was characterized by XRD. Alternate procedure for the Preparation of Formula-I: To a 100 mL round bottom flask were added Formula Ia (2.00 g, 1.00 equiv.), PVP (Povidone K30, 4.00 g) and N,N-dimethylformamide (40.0 mL, 20.0 vol.). The reaction mixture was stirred at 25±5 °C for 30±5 mins. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure at 70±2 °C. The concentrated mass was dissolved in Ethanol (60.0 mL, 30.0 vol.) at 70±2 °C and concentrated at 70±2 °C under reduced pressure to obtain foamy solid. The foamy solid was powdered and dried at 70±2 °C under reduced pressure to obtain Formula I (Amorphous Binimetinib).

Claims

CLAIMS: 1. Amorphous Binimetinib. 2. A solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier. 3. The solid dispersion according to claim 2, wherein the Binimetinib is in an amorphous form. 4. The solid dispersion according to claim 2, wherein the pharmaceutically acceptable carrier is selected from polyvinylpyrrolidone, cellulose derivative, colloidal silicon dioxide, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyethylene derivative, polyvinyl alcohol, or propylene glycol derivative. 5. A process for preparing anamorphous Binimetinib comprising: a. dissolving Binimetinib in a solvent, b. removal of solvent, and c. isolating amorphous Binimetinb. 6. A process for preparing a solid dispersion comprising Binimetinib and at least one pharmaceutically acceptable carrier, comprising: a. dissolving Binimetinib in a solvent, b. adding a pharmaceutically acceptable carrier, c. removal of solvent, and d. isolating solid dispersion of Binimetinib. 7. The process according to claim 5 or 6, wherein the solvent is selected from alcohol having 1-4 carbon atoms, alkyl nitrile having 1-4 carbon atoms, alkyl amide having 3- 5 carbon atoms, aliphatic ether including cyclic ether having 1-4 carbon atoms, ketone having 3-9 carbon atoms or water or mixtures thereof. 8. A process for preparing Binimetinib, comprising: i) reacting a 6,7-difluoro-3H-benzoimidazole-5-carboxylic acid ester of Formula –VIII-G, wherein R is an alkyl group

with a methylating agent to obtain6,7-difluoro-3-methyl-3H-benzoimidazole- 5-carboxylic acid ester of Formula-VII-G

ii) hydrolysing 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid ester of Formula-VII-G to 6,7-difluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid of Formula-VI

to obtain a compound of Formula-IV-G

to obtain a compound of Formula-II-G

v) converting a compound of Formula-II-G to Binimetinib. 9. The process according to claim 8, wherein R is an alkyl group having 1 to 4 carbon atoms. 10. The process according to claim 8, wherein them ethylating agent is selected from iodomethane, dimethyl sulfate, dimethyl carbonate, or tetramethylammonium chloride. 11. The process according to claim 8, wherein the hydrolysis is performed using an inorganic base selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide. 12. The process according to claim 8, wherein the protecting group P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups and silyl groups. 13. A process for preparing Binimetinib, comprising: i) brominating a compound of Formula-XVIII-G to obtain a compound of Formula-II-G, wherein P is a protecting group

to obtain a compound of Formula-II

ii) converting a compound of Formula-II-G to Binimetinib. ‘ 14. The process according to claim 13, wherein bromination is carried out using a brominating agent selected from N-bromo succinimide or aluminium tribromide in presence of bromine or bromine in acetic acid. 15. The process according to claim 13, wherein the protecting group P is selected from the group consisting of alkyl group, alkenyl group, tertiary aryl-alkyl groups or silyl groups.