WO2015169269A1

WO2015169269A1 - Salts of 2-chloro-n-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Info

Publication number: WO2015169269A1
Application number: PCT/CZ2014/000049
Authority: WO
Inventors: Ludek Ridvan; Violetta Kiss; Hana TOZICKOVA; Marcela Tkadlecova; Ondrej Dammer; Lukas KREJCIK
Original assignee: Zentiva, K.S.
Priority date: 2014-05-05
Filing date: 2014-05-05
Publication date: 2015-11-12

Abstract

A salt comprising compound of Formula (I) and at least one acid component (HA).

Description

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

Field of the invention

The invention relates to new solid forms of vismodegib (2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide) free base and salts of vismodegib of Formula I:

and at least one acid component wherein the salt of Formula I and acid component is presented in amorphous or crystalline form. The invention also relates to processes of preparation of free bases and salts as well as to their use in pharmaceutical compositions. Use of solid forms of vismodegib and manufactured salts in the preparation of 2-chloro-N-(4- chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in the free form or in the form of any pharmaceutical salt thereof is also part of the invention.

Background of the invention

2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide which is also known as vismodegib (CAS no. 879085-55-9) is an active pharmaceutical compound for the treatment of basal cell carcinoma (BCC). Basal cell carcinoma is a slow-growing form of skin- cancer and it belongs to the group of nonmelanoma-type skin cancer. Vismodegib is used for the treatment of adults with basal cell carcinoma in advanced stages, e.g. when the cancer is metastatic and causing symptoms, or locally advanced and therefore not suitable for surgery or treatment with radiation.

2-Chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide was specifically described in WO2006028958 dealing also with pharmaceutical composition, synthesis and a crystallization method of Vismodegib.

Preparation methods of the 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide free base are disclosed in WO2009126863.

Many pharmaceutical solid compounds can exist in various crystalline forms regarded as polymorphs and hydrates/solvates. Organic bases, like vismodegib may exist in various crystal modifications having different crystal units and hence different physico-chemical properties including melting point, solubility, dissolution rate and finally, bioavailability. In order to distinguish the distinct solid phases of a compound several solid state analytical techniques can be used, e.g. X-Ray Powder Diffraction, solid state NMR and Raman spectroscopy, thermoanalytical methods.

Discovery of new solid phases (polymorphs, solvates and hydrates) of an active pharmaceutical compound offers the opportunity to select the appropriate form having desirable physicochemical properties and processability and improve the characteristics of the pharmaceutical product. For this reason there is an explicit need for new solid forms (polymorphs, solvates, hydrates) of vismodegib.

Different salts of an active pharmaceutical ingredient may possess different properties and such variations in the properties of various salts may provide a basis for improving formulation, for example, by facilitating better processing characteristics, improving the dissolution profile or improving stability.

The objective of the present invention is to provide novel pharmaceutically acceptable solid crystalline forms od free base and salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide with good chemical purity and stability as an active pharmaceutical ingredient. It is very important from economical point of view that the preparation process is suitable for industrial scale application and easily reproducible.

Summary of the invention The invention provides new pharmaceutically acceptable solid forms of vismodegib free base and processes of their preparation. These forms can be used to prepare vismodegib salts or vismodegib free base and to prepare formulation thereof.

The invention provides new pharmaceutically acceptable salts of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in crystalline or amorphous form and methods of their production. These salts can be used to prepare vismodegib salts or vismodegib free base forms and to prepare formulation thereof.

The solid forms of vismodegib are as follows:

A) the crystalline form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methyl- sulfonyl)benzamide; B) the crystalline form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methyl- sulfonyl)benzamide;

C) the crystalline form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methyl- sulfonyl)benzamide;

D) the crystalline form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methyl- sulfonyl)benzamide;

E) the crystalline form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methyl- sulfonyl)benzamide;

The salts of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide of the present invention are as follows: F) the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and hydrobromic acid.

G) the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and benzenesulphonic acid; H) the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid;

I) the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p-toluenesulphonic acid;

Many organic compounds exist in different solid forms that can be in amorphous or in crystalline state.

The ability of a compound to crystallize in different crystalline phases is called polymorphism. The term polymorph may include the amorphous phase (disordered), hydrates (water presents in the crystal lattice) and solvates (solvents other than water present in the crystal lattice). Different crystalline modifications have different crystal structures and different free energies, therefore polymorphs represent different physico-chemical properties such as melting point, density, solubility, chemical stability and finally, bioavailability.

The difference in the crystal lattice of the crystalline modifications of a compound is expressed in different crystal symmetry and unit cell parameters which appears as the X-Ray diffraction characteristics of a crystalline powder. The different crystalline modifications generate different set of angles and different values of the intensity and finally resulted in different X-Ray powder diffractogram. Amorphous phases lack the long-range order characteristic of a crystal. The absence of crystallinity is easily observed in an X-Ray powder diffractogram. Therefore, the X-Ray Powder Diffractogram can be used to identify different crystalline modifications as well as the amorphous phase.

The term„crystalline" refers to vismodegib free base and pharmaceutically acceptable salts thereof, as used in this patent application, is synonymous to commonly used expressions polymorphic form", „crystalline form" or„crystalline modification" of vismodegib free base or vismodegib salts. The term „amorphous" refers to vismodegib salts, as used in this patent application, is synonymous to commonly used expressions„amorphous vismodegib salts".

The term „room temperature" is defined as a temperature between 15°C and 30°C; preferably it is between 20-25°C or about 25°C.

The term Jaboratory condition", as used in this patent application, means room temperature and relative humidity 20-60%. An advantage of the newly prepared forms of vismodegib and vismodegib salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form. In addition these salts are easily producible by a 1-step method in polar aprotic solvents, preferably in acetonitrile with an excellent chemical purity.

The present invention further relates to characterization of prepared forms and salts of vismodegib using Raman, ¹H-NMR, solid state NMR, XRPD and DSC techniques and to pharmaceutical formulations containing the novel salts of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide. Use of the novel salts of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in the preparation of vismodegib in its free form or in the form of any other pharmaceutical acceptable salt thereof is also part of the invention.

Brief description of the figures

Figure 1 is an XRPD pattern of the form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 2 is a Raman spectra of the form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 3 is a DSC curve of the form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide; Figure 4 is an XRPD pattern of the form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 5 is a Raman spectra of the form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 6 is a DSC curve of the form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 7 is an XRPD pattern of the form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 8 is a Raman spectra of the form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide; Figure 9 is a DSC curve of the form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 10 is an XRPD pattern of the form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 11 is a Raman spectra of the form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide; Figure 12 is a DSC curve of the form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 13 is an XRPD pattern of the form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 14 is a Raman spectra of the form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide;

Figure 15 is a DSC curve of the form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide.

Figure 16 is a Raman spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid

Figure 17 is a ¹H-NMR spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid

Figure 18 is a XRPD pattern of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid

Figure 19 is a DSC curve of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid

Figure 20 is a Raman spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid

Figure 21 is a ¹H-NMR spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid

Figure 22 is a XRPD pattern of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid

Figure 23 is a DSC curve of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid

Figure 24 is a Raman spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and p-toluenesulphonic acid

Figure 25 is a ¹H-NMR spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and p-toluenesulphonic acid

Figure 26 is a XRPD pattern of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and p-toluenesulphonic acid

Figure 27 is a DSC curve of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and p-toluenesulphonic acid

Figure 28 is a Raman spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and hydrobromic acid Figure 29 is a solid state-NMR spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide and hydrobromic acid

Figure 30 is a XRPD pattern of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and hydrobromic acid Figure 31 is a DSC curve of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and hydrobromic acid

Detailed description of the invention

The aim of the present invention is to provide novel solid forms of vismodegib and vismodegib salts with advantegous properties for pharmaceutical use regarding the physico- chemical properties and production of novel forms and salts in a reproducible manner even in industrial scale.

The above mention objects have been achieved by the novel forms and pharmaceutically acceptable salts of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide with benzenesulphonic, 4-chlorobenzenesulphonic, p-toluenesulphonic and hydrobromic acid. These salts according to the invention are easily producible by a 1-step method in polar aprotic solvents, preferably in acetonitrile with an excellent chemical purity.

It has been surprisingly found that the above-mentioned chemically and morphologically stable solid forms of vismodegib and vismodegib salts can be prepared and have not been described so far in the literature and no analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X-Ray Diffraction data etc.) serving to characterize the crystalline solid forms of vismodegib and salts in amorphous as well as in crystalline form has been provided.

Therefore present invention relates to novel solid forms of Formula I and a salt comprising Formula I - (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and at least one acid selected from the group consisting of benzenesulphonic acid, 4- chlorobenzenesulphonic acid, p-toluenesulphonic acid and hydrobromic acid.

The crystalline solid form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide characterised by a XRPD pattern has pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 6.5; 15.6; 20.3; 22.7; 25.7 and 31.8.

According to the invention has the form 1 the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). This form shows the following diffraction peaks in XRPD pattern illustrated in Table 1 below: Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

6.53 13.523 32.7

11.56 7.652 23.6

13.34 6.632 18.7

14.63 6.048 24.6

15.63 5.666 38.7

18.35 4.831 15.2

19.02 4.662 84.6

19.70 4.503 73.8

20.29 4.374 100.0

21.23 4.183 50.5

22.04 4.029 46.3

22.71 3.913 51.4

24.08 3.692 10.2

25.70 3.463 40.9

26.19 3.400 19.5

26.95 3.306 29.8

27.47 3.244 31.4

28.13 3.170 20.2

30.27 2.950 12.7

Table 1

The crystalline solid form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be characterized by Raman spectroscopy investigation (Raman (Bruker RFS 100/S, Figure 2). Crystalline form 1 characterized by Raman spectroscopy shows the spectrum comprising characteristic peaks at 3066, 2927, 2904, 1668, 1609, 1588, 1539, 1323, 992 and 678 cm ¹ wavenumbers.

The crystalline solid form 1 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be further described by thermal analytical method. (Perkin Elmer Pyris 1 DSC). Figure 3 shows the DSC curve measured in the range of 20°C to 250°C. The crystalline form 1 provides a melting process with

T₀nset,2=182.7°C and T_peak_,2=186.6⁰C measured by DSC.

The crystalline solid form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide characterised by a XRPD pattern has pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 10.3; 14.1; 18.1; 20.7 and 23.3.

According to the invention has the characteristic XRPD pattern as shown in Figure 4. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks in XRPD pattern illustrated in Table 2 below: Pos. [°2Th.] d-spacing [A] el. Int. [%]

7.69 11.485 25.5

10.29 8.590 98.2

11.75 7.524 26.1

14.06 6.295 99.4

15.36 5.763 53.9

15.84 5.590 46.7

18.07 4.904 81.6

18.74 4.730 16.4

19.04 4.658 12.1

19.96 4.445 57.7

20.65 4.297 100.0

21.68 4.096 60.0

22.17 4.007 41.6

23.31 3.813 97.2

23.69 3.752 30.2

24.77 3.591 36.4

25.11 3.544 19.3

26.53 3.357 14.8

28.19 3.163 25.9

28.69 3.109 14.0

29.19 3.056 9.2

30.54 2.925 9.8

31.96 2.798 17.6

34.65 2.587 12.5

36.92 2.433 6.8

37.44 2.400 9.0

38.11 2.360 7.75

Table 2

The crystalline form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be characterized by Raman spectroscopy investigation. Figure 5 shows the Raman (Bruker RFS 100/S) spectrum. The Crystalline form 2 characterized by Raman spectroscopy shows the spectrum comprising characteristic peaks at 3087, 3061, 3009, 2924, 1672, 1608, 1592, 1315, 1003 and 679 cm ¹ wavenumbers.

The crystalline form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be further described by thermal analytical method. Figure 6 shows the DSC (Perkin Elmer Pyris 1 DSC) curve measured in the range of 20°C to 250^eC. The crystalline form 2 provides a melting process with

measured by DSC.

The crystalline form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide characterised by a XRPD pattern has pattern having the characteristic diffraction peaks at reflection angle 2Θ (+ 0.2° 2Θ) of 7.7; 13.8; 19.7; 21.1; 23.0 and 26.6. According to the invention has the characteristic XRPD pattern as shown in Figure 7. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks in XRPD pattern illustrated in Table 3 below:

Table 3

The crystalline form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be characterized by Raman spectroscopy investigation. Figure 8 shows the Raman (Bruker RFS 100/S) spectrum. The Crystalline form 3 characterized by Raman spectroscopy shows the spectrum comprising characteristic peaks at 3066, 2999, 2916, 1688, 1609, 1586, 1538, 1319, 1250 and 992 cm ¹ wavenumbers.

The crystalline form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be further described by thermal analytical method. Figure 9 shows the DSC (Perkin Elmer Pyris 1 DSC) curve measured in the range of 20°C to 250°C. The crystalline form 3 provides a melting process with Tonset=184.2°C and T_Peak=189.3^eC measured by DSC.

The crystalline form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide characterised by a XRPD pattern has pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 7.7; 14.2; 17.1; 19.9 and 23.3.

According to the invention has the characteristic XRPD pattern as shown in Figure 10. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks in XRPD pattern illustrated in Table 4 below:

Table 4

The crystalline form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be characterized by Raman spectroscopy investigation. Figure 11 shows the Raman (Bruker RFS 100/S) spectrum. The Crystalline form 4 characterized by Raman spectroscopy shows the spectrum comprising characteristic peaks at 3069, 3009, 2930, 2251, 1681, 1608, 1592, 1549, 1322 and 1000 cm ¹ wavenumbers.

The crystalline form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be further described by thermal analytical method. Figure 12 shows the DSC (Perkin Elmer Pyris 1 DSC) curve measured in the range of 20°C to 250°C. The crystalline form 4 provides a melting process with

Tp_ea =190.8°C measured by DSC. The crystalline form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide characterised by a XRPD pattern has pattern having the characteristic diffraction peaks at reflection angle 2Θ (± 0.2° 2Θ) of 10.1; 17.4; 19.1; 22.1 and 23.7.

According to the invention has the characteristic XRPD pattern as shown in Figure 13. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks in XRPD pattern illustrated in Table 5 below: Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

8.69 10.163 15.0

10.07 8.780 59.0

11.66 7.581 20.4

12.34 7.169 23.7

14.01 6.316 20.5

15.75 5.623 13.1

16.73 5.296 58.1

17.44 5.080 79.2

19.14 4.634 52.9

20.04 4.428 29.8

20.74 4.280 54.0

21.46 4.138 31.4

21.80 4.074 27.4

22.05 4.028 100.0

23.74 3.746 21.8

24.67 3.606 17.9

25.02 3.556 13.0

26.36 3.379 15.0

26.57 3.352 20.1

26.83 3.321 11.4

27.25 3.270 7.2

28.00 3.184 6.5

29.05 3.071 7.5

30.55 2.924 10.4

30.86 2.895 11.6

31.64 2.825 8.0

32.11 2.785 5.1

33.38 2.682 3.7

Table 5

The crystalline form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be characterized by Raman spectroscopy investigation. Figure 14 shows the Raman (Bruker RFS 100/S) spectrum. The Crystalline form 5 characterized by Raman spectroscopy shows the spectrum comprising characteristic peaks at 3070, 3010, 2926, 1681, 1611, 1589, 1533, 1325, 1001 and 678 cm ¹ wavenumbers.

The crystalline form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamidecan be further described by thermal analytical method. Figure 15 shows the DSC (Perkin Elmer Pyris 1 DSC) curve measured in the range of 20°C to 250°C. The cyrtsalline form 5 provides a melting process with T₀nset,i⁼¹0⁷-5^oC and T_Peak,i=118.9°C, Tonset,2=173.3°C and

measured by DSC.

It has been found that the novel crystalline form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide of the present invention possess better stability properties in the range of relative humidity between 14 % and 91% compared to the stability of the crystalline forms 1, 2, 3 and 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide in conditions with the range between 14 % and 91% of relative humidity.

Comparative stability study in relative humidity conditions was performed according to the water activity of acetonitrile - water solvent system (Table 6) and samples were agitated in the appropriate solvent mixture at 20°C for 2 weeks.

Table 6

It has been found that the novel crystalline form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide of the present invention is the thermodynamically preferred form compared to the stability of the crystalline form 1, 2, 3 and 4 of 2-chloro-N-(4- chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide in relative stability investigation of the crystalline modifications.

In case of relative stability investigation samples were placed into ethyl acetate and continuously agitated at room temperature for 6 weeks in closed vial.

The inventive salts of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide can be obtained with high purity in amorphous or crystalline form. The salts may be an anhydrous and/or solvent-free form or be a hyd rated/sol vated form. They may exist in different solid forms with different internal structures (polymorphism), which may have different physicochemical properties, depending on the conditions of the preparation method applied for the synthesis of the salt. Therefore, crystalline modifications of the inventive salt cover individual crystals and/or mixtures thereof in any ratio.

All salts were prepared by the reaction of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide with an acid selected from the group consisting of benzenesulphonic acid, 4-chlorobenzenesulphonic acid, p-toluenesulphonic acid and hydrobromic acid in the solvent selected from polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone and acetonitrile, preferably in acetonitrile. The reaction was carried out in the range of temperature 40-60°C, preferably at temperature 50°C. The resulting salt was isolated from the reaction mixture at room temperature.

The present invention provides the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid. This salt can be characterized by RAMAN spectroscopy investigation. Figure 16 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 2926, 1683, 1590, 1549, 1416, 1327, 1030, 998 and 617 cm ^xwavenumbers.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and benzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 18. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid is an essentially amorphous phase.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and benzenesulphonic acid can be further described by thermal analytical methods. Figure 19 shows the DSC (TA Instruments Discovery DSC) curve measured in the range of 0°C to 280°C. The DSC measurement gives a melting process with T_g=92.1° C.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and benzenesulphonic acid obtained exhibits excelent purity (98.8%).

In another embodiment, the present invention provides salt of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 4-chlorobenzenesulphonic acid that can be characterized by RAMAN spectroscopy investigation Figure 20 shows the Raman (Bruker RFS 100/S)spectrum comprising characteristic peaks at 3068, 2925, 1682, 1590, 1548, 1237, 2031, 1007, 757 and 680 cm ¹ wavenumbers.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 4- chlorobenzenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 22. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and 4-chlorobenzenesulphonic is an essentially amorphous phase.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 4- chlorobenzenesulphonic acid can be further characterized by thermal analytical methods. Figure 23 shows the DSC (TA Instruments Discovery DSC) curve measured in the range of 0°C to 280°C. The DSC measurement gives a melting process with T_g=97.8° C.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 4- chlorobenzenesulphonic acid obtained exhibits excellent purity (98.4%).

In another embodiment, the present invention provides a salt of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p-toluenesulphonic acid that can be characterized by RAMAN spectroscopy investigation. Figure 24 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3065, 2925, 1683, 1591, 1548, 1327, 1153, 1124, 1030 and 679 cm ¹ wavenumbers.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p- toluenesulphonic acid according to the invention has the characteristic XRPD pattern as shown in Figure 26. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and p-toluenesulphonic acid is an essentially amorphous phase. The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p- toluenesulphonic acid can be further characterized by thermal analytical methods. Figure 27 shows the DSC (TA Instruments Discovery DSC) curve measured in the range of 0°C to 280°C. The DSC measurement gives a melting process with

(water) and T_g=97.4° C.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p- toluenesulphonic acid obtained exhibits excellent purity (98.8%). In another embodiment, the present invention provides a salt of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and hydrobromic acid that can be characterized by RAMAN spectroscopy and solid state NMR spectroscopy investigations. Figure 28 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 2919, 1673, 1624, 1589, 1457, 1382, 1103, 1052 and 678 cm ¹ wavenumbers. Figure 29 shows the solid state NMR spectra of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)- 4-(methylsulfonyl)benzamide and hydrobromic acid.

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and hydrobromic acid according to the invention has the characteristic XRPD pattern as shown in Figure 30. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and hydrobromic acid shows the following peaks in XRPD pattern as illustrated in Table 7, below:

Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

10.29 8.592 33.2

12.19 7.256 6.5

12.43 7.117 10.8

14.94 5.927 12.9

16.44 5.388 20.4

16.86 5.254 22.7

20.3 4.430 13.2

20.81 4.264 100.0

21.39 4.151 26.1

21.94 4.048 26.9

22.42 3.963 77.8

22.95 3.873 29.8

23.64 3.760 17.5

24.2 3.702 24.0

24.71 3.601 50.7

25.67 3.468 12.2

26.41 3.372 9.8

26.89 3.313 21.2

27.65 3.223 15.5

28.28 3.154 12.2

29.25 3.051 11.6

30.81 2.900 17.1

31.55 2.834 16.2

31.85 2.807 12.7

33.61 2.665 12.6

Table 7

The salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and hydrobromic acid can be further characterized by thermal analytical methods. Figure 31 shows the DSC (TA Instruments Discovery DSC) curve measured in the range of 0°C to 280°C. The DSC measurement gives a melting process with

(water); Tonset,2=233.2°C and T_peak<2=244.4⁰C.

The crystalline salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and hydrobromic acid exhibits excelent purity (98.8%). Examples

Example 1

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

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide was dissolved in IN HCI solution and then 0.5M NaOH solution is added up to pH=ll. The resulting precipitate was filtered and dried in vacuum oven at 40°C under 200 mbar vacuum pressure.

Yield: 66.5 mg (67%)

HPLC: 99.2%

This form was characterized by XRPD (Fig. 1), Raman spectroscopy (Fig. 2) and by DSC technique (Fig. 3)

Example 2

Preparation of form 2 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide was dissolved in a solvent mixture of acetone and ethyl acetate with a ratio of 80 to 20 by heating to 50°C. Then the solution is cooled back to room temperature and the resulting precipitate was filtered and dried in vacuum oven at 40°C under 200 mbar vacuum pressure.

Yield: 21.7 mg (22%)

HPLC: 99.9%

This form was characterized by XRPD (Fig. 4), Raman spectroscopy (Fig. 5) and by DSC technique (Fig. 6) Example 3

Preparation of form 3 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide was suspended in hot isopropyl acetate at 60-70°C and stirred for 4 hours. The hot solution was then cooled back to room temperature. The resulting precipitate is filtered and dried in vacuum oven at 40°C under 200 mbar vacuum pressure.

Yield: 55.7 mg (56%)

HPLC: 99.8%

This form was characterized by XRPD (Fig. 7), Raman spectroscopy (Fig. 8) and by DSC technique (Fig. 9)

Example 4

Preparation of form 4 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide

25 mg (0.059 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide was suspended in 250 μΐ of a solvent mixture of acetonitrile and water in a ratio of 75 to 25 at 20°C. The suspension was agitated with an agitation rate of 750 rpm at 20°C for 2 weeks in closed vial. After 2 weeks the residue was collected by filtration and then dried at laboratory condition.

Yield: 20 mg (80%) HPLC: 100%

This form was characterized by XRPD (Fig. 10), Raman spectroscopy (Fig. 11) and by DSC technique (Fig. 12)

Similarly, the same result was obtained using any of the solvents listed in the Table 8.

Table 8

Example 5

Preparation of form 5 of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide

50 mg (0.119 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide was suspended in 0.5 mL of ethyl acetate at room temperature. The suspension was agitated with an agitation rate of 750 rpm at room temperature for 2 weeks in closed vial. After 2 weeks the residue was collected by filtration and then dried at laboratory condition.

Yield: 42 mg (84%)

HPLC: 99.9%

This form was characterized by XRPD (Fig. 13), Raman spectroscopy (Fig. 14) and by DSC technique (Fig. 15) Example 6

Preparation of salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and benzenesulphonic acid

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl- Jbenzamide was dissolved in 4 mL of acetonitrile by heating to 50°C. 37.5 mg (0.237 mmol) of benzenesulphonic acid was dissolved in 0.5 mL of acetonitrile at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C.

The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The solvent was evaporated completely by rotary evaporation and then 2 mL of methyl tert-butyl ether was added and stirred at room temperature for 5 hours. The resulting suspension was filtered off and dried at laboratory conditions.

¹H-NMR analysis showed a 1:1 stoichiometry of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)- 4-(methylsulfonyl)benzamide and benzenesulphonic acid. This salt was characterized by Raman spectroscopy (Fig. 16), ¹H-NMR (Fig. 17), XRPD (Fig. 18), and by DSC technique (Fig. 19).

Example 7

Preparation of salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and 4-chlorobenzenesulphonic acid

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide was dissolved in 4 mL of acetonitrile by heating to 50°C. 45.7 mg (0.237 mmol) of 4-chlorobenzenesulphonic acid was dissolved in 0.5 mL of acetonitrile at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C.

¹H-NMR analysis showed a 1:1 stoichiometry of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)- 4-(methylsulfonyl)benzamideand 4-chlorobenzenesulphonic acid.

This salt was characterized by Raman spectroscopy (Fig. 20), ¹H-NMR (Fig. 21), XRPD (Fig. 22), and by DSC technique (Fig. 23). Example 8

Preparation of salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and p-toluenesulphonic acid

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide was dissolved in 4 mL of acetonitrile by heating to 50°C. 45.2 mg (0.237 mmol) of p-toluenesulphonic acid was dissolved in 0.5 mL of acetonitrile at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C.

¹H-NMR analysis showed a 1:1 stoichiometry of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)- 4-(methylsulfonyl)benzamide and p-toluenesulphonic acid.

This salt was characterized by Raman spectroscopy (Fig. 24), ^XH-NMR (Fig. 25), XRPD (Fig. 26), and by DSC technique (Fig. 27). Example 9

Preparation of salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide and hydrobromic acid

100 mg (0.237 mmol) of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide was dissolved in 4 mL of acetonitrile by heating to 50°C. 26.9 μΐ (0.237 mmol) of hydrobromic acid was dissolved in 0.5 mL of acetontirile at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C. The solution at 50°C is stirred for 1 hour in closed vial, cooled back to room temperature and stirred overnight. The resulting suspension was filtered off and dried at laboratory conditions.

This salt was characterized by Raman spectroscopy (Fig. 28), ¹H-NMR (Fig. 29), XRPD (Fig. 30), and by DSC technique (Fig. 31).

Example 10

Preparation of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide from the benzenesulphonic acid salt thereof 50 mg (0.086 mmol) of the salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide and benzenesulphonic acid was suspended in 1.5 mL of dichloromethane with stirring. 0.75 mL of 2M K₂C0₃ was added to the suspension and stirred for complete dissolution. The clear solution was shaken. The organic phase was separated and shaken with 0.5 mL of water by 3 times. The water phases were combined and shaken with 0.5 mL of dichloromethane by 3 times. Organic phases were collected and few spoons (2-3 grams) of Na₂S0₄ were added as a desiccant. After several minutes the desiccant was filtered with vacuum.

The dichloromethane was evaporated by rotadest and the free base was suspended in 0.1 mL of ethyl acetate. The resulting suspension was stirred at room temperature overnight then was filtered off and dried at laboratory conditions.

Yield: 38 mg (76%)

HPLC: 99.8%

Similarly, the same result was obtained using the 4-chlorobenzenesulphonic acid, p- toluenesulphonic acid and the hydrobromic acid salt of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 9. Solvent

acetone

acetonitrile

acetonitrile - water solvent mixture

2-propanol

Table 9 Analysis - RAMAN (Fourier-Transformed Infra-Red) spectroscopy

RAMAN spectra were recorded by Nicolet Thermo 6700 spectrometer.

General settings:

Number of sample scans: 45

Number of background scans: 45

Resolution: 4.000

Sample gain: 4.0

Optical velocity: 0.6329

Aperture: 100.00

Analysis - 1H-NMR spectroscopy

For 1H NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts was determined from integrals of corresponding signals of API and counterion.

Analysis - Solid State NMR spectroscopy

13C CP-MAS ss NMR spectra were measured on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency.

The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of counterion.

Analysis -XRPD (X-Ray Powder Diffractometry)

Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer, used radiation CuKoc (λ = 1.542A).

Generator settings:

excitation voltage 45 kV

anodic current 40 mA.

Scan description:

- scan type - gonio

- measurement range 2 - 40⁵ 2Θ

- step size 0.01^s 2Θ

- step time: 0.5 s.

Samples were measured as received on Si plate (zero background holder).

Incident beam optics: programmable divergence slits (irradiated length 10 mm). 10 mm mask. l/4^e anti-scatter fixed slit, 0.02 rad Soller slits.

Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122^s, 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter. Analysis - DSC (Differential Scanning Calorimetry)

DSC measurements were performed on a TA Instruments Discovery DSC.

The sample were weighed in aluminium pans and covers (40 μί) and measured in a nitrogen flow. Investigations were performed in a temperature range of 0°C to 280°C with a heating rate of 5°C/min. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima (T_peak) and onset temperature (T_onset) of peaks for the crystalline form and a glass transition temperature (T_g) of the amorphous form. The enthalpy is given in J/g.

The weight sample was about 1 mg.

Some of the results of the further characterization of the inventive salts are given in detail in the following tables:

A) Salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and benzenesulphonic acid

B) Salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 4-chlorobenzenesulphonic acid

C) Salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and p-toluenesulphonic acid

D) Salt of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide hydrobromic acid

Claims

Claims:

1. A salt comprising compound of Formula I:

and at least one acid component (HA).

2. The salt according to claim 1, wherein acid component HA is selected from hydrobromic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid and p-toluenesulphonic acid.

3. The salt according to any preceding claims, wherein the Formula I and acid component (HA) are presented in amorphous or crystalline form.

4. The salt according to claim 1, wherein HA is hydrobromic acid characterized in that with using CuKa it reveals an XRPD pattern having characteristic peaks at reflection angle 2Θ (±

0.2° 2Θ) of 10.3; 16.9; 20.8; 22.4; 24.7 and 26.9.

5. The salt according to claim 1, wherein HA is benzenesulphonic acid characterized in that with using CuKa it reveals an amorphous form.

6. The salt according to claim 1, wherein HA is 4-chlorobenzenesulphonic acid characterized in that with using CuKa it reveals an amorphous form.

7. The salt according to claim 1, wherein HA is p-toluenesulphonic acid characterized in that with using CuKa it reveals an amorphous form.

8. A process for preparation of salt according to any preceding claims characterized in that it comprises dissolving of 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)- benzamide in polar aprotic solvent and dissolving of HA in polar aprotic solvent.

9. The process of claim 8 wherein the polar aprotic solvent is acetonitrile.

10. The process of claim 8 wherein mixing of prepared solutions is performed at 50°C and HA dissolved in polar aprotic solvent is added drop-wise.

11. A pharmaceutical composition comprising the salt of any of claims 1-8.

12. Use of salt according to claim 1 in preparation of 2-chloro-N-(4-chloro-3-(pyridin-2- yl)phenyl)-4-(methylsulfonyl)benzamide of Formula I in the free form or in the form of any pharmaceutically acceptable salt.