PROCESS FOR PREPARATION OF CRYSTALLINE 2-CHLORO-N-(4-CHLORO-3-PYRIDIN-2-YLPHENYL)-4-METHYLSULFONYLBENZAMIDE

FIELD OF THE INVENTION

The present invention relates to a process for preparation of crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide (I). The crystalline form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-niethylsulfonylbenzamide designated as Form- SV, obtained by the process/es according to the present invention may be useful as an anti-cancer agent.

INTRODUCTION

Particular aspects of the present application relate to process for preparation of crystalline (2-chloro N(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide or Vismodegib, designated as Form-SV. The invention of the present application further relates to pharmaceutical compositions comprising crystalline (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide designated as Form-SV having anti-cancer activity. Vismodegib is approved by USFDA on Jan 2012 and is marketed under the trade name ERIVEDGE™. It is chemically mentioned in the USFDA label as (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (I). Vismodegib is a crystalline free base and is a white to tan coloured crystalline powder having pH dependent solubility. Gunzner et al in US7888364 provide the first disclosure of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (also known as Vismodegib), which also describes the process for preparing (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

Gunzner et al further in US2009281089 disclose a process for preparation of (2-chloro-Af-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide by reacting organometallic-pyridyl compound with a chloro-substituted nitrobenzene, followed by reduction and coupling reaction with mesyl and chloro substituted benzoic acid derivatives. As of now, only polymorphism details that is known for (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl) benzamide, is in USFDA label, where it has been described as a crystalline powder, but no characterization details are available for the said crystalline form. Perhaps now, polymorphism is increasingly becoming relevant to the drugs with oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles. Polymorphism is known to be peculiar phenomenon in solid materials, wherein existence of different physical forms including shape, size, and arrangement of molecules in the physical state or polymorphs of same compound are known to exist in the natural and other conditions.

A single compound, or a salt complex, may give rise to a variety of solids having distinct physical properties, which often results in substantial differences in bioavailability, stability, and other differences between production lots of formulated pharmaceutical products. Since polymorphic forms can vary in their chemical and physical properties, regulatory authorities often require that efforts be made to identify all possible polymorphic forms, e.g., hydrate or anhydrate, crystalline or amorphous, solvated or un-solvated forms, etc. of the drug substances. However, the existence, and possible numbers, of polymorphic forms for a given compound may not be predicted. In addition, there are no "standard" procedures that can be applied/ utilized to prepare different polymorphic forms of a substance. Moreover, it is often uncertain for a chemical entity-whether any polymorphism phenomenon exists in the molecule or not. Nevertheless, new forms of pharmaceutically active / useful compounds may provide an opportunity to improve the drug performance characteristics of such product. Hence, it was thought worthwhile to explore new stable and usable forms of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and processes for their preparation, which may be cost-effective and industrially amenable. Thus scientists of the present invention provide a stable crystalline form of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, designated as Form-SV and an economical process for preparation thereof.

SUMMARY OF INVENTION

Particular aspects of the present application relate to the process for the preparation crystalline (2-chloro-7vr-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, designated as Form-SV. The application further relates to processes for preparation of crystalline Form-SV, substantially free from process related impurities. The crystalline polymorphic Form-SV of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide obtained by the processes according to the present invention may be 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 compound which is crystalline form of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide, designated as Form-SV characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C. In a further aspect of the present application, it relates to 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide crystalline Form-SV characterized by X-ray powder diffraction pattern substantially according to Fig-1 and DSC isothermal pattern substantially according to Fig-2.

In yet another aspect of the present application, it relates to process for preparing crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C, comprising the steps of:

(i) Providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide in a C3-C8 ketone solvent or C1-C2 alcohol;

(ii) Heating the reaction to a temperature ranging between 45 °C to reflux temperature;

(iii) Optionally filtering the reaction mass;

(iv) Cooling the reaction mass to a temperature of about 35 °C or below at a rate of not exceeding 1° C/min;

(v) Filtering and isolating pure Crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)- 4-methylsulfonylbenzamide Form-SV.

In another aspect, crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide obtained by the process of the present invention is having HPLC purity greater than 99.5 %. In another aspect, the present invention also relates to a composition comprising crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, of which at least 95% by total weight of the 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide in the composition is Form-SV. The composition is substantially free of any other known forms of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide. In a further aspect, the present application also relates to a pharmaceutical composition comprising crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, Form-SV and at least one or more pharmaceutically acceptable excipients. Further particular aspects of the invention are detailed in the detailed description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline 2-Chloro-iV-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide designated as Form-SV.

Fig. 2 is an example of a Differential Scanning Calorimetry ("DSC") curve of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide designated as Form-SV.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to a compound which is crystalline form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, designated as Form-SV and a process for preparation thereof. In an embodiment of the present application, the 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide (I) crystalline Form-SV

(I) produced by the process of the present invention is characterized by-i. X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ±0.2° ii. DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C. In another embodiment of the present application, it provides 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide crystalline Form-SV, characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C. In a further embodiment of the present application, substantially pure 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide crystalline Form-SV exhibits an X-ray powder diffraction pattern as shown in FIG-1 and DSC isothermal pattern as shown in Fig-2. The characteristic peaks and the d-pacing values of the new crystalline Form-SV are tabulated in the Table-1.

Table-1: Characteristic XRPD Peaks of Crystalline Form-SC Minor variations in the observed 2 9° angles values may be expected based on the analyst person, the specific XRPD diffractometer employed and the sample preparation technique. Further possible variations may also be expected for the relative peak intensities, which may be largely affected by the non-uniformity of the particle size of the sample. Hence, identification of the exact crystalline form of a compound should be based primarily on observed 2 theta angles with lesser importance attributed to relative peak intensities. The 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed 2 theta angles and copper K a wavelength using the Bragg equation well known to those of having skill in the art of XRPD diffractometry science.

In view of possibility of marginal error in the assigning 2 theta angles and d-spacing, the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown form over the X-ray powder diffraction pattern of a known form. For example, one skilled in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide over FIG. 1 and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same as the X-ray powder diffraction pattern of the crystalline Form-SV of this invention. If the X-ray powder diffraction pattern is substantially the same as FIG. 1, the previously unknown crystalline form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4 methylsulfonylbenzamide can be readily and accurately identified as the crystalline Form SV of this invention.

The new crystalline form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide designated as Form-SV which is characterized by X-ray powder diffraction pattern as shown in FIG-1 and DSC isothermal pattern as shown in Fig-2 has been found to be quite stable and easy to handle and store for longer time without any measurable change in its morphology and physicochemical characteristics, while retaining its characteristics within the defined limits. This offers advantages for large scale manufacturing in terms of handling, storage, shelf life and favorable impurity profile. In another embodiment of the present application, it provides process for preparing 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide crystalline Form-SV characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (29) of 9.5, 19.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.9 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C comprising the steps of:

(i) Providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide in a C3-C8 ketone solvent or C1-C2 alcohol;

(ii) Heating the reaction to a temperature ranging between 45 °C to reflux temperature;

(iii) Optionally filtering the reaction mass;

(iv) Cooling the reaction mass to a temperature of about 35 °C or below at a rate of not exceeding 1° C/min;

(v) Filtering and isolating pure Crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)- 4-methylsulfonylbenzamide Form-SV. The individual steps of the process according to the present invention for preparing 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide crystalline Form-SV are detailed separately herein below.

Step i) comprises providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide in a C3-C8 ketone solvent or C1-C2 alcohol; 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide from any source or as synthesized by the process of the present invention is dissolved in an organic solvent selected from C3-Cg ketone solvent or Ci-C2 alcohol. Amount of organic solvent (in mL) used to dissolve 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide (in g) ranges from 10-35 times (v/w: mL/g). C3-C8 ketone solvent used in the current step may be selected from acetone, acetophenone, butanone, methyl isobutyl ketone, methyl isopropyl ketone or ethyl isopropyl ketone. C1-C2 alcohol, when used as solvent in this reaction, may be selected from methanol or ethanol.

Step ii) comprises heating the reaction to a temperature ranging between 45 °C to reflux temperature; Reaction mixture prepared in step i) is heated to a temperature ranging between 45 °C and the reflux temperature of the organic solvent used, to provide a clear solution. In one particular embodiment of the present application, wherein methanol was used as a solvent, the reaction mixture was heated to a temperature of -60 °C. After the clear solution is obtained, the reaction mass is maintained at the same raised temperature for a time duration of 40 mins to 4 hrs.

Step iii) which is optional, comprises filtering the reaction mass; The reaction mass obtained in step ii) may optionally be filtered before proceeding further. Filtration may be performed at a raised temperature-suitable to avoid crystallization, and by methods well known in the art for e.g. by use of micron filter rjaper etc. The filtrate obtained from the filtration process may be re¬heated to a temperature ranging between 45 °C to reflux temperature, in order to obtain the clear solution.

Step iv) comprises cooling the reaction mass to a temperature of about 35 °C or below at a rate of not exceeding 1° C/min Reaction mass obtained from step ii) or iii) is cooled down to 30-35 °C. This temperature condition may be maintained for the time duration of 2-4 hrs. Further cooling of the reaction mass up to temperature of 0-5 °C may also be carried out as per requirement to perform crystallization. To obtain crystalline Form-SV 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 55 °C to ~5 ° C was performed in 2 hrs.

Step v) comprises filtering and isolating pure Crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV. The reaction mass obtained from step iv) is filtered to obtain a solid product. Filtration may be performed by using conventional methods for example but not limited to use of Buchner Funnel. Wet solid product obtained after filtration is subjected to drying at a temperature ranging between 40-60 °C or above. The drying process may be performed under reduced pressure condition, which may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying process may be performed for time ranging from 2-4 hrs depending upon the physical attributes of the end product obtained i.e. Crystalline 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (Form-SV).

Process of isolating crystalline form-SV may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the crystalline form characteristics. In another embodiment of the present invention the crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV of the present invention is prepared by a process comprising the steps of:

i) Reacting 2-bromo-l-chloro-4-nitrobenzene with boronic ester to give compound of Formula (B); 2-bromo-l-chloro-4-nitrobenzene (A) is reacted with boronic ester to give compound of Formula (B).

(ii) Combining compound of Formula (B) with bromo-pyridine followed by reduction of the nitro compound (D) to obtain compound of Formula (E); Boronated compound of Formula (B) is reacted with 2- bromo-pyridine to yield 2-(2-chloro-5-nitrophenyl)pyridine (D). Nitro compound (D) is then reduced by methods known in prior art to 4-chloro-3-(pyridin-2-yl)aniline (E).

(iii) Reacting the compound of Formula (E) with 2-chloro-4-(methylsulfonyl) benzoic acid of Formula (F) in the presence of a coupling reagent, organic base and an organic solvent to yield 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide of Formula (i); The coupling agent used in this reaction may be selected from Ethylchloroformate, 2-Chloro-4,6-dimethoxy-l,3,5-traizine (CDMT), l,l'-carbonyldiimidazole (CDI) or N,N-dicyclohexyl carbbdiimide (DCC). Organic base used in this reaction may be selected from triethylamine, N-methyl morpholine or 4-dimethylaminopyridine (DMAP) and organic solvent may be selected from a chlorinated hydrocarbon like DCM, cyclic ether like THF or an organic nitrile like acetonitrile.

(iv) Optionally purifying the 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide obtained in step (iii) by acid-base treatment; In one of the embodiment acid-base treatment for purification of crude 2-Chloro-JV-(4-chloro- 3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide may be performed by using hydrochloric acid and sodium hydroxide.

(v) Providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide obtained in step (iii) or (iv) in a C3-C8 ketone solvent or C1-C2 alcohol; 2-Chloro-J/V-(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide from any source or as synthesized by the process of the present invention is dissolved in an organic solvent selected from C3-C8 ketone solvent or C1-C2 alcohol. Amount of organic solvent (in mL) used to dissolve 2-Chloro-./V-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide (in g) ranges from 10-35 times (v/w: mL/g). C3-C8 ketone solvent used in the current step may be selected from acetone, acetophenone, butanone, methyl isobutyl ketone, methyl isopropyl ketone or ethyl isopropyl ketone. C1-C2 alcohol, when used as solvent in this reaction, may be selected from methanol or ethanol. (vi) Processing the solution obtained in step (v); The solution obtained in step (v) is heated to a temperature ranging between 45 °C and the reflux temperature of the organic solvent used. The reaction mixture is then gradually cooled to a temperature below 35 °C, to yield a precipitate.

(vi) Isolating pure crystalline 2-Chloro-JV-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV. The solid material obtained in step (vi) is filtered and dried to afford pure crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV. Any 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide material i.e. its crystalline form or any of its less stable form or impure/pure form obtained from any source or by any of the processes as mentioned herein or already known in the prior art may be utilized to result directly into the crystalline Form-SV of the present invention, by performing the process mentioned herein. The process related impurities that appear in the impurity profile of the 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide may be substantially removed by the process of the present invention resulting in the formation pure crystalline Form-SV. The merit of the process according to the present invention resides in that - product obtained after drying is directly obtained as crystalline Form-SV. Said material is found to be adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Substantially pure crystalline Form-SV obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w. Melting range of the crystalline Form-SV of the present invention ranges from 175-180 °C. The crystalline form-SV of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline form-SV were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Jade instrument. Illustrative examples of analytical data for the crystalline form-SV obtained in the examples are set forth in the Figs. 1-2. In a further embodiment according to the specification, the invention also relates to a composition containing crystalline Form-SV of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide of which at least 95%, by total weight of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in the composition, is the Form-SV. In yet another embodiment of the invention, the composition may be substantially free of any other forms of 2-chloro-A'-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

The crystalline form-SV of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin. In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with crystalline Form-SV of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, while retaining the crystalline nature of the premix. 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 of 2-chloro-N(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (Form-SV) of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like. Pharmaceutically acceptable excipients used in the compositions of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide crystalline form-SV, 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.

EXAMPLE

Example-01: Process for preparation of crystalline 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (Form-SV) 0.5 gm 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide was charged to a 100 ml RBF. Further 7 ml acetone was added to the RBF and temperature was raised to -55 °C to get clear solution. Same temperature was maintained for -50 mins. The solution was then filtered through micron filter paper at same temperature. Filtrate was then charged to 100 ml RBF and solution was heated to a temperature of about 50 °C to get clear solution. Solution was maintained at same temperature for -45 mins. Solution was gradually cooled to -30 °C. Gradually temperature was further lowered to 0-5 °C, and solution was maintained at this temperature for ~ 2.5 hrs. The precipitated solid was filtered on Buchner funnel to get the wet product. The wet product was dried under vacuum at -45 °C for 3 hrs and unloaded to afford 0.30 gm crystalline 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide Form-SV having the XRPD diffractogram and DSC isotherm as shown in Figs. 1 and 2 resp. Yield: 0.30 gm, HPLC purity: 99.64%

Example-02: Process for preparation of crystalline 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (Form-SV) 1.0 gm 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide was charged to a 100 ml RBF. Further 30 ml methanol was added to the RBF and temperature was raised to -60 °C. Same temperature was maintained for 3 hours. Solution was gradually cooled to -25 °C. Solution was maintained at this temperature for - 2 hrs. The precipitated solid was filtered on Buchner funnel to get the wet product. The wet product was dried under vacuum at -45 °C for 3 hrs and unloaded to afford 0.7 gm crystalline 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide Form-SV having the XRPD diffractogram and DSC isotherm similar to the figures shown in Figs. 1 and 2 resp. Yield: 0.7 gm, HPLC purity: 99.66% While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

We Claim:

1) A compound which is designated as crystalline Form-SV of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide(I), which comprises at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2°.

2) Crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, according to claim 1, further characterized by DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C.

3) Crystalline 2-Chloro-N(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C.

4) Crystalline 2-Chloro-N(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, according to any of claim 1 to 3, characterized by X-ray powder diffraction pattern substantially according to Fig-1 and DSC isothermal pattern substantially according to Fig-2.

5) A process for preparing crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, characterized by X-ray powder diffraction pattern comprising at least five characteristic X-ray diffraction peaks at angles of refraction (20) of 9.5, 10.7, 12.2, 15.8, 16.7, 17.4, 21.4, 24.0 and 26.0 ± 0.2° and DSC isotherm comprising at least one endothermic peak ranging between 165 to 185 °C, comprising the steps of:

(i) Providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide in a C3-C8 ketone solvent or C1-C2 alcohol;

(ii) Heating the reaction to a temperature ranging between 45 °C to reflux temperature;

(iii) Optionally filtering the reaction mass;

(iv) Cooling the reaction mass to a temperature of about 35 °C or below at a rate of not exceeding 1 ° C/min;

(v) Filtering and isolating pure Crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)- 4-methylsulfonylbenzamide Form-SV.

6) A process for preparing crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, according to claim 5, wherein C3-C8 ketone solvent is selected from acetone, acetophenone, butanone, methyl isobutyl ketone, methyl isopropyl ketone or ethyl isopropyl ketone and C1-C2 alcohol is selected from methanol or ethanol.

7) A process for preparing crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV, characterized according to claim 1 and 2, comprising the steps of:

i) Reacting 2-bromo-l-chloro-4-nitrobenzene with boronic ester to give compound of Formula (B);

(ii) Combining compound of Formula (B) with bromo-pyridine followed by reduction of the nitro compound (D) to obtain compound of Formula (E);

(iii) Reacting the compound of Formula (E) with 2-chloro-4-(methylsulfonyl) benzoic acid of Formula (F) in the presence of a coupling reagent, organic base and an organic solvent to yield 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide of Formula (I);

(iv) Optionally purifying the 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide obtained in step (iii) by acid-base treatment;

(v) Providing a solution of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide obtained in step (iii) or (iv) in a C3-C8 ketone solvent or C1-C2 alcohol;

(vi) Processing the solution obtained in step (v);

(vi) Isolating pure crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide Form-SV.

8) A process for preparing crystalline 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide Form-SV, according to claim-7, wherein in step (iii):

a) the coupling agent used is selected from Ethylchloroformate, 2-Chloro-4,6-dimethoxy- 1,3,5-traizine (CDMT), l,l'-carbonyldiimidazole (CDI) or N,N-dicyclohexyl carbodiimide (DCC);

b) organic base is selected from triethylamine, N-methyl morpholine or 4- dimethylaminopyridine (DMAP);

c) organic solvent is selected from a chlorinated hydrocarbon, cyclic ether or an organic nitrile.

9) Crystalline 2-Chloro-iV-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide or a salt thereof having HPLC purity greater than 99.5 %.

10) A pharmaceutical composition comprising crystalline 2-Chloro-iV-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide Form-SV or a salt thereof, according to any of the preceding claims, together with one or more pharmaceutically acceptable excipients.