SK7185Y1 - Pharmaceutically acceptable salts of 2-chloro-N-(4-chloro-3- (pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide - Google Patents

Abstract

The technical solution describes a salt of a compound of formula (I) with the acid component selected from the group consisting of hydrobromic acid, benzenesulfonic acid, 4-chlorobenzenesulphonic acid and p-toluenesulfonic acid.

Description

SK 7185 Υ1

Technical field

The present invention relates to novel pharmaceutically acceptable salts of vismodegib free base (2-chloro-N (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide) and vismodegib salts of formula (I):

and an acid component, wherein the salt of the compound of formula (I) and the acid component is in amorphous or crystalline form. This technical solution also relates to the use of prepared free bases and salts in pharmaceutical preparations.

BACKGROUND OF THE INVENTION

2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, also known as vismodegib (CAS No 879085-55-9), is an active pharmaceutical a substance used to treat basocellular carcinoma (BCC). Basocellular carcinoma is a slow-growing form of skin cancer and belongs to the non-melanoma type of skin cancer. Vismodegib is used to treat basocellular carcinoma in advanced stages, e.g. when it is metastatic and causes symptoms or is locally widespread and is therefore not suitable for surgical removal or radiation therapy.

2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide has been specifically described in WO 2006028958, which also deals with the pharmaceutical composition, synthesis and method of crystallizing vismodegib.

The preparation of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) -benzamide free base is described in WO 2009126863.

Many solid pharmaceuticals can exist in various crystalline forms considered to be polymorphs and hydrates / solvates. Organic bases such as vismodegib can occur in different crystalline modifications with different types of crystals and hence with different physicochemical properties including melting point, solubility, dissolution rate and ultimately bioavailability. Several different solid phase analytical methods, e.g. X-ray powder diffraction, solid phase NMR, Raman spectroscopy and thermoanalytical methods.

The discovery of new solid forms (polymorphs, solvates and hydrates) of the active pharmaceutical substance offers the opportunity to choose a suitable form with desirable physicochemical properties and processability and to improve the properties of the pharmaceutical product. Therefore, there is an explicit need to find new solid forms (polymorphs, solvates, hydrates) of vismodegib.

Different salts of the active pharmaceutical agent may have different properties, and such changes in the properties of different salts may provide a basis for improving the pharmaceutical composition, e.g. by providing better processing options or improving the dissolution profile or stability.

The object of the present invention is to provide novel pharmaceutically acceptable solid crystalline forms of the free base and 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide salt with good chemical purity and stability as an active pharmaceutical ingredient. From an economic point of view, it is very important that the preparation process is suitable for industrial scale use and is easy to reproduce.

The essence of the technical solution

The technical solution provides novel pharmaceutically acceptable salts of vismodegib free base in solid form. These forms can be used to prepare salts of vismodegib or vismodegib free base and to prepare formulations thereof.

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

The solid forms of vismodegib are as follows:

A) crystalline Form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

B) crystalline Form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

C) crystalline Form 3 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

D) crystalline Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

SK 7185 Υ1

E) crystalline Form 5 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

The salts of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide according to this invention are as follows:

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

G) 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid salt;

H) 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt;

I) 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid salt; Many organic compounds exist in various solid forms, which may be in an amorphous or crystalline state.

The ability of a compound to crystallize in different crystalline phases is called polymorphism. The term polymorph may include an amorphous phase (disordered), hydrates (in the presence of water in the crystal lattice) and solvates (in the presence of solvents other than water in the crystal lattice).

Different crystalline forms have different crystal structures and different free energy, and therefore polymorphs have different physicochemical properties such as melting point, density, solubility, chemical stability and finally bioavailability.

The difference in the crystal lattice of the crystalline forms of the compound is expressed in the different symmetry of the crystals and the parameters of the crystal units, which are manifested as the X-ray diffraction characteristics of the crystalline powder. Different crystalline forms produce different angle groups and different intensity values, which ultimately means a different X-ray powder diffractogram. The amorphous phases do not exhibit a characteristic crystal pattern on a larger scale. The absence of a crystalline arrangement is readily observed on the X-ray powder diffraction pattern. As a result, the X-ray powder diffractogram can be used to identify various crystalline variants as well as the amorphous phase.

The term crystalline refers to the vismodegib free base and its pharmaceutically acceptable salts according to the present invention, is synonymous with the commonly used terms polymorphic form, crystalline form or crystalline modification of vismodegib free base or vismodegib salts.

The term amorphous refers to the salts of vismodegib of the present application, and is synonymous with the commonly used terms of the amorphous salt of vismodegib.

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

The term laboratory conditions as used in this application means room heat and a relative humidity of 20-60%.

The advantage of the novel formulations of vismodegib and of the salts of vismodegib lies in their good physical and chemical properties, which makes them suitable for the preparation of dosage forms. In addition, these salts can be easily prepared by a 1-step process in polar aprotic solvents, preferably acetonitrile, of excellent chemical purity.

The present invention further relates to the characterization of the prepared forms and salts of vismodegib by Raman spectrometry, 1H-NMR, solid-phase NMR, XRPD and DSC, and pharmaceutical compositions containing the novel salts of 2-chloro-N- (4-chloro-3- (pyridine- 2-yl) phenyl) -4- (methylsulfonyl) benzamide. This technical solution also includes the use of the novel salts of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide for the preparation of vismodegib in its free form or in the form of any of its pharmaceuticals. an acceptable salt.

Detailed description of the technical solution

The object of the present invention is to provide new solid forms of vismodegib and a vismodegib salt with advantageous properties for pharmaceutical use with regard to physico-chemical properties and reproducible production, even on an industrial scale.

These objectives have been achieved using novel forms and pharmaceutically acceptable salts of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide with benzenesulfonic acid, 4-chlorobenzenesulfonic acid, p- toluenesulfone and hydrogen bromide. The salts of this invention can be easily produced by a 1-step process in polar aprotic solvents, preferably acetonitrile, of excellent chemical purity.

Surprisingly, it has been found that the morphologically stable solid forms of vismodegib and the vismodegib salt can be prepared, have not been described in the literature and no analytical data (X-ray powder diffraction data, single crystal X-ray diffraction data, etc.) are available to characterize the crystalline forms. and salts in both amorphous and crystalline form.

Therefore, this invention relates to new solid forms of the compound of formula (I) and a salt of the compound of formula (I) - (2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) ) a benzamide and an acid selected from the group consisting of benzenesulfonic acid, 4-chlorobenzenesulfonic acid, p-toluenesulfonic acid and hydrobromic acid.

SK 7185 Υ1

The crystalline solid form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide characterized by XRPD pattern has a spectrum with characteristic diffraction peaks at a reflection angle of 20 (± 0) 2 ° 20) 6.5; 15.6; 20.3; 22.7; 25.7 and 31.8.

According to this technical solution, the characteristic XRPD pattern corresponds to Form 1 spectrum shown in Figure 1. The XRPD pattern was generated using an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks on the XRPD spectrum as shown in Table 1.

Table 1

Pol. [° 2Th.J distance d [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

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

The crystalline solid form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be further described by the thermoanalytical method (Perkin Elmer Pyris 1 DSC). Figure 3 shows a DSC curve measured in the range of 20 ° C to 250 ° C. Crystalline Form 1 shows a melting process with T _onsetil = 168.8 ° C and T _{peak 1} = 174.7 ° C; T _onset2 = 182.7 ° C and T _peak2 = 186.6 ° C, as measured by DSC (onset = peak, peak = peak).

The crystalline solid form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide characterized by XRPD pattern has a spectrum with characteristic diffraction peaks at a reflection angle of 20 (± 0) 2 ° 2Θ) 10.3; 14.1; 18.1; 20.7 and 23.3.

According to this invention, the characteristic XRPD pattern corresponds to that of the form shown in Figure 4. The XRPD pattern was generated using an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks on the XRPD spectrum as shown in Table 2.

Table 2

Pol. [° 2Th.J distance d [A] Rel. 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

SK 7185 Υ1

Pol. [° 2Th.J distance d [A] Rel. int. [%] 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

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

Crystalline Form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be further described by the thermoanalytical method. Figure 6 shows a DSC curve (Perkin Elmer Pyris 1 DSC) measured in the range of 20 ° C to 250 ° C. Crystalline Form 2 shows a melting process with a T _onset = 181.8 ° C and a T _peak = 187.0 ° C as measured by DSC.

The crystalline form 3 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide characterized by XRPD pattern has a spectrum with characteristic diffraction peaks at a 2θ reflection angle (± 0, 2 ° 2Θ) 7.7; 13.8; 19.7; 21.1, 23.0 and 26.6.

According to this invention, the characteristic XRPD pattern corresponds to that of the form of the spectrum depicted in Figure 7. The XRPD pattern was generated using an X-ray powder diffractometer (XPERT PRO MPD PANalytical). This form shows the following diffraction peaks on the XRPD spectrum as shown in Table 3.

Table 3

Pol. [° 2Th.J distance d [A] Rel. int. [%] 7.70 11,473 20.4 12,30 7,190 8.5 13.84 6,393 24.8 15.29 5,788 9.8 17.36 5,105 10.7 17.59 5,038 6.0 18.22 4,866 5.4 19.14 4,633 9.2 19.73 4,496 100.0 20.25 4,382 9.6 21.06 4,216 38.2 21.51 4,127 17.8 21.82 4,070 20.7 23.01 3,862 28.7 23.43 3,793 5.8 25.49 3,492 5.1 26,27 3,389 8.5 26.61 3,348 21.8

SK 7185 Υ1

Pol. [° 2Th.J distance d [A] Rel. int. [%] 27.48 3,244 13.8 28.09 3,174 7.3 29,09 3,067 7.3 29.48 3,028 14.7 30.58 2,922 3.6 35.51 2,526 4.6

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

Crystalline Form 3 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be further described by the thermoanalytical method. Figure 9 shows a DSC curve (Perkin Elmer Pyris 1 DSC) measured in the range of 20 ° C to 250 ° C. Crystalline Form 3 shows a melting process with a T _onset = 184.2 ° C and a T _peak = 189.3 ° C as measured by DSC.

Crystalline Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide characterized by XRPD pattern has a spectrum with characteristic diffraction peaks at a reflection angle of 2θ (± 0, 2 ° 2Θ) 7.7; 14.2; 17.1; 19.9 and 23.3.

According to this invention, the characteristic XRPD pattern corresponds to that of the form shown in Figure 10. The XRPD pattern was generated using an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). This form shows the following diffraction peaks on the XRPD spectrum as shown in Table 4.

Table 4

Pol. [° 2Th.J distance d [A] Rel. int. [%] 6.62 13,346 9.8 6.99 12,635 15.4 7.71 11,457 80.5 9.42 9,385 22.5 11.94 7,403 10.1 14.21 6,227 41.1 15.63 5,666 37.6 17.08 5,188 100.0 19.26 4,606 24.9 19.91 4,457 26.1 21.06 4,215 22.8 21.83 4,068 14.3 22.88 3,883 23.4 23,33 3,811 28.6 24.47 3,634 15.0 27,02 3,298 20.4 27.48 3,243 21.0 29,12 3,064 14.6

Crystalline Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be characterized by Raman spectroscopy. Figure 11 represents a Raman spectrum (Bruker RFS 100 / S). Crystalline Form 4 characterized by Raman spectroscopy shows a spectrum containing characteristic peaks at 3069, 3009, 2930, 2251, 1681, 1608, 1592, 1549, 1322 and 1000 cm ⁴ .

Crystalline Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be further described by the thermoanalytical method. Figure 12 shows a DSC curve (Perkin Elmer Pyris 1 DSC) measured in the range of 20 ° C to 250 ° C. Crystalline Form 4 shows a melting process of ST _{onset: 1} = 111.6 ° C and T _{peak 1} = 120.4 ° C; T _{onset> 2} = 130.1 ° C and T _{peak> 2} = 137.7 ° C, T _{onset> 3} = 172.7 ° C and T _{peak> 3} = 177.3 ° C, T _{onset> 4} = 185.3 ° C and T _{peak 44} = 190.8 ° C measured by DSC.

The crystalline form 5 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide characterized by XRPD pattern has a spectrum with characteristic diffraction peaks at a reflection angle of 2 ° (± 0, 2 ° 2Θ) 10.1; 17.4; 19.1; 22.1 and 23.7.

SK 7185 Υ1

According to this invention, the characteristic XRPD pattern corresponds to that of the form shown in Figure 13. An XRPD pattern was generated using an X-ray powder diffractometer (X'PERT PRO MPD PANalytical). This form exhibits the following diffraction peaks on the XRPD spectrum as shown in Table 5 below:

Table 5

Pol. [° 2Th.J distance d [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

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

Crystalline Form 5 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide can be further described by the thermoanalytical method. Figure 15 shows a DSC curve (Perkin Elmer Pyris 1 DSC) measured in the range of 20 ° C to 250 ° C. Crystalline Form 5 shows a melting process with T _onset ! = 107.5 ° C and T _{peak> 1} = 118.9 ° C, T _{onset> 2} = 173.3 ° C and T _{peak> 2} = 178.2 ° C, T _{onset> 3} = 183.5 ° C and T _{peak &gt}; ₃ = 187.5 ° C as measured by DSC.

It has been found that the new crystalline Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide according to the present invention exhibits better stability behavior in the relative range humidity between 14% and 91% compared to the stability of crystalline forms 1, 2, 3 and 5 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide under conditions relative humidity ranging from 14% to 91%. A comparative stability study under relative humidity conditions was performed based on the water activity of the acetonitrile-water solvent system (Table 6) and the samples were mixed in the appropriate solvent mixture at 20 ° C for 2 weeks.

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Table 6

mixture of solvents solvent ratio water activity (%) acetonitrile - water 75: 25 91 acetonitrile - water 90: 10 82 acetonitrile - water 92.5: 7.5 74 acetonitrile - water 95: 5 66 acetonitrile - water 96: 4 57 acetonitrile - water 97: 3 48 acetonitrile - water 98: 2 38 acetonitrile - water 99: 1 27 acetonitrile - water 99.5: 0.5 14

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

To investigate relative stability, the samples were placed in ethyl acetate and stirred continuously at room temperature for 6 weeks in a sealed beaker.

The 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide salts of this invention can be obtained in high purity in amorphous or crystalline form. The salts may be anhydrous and / or solvent-free, or may be in hydrated / solvated 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 used in the salt synthesis. Therefore, the crystalline forms of the novel salts of the present invention cover the individual crystals and / or mixtures thereof in any ratio.

All salts were prepared by reacting 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide with an acid selected from the group consisting of benzenesulfonic acid, 4-chlorobenzenesulfonic acid, p toluenesulfonic acid and hydrobromic acid in a solvent selected from polar aprotic solvents such as tetrahydrofuran, ethyl acetate, acetone and acetonitrile, preferably acetonitrile.

The reaction was carried out in a temperature range of 40-60 ° C, preferably at 50 ° C. The resulting salt was isolated from the reaction mixture at room temperature.

This technical solution provides a salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid. This salt can be characterized by the Raman spectroscopy method. Figure 16 is a Raman (Bruker RFS 100 / S) spectrum containing characteristic peaks at 3066, 2926, 1683, 1590, 1549, 1416, 1327, 1030, 998, and 617 cm ^-1 .

The characteristic XRPD spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid salt according to this technical solution is shown in Figure 18. using an X-ray powder diffractometer (XPERT PRO MPD PANalytical). The salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid is essentially an amorphous phase.

The salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid can be further described by thermoanalytical methods. Figure 19 is a DSC curve (TA of the Discovery DSC) measured over a range of 0 ° C to 280 ° C. The result of the DSC measurement is a process of melting a _Tg = 92 DEG C. l.

The obtained 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid salt shows 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 4-chlorobenzenesulfonic acid, which can be characterized by the RAMAN method. spectroscopy. Figure 20 is a Raman spectrum (Bruker RFS 100 / S) showing characteristic peaks at 3068, 2925, 1682, 1590, 1548, 1237, 2031, 1007, 757, and 680 cm ^-1 .

The characteristic XRPD spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt according to this technical solution is shown in Figure 22. was generated using 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-chlorobenzenesulfonic acid is essentially an amorphous phase.

The salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid can be further characterized by thermoanalytical methods. Figure 23 is a DSC

SK 7185 Υ1 curve (TA Instrument Discovery DSC) measured in the range of 0 ° C to 280 ° C. DSC measurement results in a melting process with T _g = 97.8 ° C.

The obtained 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt showed 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-toluenesulfonic acid, which can be characterized by the Raman method spectroscopy. Figure 24 is a Raman (Bruker RFS 100 / S) spectrum containing characteristic peaks at 3065, 2925, 1682, 1591, 1548, 1327, 1153, 1124, 1030, and 679 cm ^-1 .

The characteristic XRPD spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid salt according to the present invention is shown in Figure 26. was generated using 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-toluenesulfonic acid is essentially an amorphous phase.

The salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid can be further characterized by thermoanalytical methods. Figure 27 is a DSC curve (TA of the Discovery DSC) measured over a range of 0 ° C to 280 ° C. DSC measurement results in a melting process with T _peak = 77.9 ° C (water) and Tg = 97.4 ° C.

The obtained 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid salt showed 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, which can be characterized by Raman spectroscopy and Solid state NMR spectroscopy. Figure 28 is a Raman (Bruker RFS 100 / S) spectrum containing characteristic peaks at 3066, 2919, 1673, 1624, 1589, 1457, 1382, 1103, 1052, and 678 cm ^-1 . Figure 29 is a solid phase NMR spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid salt.

The characteristic XRPD spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid salt according to this technical solution is shown in Figure 30. using 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 the XRPD spectrum as shown in Table 7.

Table 7

Pol. [° 2Th.J Distance d [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

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The salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid can be further characterized by thermoanalytical methods. Figure 31 is a DSC curve (TA Instruments Discovery DSC) measured in the range of 0 ° C to 280 ° C. DSC measurement results in a melting process with T _{onset 1} = 75.7 ° C and T _{peak> 1} = 88.8 ° C (water); T _{onset> 2} = 233.2 ° C and T _{peak> 2} = 244.4 ° C.

The crystalline salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid shows excellent pure (98.8%).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 represents an XRPD pattern (X-ray powder diffraction pattern) of Form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 2 represents the Raman spectrum of Form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 3 represents the DSC curve of Form 1 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 4 represents an XRPD pattern of Form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 5 shows the Raman spectrum of Form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 6 shows the DSC curve of Form 2 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

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

Figure 8 shows the Raman spectrum of Form 3 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 9 shows the DSC curve of Form 3 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

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

Figure 11 represents the Raman spectrum of Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

Figure 12 shows the DSC curve of Form 4 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

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

Figure 14 shows the Raman spectrum of Form 5 of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide.

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

Figure 16 shows the Raman spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide salt and benzenesulfonic acid salt.

Figure 17 represents the H-X.M R spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide salt and benzenesulfonic acid salt.

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

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

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

Figure 21 represents the 1 H-NMR spectrum of the salt of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid.

Figure 22 is an XRPD plot of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt.

Figure 23 shows the DSC curve of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt.

Figure 24 is a Raman spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 7-toluenesulfonic acid salt.

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

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

Figure 27 shows the DSC curve of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid salt.

Figure 28 shows the Raman spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid salt.

Figure 29 is a solid phase NMR spectrum of the 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide salt and the bromo-hydrogen acid salt.

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

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

EXAMPLES

Example 1

Preparation of Form 1 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 1 N HCl solution and then 0.5 M solution was added. NaOH to pH = 11. The resulting precipitate was filtered and dried in a vacuum oven at 40 ° C under a vacuum of 200 mbar.

Yield: 66.5 mg (67%)

HPLC: 99.2%

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

Example 2

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

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 at a ratio of 80 to 20 by heating to Deň: 32 ° C. Then the solution was cooled back to room temperature and the resulting precipitate was filtered and dried in a vacuum oven at 40 ° C under a vacuum of 200 mbar.

Yield: 21.7 mg (22%)

HPLC: 99.9%

This form was characterized by XRPD (Figure 4), Raman spectroscopy (Figure 5) and DSC method (Figure 6).

Example 3

Preparation of Form 3 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. hours. The hot solution was then cooled back to room temperature. The resulting precipitate was filtered and dried in a vacuum oven at 40 ° C under a vacuum of 200 mbar. Yield: 55.7 mg (56%) HPLC: 99.8%

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

Example 4

Preparation of Form 4 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide mg (0.059 mmol) 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide was suspended in a 250 to 25 solvent mixture of acetone and ethyl acetate at 20 ° C. The suspension was stirred at 750 rpm and 20 ° C for 2 weeks in a sealed beaker. After 2 weeks, the product was filtered off and then dried under laboratory conditions.

Yield: 20 mg (80%).

HPLC: 100%

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

A similar result was obtained with any of the solvents listed in Table 8.

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Table 8

mixture of solvents solvent ratio acetonitrile - water 90 1 acetonitrile - water 92.5 7.5 acetonitrile - water 95 5 acetonitrile - water 96 4 acetonitrile - water 97 3 acetonitrile - water 98 2 acetonitrile - water 99 1 acetonitrile - water 99.5 0.5

Example 12

Preparation of Form 5 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide mg (0.119 mmol) 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide was suspended in 0.5 mL ethyl acetate at room temperature. The suspension was stirred at 750 rpm and at room temperature for 2 weeks in a sealed beaker. After 2 weeks, the product was filtered off and then dried under laboratory conditions.

Yield: 42 mg (84%).

HPLC: 99.9%

This form was characterized by XRPD (Figure 13), Raman spectroscopy (Figure 14), and DSC method (Figure 15).

Example 6

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

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. Benzenesulfonic acid (37.5 mg, 0.237 mmol) was dissolved in acetonitrile (0.5 mL) at room temperature and the vapor ion solution was gradually added dropwise to the API (active pharmaceutical agent) solution at 50 ° C. The solution was stirred at 50 ° C for 1 hour in a sealed beaker, cooled back to room temperature and stirred overnight. The solvent was completely evaporated on a rotary evaporator, and then 2 ml of methyl tert-butyl ether was added and the mixture was stirred at room temperature for 5 hours. The resulting suspension was filtered and dried under laboratory conditions.

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

This salt was characterized by Raman spectroscopy (Figure 16), 1 H-NMR (Figure 17), XRPD (Figure 18), and DSC method (Figure 19).

Example 12

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

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-chlorobenzenesulfonic acid was dissolved in 0.5 ml of acetonitrile at room temperature and the vapor ion solution was gradually added dropwise to the API solution at 50 ° C. The solution was stirred at 50 ° C for 1 hour in a sealed beaker, cooled back to room temperature and stirred overnight. The solvent was completely evaporated on a rotary evaporator, and then 2 ml of methyl tert-butyl ether was added and the mixture was stirred at room temperature for 5 hours. The resulting suspension was filtered and dried under laboratory conditions.

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

This salt was characterized by Raman spectroscopy (Figure 20), 1 H-NMR (Figure 21), XRPD (Figure 22), and DSC method (Figure 23).

Example 8

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

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-toluenesulfonic acid was dissolved in 0.5 ml of acetonitrile at room temperature and the vapor ion solution was gradually added dropwise to the API solution at

SK 7185 -1 ° C. The solution was stirred at 50 ° C for 1 hour in a sealed beaker, cooled back to room temperature and stirred overnight. The solvent was completely evaporated on a rotary evaporator and then 2 ml of methyl tert-butyl ether was added and the mixture was stirred at room temperature for 5 hours. The resulting suspension was filtered and dried under laboratory conditions.

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

This salt was characterized by Raman spectroscopy (Figure 24), 1 H-NMR (Figure 25), XRPD (Figure 26), and DSC method (Figure 27).

Example 13

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

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 acetonitrile at room temperature and the vapor ion solution was gradually added dropwise to the API solution at 50 ° C. The solution was stirred at 50 ° C for 1 hour in a sealed beaker, cooled back to room temperature and stirred overnight. The resulting suspension was filtered and dried under laboratory conditions.

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

Example 10

Preparation of 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide from the benzenesulfonic acid salt of this compound mg (0.086 mmol) of the 2-chloro-N- ( 4-Chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid was suspended in 1.5 mL of dichloromethane by stirring. 0.75 ml of 2M K 2 CO 3 was added to the suspension and stirred until complete dissolution. The clear solution was shaken. The organic phase was separated and shaken 3 times with 0.5 ml of water. The aqueous phases were combined and shaken 3 times with 0.5 ml of dichloromethane. The organic phases were collected and several teaspoons (2-3 grams) of Na ₂ SO 4 were added as desiccants. After a few minutes, the desiccant was filtered off by suction. The dichloromethane was evaporated on a rotary evaporator and the free phase was suspended in 0.1 ml of ethyl acetate. The resulting suspension was stirred at room temperature overnight, then filtered and dried under ambient conditions.

Yield: 38 mg (76%)

HPLC: 99.8%

Analogously, the same result was obtained using 2-chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide with 4-chlorobenzenesulfonic acid, p-toluenesulfonic acid and hydrobromic acid. .

A similar result was achieved with any of the recrystallization solvents listed in Table 9.

Table 9 ___________ Solvent ___________ ______________ Acetone ______________ _______________ Acetonitrile_______________ Acetonitrile - water-solvent mixture 2-Propanol

Analysis - Raman Spectroscopy (Fourier Transform Infrared)

Raman spectra were measured using a Nicolet Thermo 6700 spectrometer.

General settings:

Number of sample measurements: 45

Number of background measurements: 45

Resolution: 4000

Sample Gain: 4.0

Optical Speed: 0.6329

Aperture: 100.00

Analysis - 1 H-NMR spectroscopy

For measurement of 1 H NMR spectra, a Bruker NMR AVANCE 500 MHz spectrometer and DMSO were used

71 solvent. The stoichiometry of the salts was determined from the integrals of the corresponding API and counter ion signals.

Analysis - Solid State NMR spectroscopy

13C CP-MAS DC NMR spectra were measured on a Bruker 400 WB spectrometer with a 4 mm rotor at a rotational frequency of 13 kHz. The salt spectra were compared to the spectrum of the initial API, since salt formation should be accompanied by changes in the positions of the API signals and the presence of paired ion signals.

XRPD (X-ray powder diffractometry) analysis

Diffractograms were generated using an X'PERT PRO MPD PANalytical laboratory diffractometer using CuKα radiation (λ = 1.542A).

Generator settings:

- excitation voltage 45 kV

- anode current of 40 mA.

Scan Description:

- scan type

- gonio measuring range 2 - 40 ° 2θ

- step size 0,01 ° 2θ

- step duration: 0.5 s.

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

Optical beam: programmable divergence iris (irradiated length 10 mm). 10 mm mask. 1/4 ° anti-scattering fixed aperture, 0.02 row Soller aperture.

Diffracted beam optics: X‘Celerator detector, sensing mode, 2.122 ° active length, 0.02 row Soller iris, 5.0 mm anti-scatter iris. Filter Ni.

DSC (Differential Scanning Calorimetry) Analysis

DSC measurements were performed on the TA Discovery DSC Instrument.

The samples were weighed in aluminum dishes with lids (40 μΐ) and measured in a nitrogen stream. The investigations were carried out in a temperature range of 0 ° C to 280 ° C at a heating rate of 5 ° C / min. The temperatures reported in conjunction with DSC analyzes are maximum peak temperatures (T _peak ) and _peak onset temperatures (T _onset ) for crystalline form and glass transition temperature (T _g ) for amorphous form. Enthalpy is reported in J / g.

The sample weight was about 1 mg.

Some results of further characterization of the new salts according to this invention are detailed in the following tables:

A) 2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and benzenesulfonic acid salt

A H NMR 1 - 1 HPLC 98.8 XRPD mostly amorphous DSC M.p. = 92.1 ° C

B) 2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and 4-chlorobenzenesulfonic acid salt

B H NMR 1 - 1 HPLC 98.4 XRPD mostly amorphous DSC _Te - 97.8 ° C

C) 2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and p-toluenesulfonic acid salt

C H NMR 1 - 1 HPLC 98.8 XRPD amorphous DSC Tpeak, i = 77.9 ° C (water) T _s = 97.4 ° C

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D) 2-Chloro-N- (4-chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide and hydrobromic acid salt;

D 1 H-NMR suits HPLC 98.4 XRPD crystalline DSC T _offset , i = 75.7 ° C; = 88.8 ° C (water) T _onset .2 = 233.2 ° C; T _Deak , ₂ = 244.4 ° C

PROTECTION REQUIREMENTS

Claims (7)

A salt of a compound of formula (I) with an acid component selected from the group consisting of hydrobromic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid and p-toluenesulfonic acid. The salt of claim 1, which is in amorphous or crystalline form. The hydrobromic acid salt of the compound of formula (I) according to claim 1, which, by CuKa, exhibits an X-ray diffractogram (XRPD) with characteristic peaks at a reflection angle of 2θ (± 0.2 ° 2Θ) 10.3; 16.9; 20.8; 22.4; 24.7 and 26.9. A salt of the compound of formula (I) with benzenesulfonic acid according to claim 1, which, with CuKa, has an amorphous form. A salt of a compound of formula (I) with 4-chlorobenzenesulfonic acid according to claim 1, which, by CuKa, has an amorphous form. A salt of a compound of formula (I) with p-toluenesulfonic acid according to claim 1, which, with CuKa, has an amorphous form. A pharmaceutical composition comprising a salt according to any one of claims 1 to 6.