AMORPHOUS 2-CHLORO-N-(4-CHLORO-3-(PYRIDIN-2-YL)PHENYL)-4-(METHYLSULFONYL)BENZAMIDE

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

FIELD OF THE INVENTION

The present invention relates to amorphous form of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide (I) or its pharmaceutically active salts,

and process for preparation thereof.

The invention further relates to pharmaceutical compositions comprising amorphous form of (2-chloro-A'-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide having anti-cancer activity.

INTRODUCTION

Particular aspects of the present application relate to amorphous form of (2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide or Vismodegib and its process for preparation. The invention of the present application further relates to pharmaceutical compositions comprising amorphous form of (2-chloro-Af-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 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 provides the first disclosure of (2-chloro-A^-(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-N-(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 as a crystalline powder. Perhaps recently, polymorphism is increasingly becoming relevant to the 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 an amorphous form of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and a process for preparation thereof.

SUMMARY OF INVENTION

Particular aspects of the present specification relate to the amorphous form of (2- chloro-N-(4-chloro-3 -(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide or its pharmaceutically active salts, and process for preparation thereof.

In one aspect according to the present invention, the present invention provides an amorphous form of (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide or Vismodegib (I):

In another aspect, the present invention provides a process of preparation of amorphous (2-chloro-N (4-chloro-3 -(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide characterized by XRPD pattern as per Fig-1 and DSC pattern as per Fig-2 comprising the steps of-

a) Providing a solution of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide in organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Filtering the reaction mixture and subjecting the filtrate to distillation to yield a residue;

d) Optionally repeating the steps a) to c);

e) Drying the material obtained from step c) or d) to obtain amorphous form of 2-chloro-Ar-(4-chloro-3-(pyridin-2-yI)phenyI)-4-(methylsulfonyl)benzamide.

In another aspect, amorphous 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 %.

In a further aspect, the present invention also relates to a composition comprising amorphous 2-Chloro-A^-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide of which at least 95%, by total weight of 2-Chloro-A/-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide in the composition, is the amorphous form. The composition is substantially free of any other forms of 2-Chloro-Ar-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfony lbenzamide.

In a further aspect, the present application also relates to a pharmaceutical composition comprising amorphous 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4- methylsulfonylbenzamide of the present application and at least one or more pharmaceutically acceptable excipients.

Further particular aspects of the invention are detailed in the 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 2-Chloro-N-(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide amorphous form.

Fig. 2 is an example of a Differential Scanning Calorimetry ("DSC") curve of 2-Chloro-iV-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide amorphous form.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention relate to amorphous form of 2-Chloro-./V-(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide or its pharmaceutically active salts and a process for preparation thereof.

In one embodiment of the present application, it provides amorphous form of (2-chloro-jV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide or Vismodegib (I):

Substantially pure amorphous form of 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide exhibits an X-ray powder diffraction pattern substantially as shown in FIG. 1 indicating a solid form that lacks the long-range order (a characteristic of crystal) and having no pattern or structure.

The amorphous form of 2-Chloro-./V-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide produced by the inventors of the present application is characterized by-

1. XRPD pattern similar to as shown in FIG. 1

2. DSC isotherm similar to as shown in FIG. 2 or comprising at least one exothermic peak ranging between 135 to 160 °C and at least one endothermic peak ranging between:

a. Peak-1: Between 80 to 100 °C

b. Peak-2: Between 170 to 190 °C

In another embodiment of the present application, it provides a process for preparation of amorphous 2-Chloro-Ar-(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, comprising the steps of-

a) Providing a solution of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide in organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Filtering the reaction mixture and subjecting the filtrate to distillation to yield a residue;

d) Optionally repeating the steps a) to c);

e) Drying the material obtained from step c) or d) to obtain amorphous form of 2-chloro-N- (4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

The individual steps of the process according to the present invention for preparing amorphous 2-chloro-iV-(4-chloro-3-(pyridiri-2-yl)phenyl)-4-(methylsulfonyl)benzamide are detailed separately herein below.

Step a) comprises providing a solution of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in an organic solvent;

2-chloro-N-(4-chloro-3 -(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide is dissolved in an organic solvent. Organic solvent may be selected from alcohols (C1-C4) selected from methanol, ethanol, IP A, n-propanol and the like, halohydrocarbon solvent selected from dichlormethane, dichloroethane and the like, or organic ester solvent selected from ethyl acetate and the like.

In one particular embodiment organic solvent used to prepare solution of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide is methanol. The amount of solvent methanol (in mL) used in this step ranges from 30-50 times (v/w) w.r.t. weight (in g) of 2-chloro-Ar-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide taken for the reaction. In one particular embodiment, of the present application, for 1 gm of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, 50 mL methanol was used.

Step b) comprises heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

Reaction mixture prepared in step a) is heated to a temperature ranging between 40 °C and the boiling point 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, temperature employed for the current step was 55-65 °C. After the clear solution is obtained, the reaction mass is maintained at the same raised temperature for a time duration of 20 mins to 1 hr.

Step c) comprises filtering the reaction mixture and subjecting the filtrate to distillation to yield a residue

The solution obtained from step b) is filtered at the same raised temperature wherein clear solution was achieved. Any conventional process for filtration may be employed to perform the current step. In one particular embodiment of the current application, filtration was performed by using micron filter paper. Filtration is performed to get impurities levels controlled in the clear solution.

The filtrate obtained is subjected to distillation to remove the solvent. Distillation is carried out at temperature ranging between 40 °C and the boiling point of the organic solvent used. Distillation may optionally be performed under reduced pressure conditions. In one particular embodiment of the current application, distillation was performed under vacuum, wherein vacuum strength was slowly increased from 100 mm Hg to 650 mm Hg.

Step d) which is optional comprises repeating the steps a) to c)

The optional step d) which comprises repeating the steps a) to c) i.e. re-dissolving the residue obtained in step c) in organic solvent, heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used, filtering the reaction mixture and again subjecting the filtrate to distillation to yield a residue, is performed if required, to achieve the purity of greater than 99 % (area %) by HPLC along with equilibration to impurity profile compliance. In view of maintaining the equilibrium to the impurity profile compliance, the process may require in-process quality checks to avoid unnecessary repetitions of the same process step.

Step e) comprises drying the material obtained from step c) or d) to obtain amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

The material obtained from step c) or d) is dried at a temperature ranging between 55-60 °C or above. The drying process may be performed under reduced pressure conditions. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed for time ranging from 20 mins to 4 hrs depending upon the physical attributes of the end product obtained i.e. amorphous 2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

Process of isolating amorphous form of 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 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 amorphous form characteristics.

Any 2-chloro-iV-(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 form obtained from any source or by any of the processes known in the prior art may be utilized to result directly into the amorphous 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide of the present invention.

The process related impurities that appear in the impurity profile of the 2-chloro-iV-(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 amorphous form.

The merit of the process according to the present invention resides in that - product obtained after drying is directly obtained as amorphous form of 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. Said material is found devoid of any crystal lattice and adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Substantially pure amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide obtained according to the process of the present invention results in the final API purity by HPLC of more than 99 % w/w.

The amorphous form 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 amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 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 Pyris 7.0 instrument. Illustrative examples of analytical data for the amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 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 amorphous 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide of which at least 95%, by total weight of 2-chloro-/V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzarnide in the composition, is the amorphous form. In yet another embodiment of the invention, the composition may be substantially free of any other forms of 2-chloro-N-(4-chloro-3 -(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

The amorphous form 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 amorphous form of 2-chloro-A^-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, while retaining the amorphous 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 amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide of the present application include, but are 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 amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 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.

EXAMPLES

Example-01: Process for preparation of amorphous 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyI)-4-(methyIsulfonyl)benzamide

lgm 2-chloro-AA-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide was charged to 100ml RBF. 50 ml methanol was added to the reaction mass and heating was performed to about 60 °C to get clear solution. Temperature of 55-65°C was maintained for 30 mins after getting clear solution. At the same raised temperature, the solution was filtered through micron filter paper. The filtrate was then charged to the rotavapour flask and distillation was performed at about 55 °C under vacuum. Vacuum was applied slowly from 100mm/Hg and increased to 650mm/Hg. After complete distillation of solvent, material was dried under vacuum at 60°C for 25 min with high RPM. Further 50 ml methanol was charged to the residue obtained in rotavapour flask. The solution was heated to 60°C to get clear solution without applying vacuum. After getting clear solution, temperature of 60 °C was maintained for 30 mins. Then distillation was performed again at 50-60°C under vacuum. As earlier, vacuum was applied slowly from lOOmm/Hg and increased to 650mm/Hg. The material obtained after distillation was dried under vacuum at 55 °C for 2.5 hrs to afford amorphous 2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide having the XRPD diffractogram and DSC isotherm as shown in Figs. 1 and 2 resp.

Yield: 0.96 gm, HPLC purity: 99.43 %

ExampIe-02: Process for preparation of amorphous 2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

1 g 2-chloro-A^-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide was charged to 100 ml RBF having 50 ml methanol. The temperature was raised to about 65 °C till a clear solution is attained. Temperature of 60-65°C was maintained for 40 mins after getting clear solution. At the same raised temperature, the solution was filtered through micron filter paper. The filtrate was then charged to the rotavapour flask and distillation was performed at about 50 °C under vacuum. Vacuum was applied slowly from lOOmm/Hg and increased to 650mm/Hg. After complete distillation of solvent, material obtained was dried under vacuum at 60°C for 30 min with high RPM. Further 55 ml methanol was charged to the residue obtained in rotavapour flask. Without applying vacuum the solution was heated again to about 65 °C to get clear solution. After getting clear solution, temperature of about 60 °C was maintained for 25 mins. Then distillation was performed again at 50-60°C under vacuum. Vacuum was applied slowly from lOOmm/Hg and increased to 650mm/Hg. The material obtained after distillation was dried under vacuum at 60 °C for 3 hrs to afford amorphous 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide having the XRPD diffractogram and DSC isotherm similar to the ones shown in Figs. 1 and 2 resp.

Yield: 0.92 gm, HPLC purity: -99 %

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.

Claims:

1) Amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide (I)

or pharmaceutically active salts thereof.

2) Amorphous form of 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide, according to claim-1, characterized by DSC isotherm comprising at least one exothermic peak ranging between 135 to 160 °C and at least one endothermic peak ranging between

a. Peak-1: Between 80 to 100 °C

b. Peak-2: Between 170 to 190 °C

3) Amorphous form of 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, according to claim-1, characterized by XRPD similar to Fig -1 and DSC similar to Fig-2.

4) A process for the preparation of an amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, comprising the steps of:

a) Providing a solution of 2-chloro-N-(4-chIoro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide in organic solvent;

b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;

c) Filtering the reaction mixture and subjecting the filtrate to distillation to yield a residue;

d) Optionally repeating the steps a) to c);

e) Drying the material obtained from step c) or d) to obtain amorphous form of 2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide.

5) A process for the preparation of an amorphous form of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, according to claim-4, wherein organic solvent in step a) is selected from alcohols (C1-C4), halohydrocarbon solvent or organic ester solvent.

6) A process for the preparation of an amorphous form of 2-chIoro-/V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, according to claim-5, wherein C1-C4 alcohol is methanol and is used in quantity (in mL) ranging between 30-50 times (v/w) w.r.t. weight of 2-chloro-AL(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide(ing).

7) A process for the preparation of an amorphous form of 2-chloro-iV-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, according to claim-4, wherein in step b) the reaction mixture is heated to a temperature ranging between 55-65 °C.

8) A process for the preparation of an amorphous form of 2-chloro-./V-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide, according to claim-4, wherein in step c) distillation is carried out under reduced pressure conditions.

9) Amorphous 2-Chloro-iV-(4-chloro-3 -pyridin-2-ylphenyl)-4-methylsulfonylbenzamide having HPLC purity greater than 99 %.

10) A pharmaceutical composition comprising amorphous 2-Chloro-Af-(4-chloro-3-pyridin-2- ylphenyl)-4-methylsulfonylbenzamide according to any of the preceding claims, and at least one or more pharmaceutically acceptable excipients.