WO2015169269A1 - Sels de 2-chloro-n- (4-chloro -3- (pyridin -2-yl)phényl)-4- (méthylsulfonyl)benzamide - Google Patents

Sels de 2-chloro-n- (4-chloro -3- (pyridin -2-yl)phényl)-4- (méthylsulfonyl)benzamide Download PDF

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WO2015169269A1
WO2015169269A1 PCT/CZ2014/000049 CZ2014000049W WO2015169269A1 WO 2015169269 A1 WO2015169269 A1 WO 2015169269A1 CZ 2014000049 W CZ2014000049 W CZ 2014000049W WO 2015169269 A1 WO2015169269 A1 WO 2015169269A1
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chloro
pyridin
phenyl
benzamide
methylsulfonyl
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PCT/CZ2014/000049
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English (en)
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Ludek Ridvan
Violetta Kiss
Hana TOZICKOVA
Marcela Tkadlecova
Ondrej Dammer
Lukas KREJCIK
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Zentiva, K.S.
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Priority to PCT/CZ2014/000049 priority Critical patent/WO2015169269A1/fr
Publication of WO2015169269A1 publication Critical patent/WO2015169269A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • 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:
  • 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.
  • 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.
  • 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.
  • 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 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.
  • polymorph The ability of a compound to crystallize in different crystalline phases is called polymorphism.
  • 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).
  • amorphous phase disordered
  • hydrates water presents in the crystal lattice
  • 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 effortlessroom temperature is defined as a temperature between 15°C and 30°C; preferably it is between 20-25°C or about 25°C.
  • Jaboratory condition means room temperature and relative humidity 20-60%.
  • the present invention further relates to characterization of prepared forms and salts of vismodegib using Raman, 1 H-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.
  • 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 1 H-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 1 H-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 1 H-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
  • 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.
  • 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 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) of 6.5; 15.6; 20.3; 22.7; 25.7 and 31.8.
  • 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. [%]
  • 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
  • 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 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) of 10.3; 14.1; 18.1; 20.7 and 23.3.
  • 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. [%]
  • 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 e C.
  • 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 2 ⁇ (+ 0.2° 2 ⁇ ) of 7.7; 13.8; 19.7; 21.1; 23.0 and 26.6.
  • 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:
  • 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 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 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) of 7.7; 14.2; 17.1; 19.9 and 23.3.
  • 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:
  • 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 2 ⁇ ( ⁇ 0.2° 2 ⁇ ) of 10.1; 17.4; 19.1; 22.1 and 23.7.
  • 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. [%]
  • 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)benzamide can 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.
  • 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.
  • 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.
  • 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.
  • 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 x wavenumbers.
  • 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 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.
  • Raman Bruker RFS 100/S
  • 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.
  • 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.
  • 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%).
  • 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:
  • 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.
  • DSC T Instruments Discovery DSC
  • This salt was characterized by Raman spectroscopy (Fig. 28), 1 H-NMR (Fig. 29), XRPD (Fig. 30), and by DSC technique (Fig. 31).
  • 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.
  • RAMAN spectra were recorded by Nicolet Thermo 6700 spectrometer.
  • 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)
  • the sample were weighed in aluminium pans and covers (40 ⁇ ) 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.

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Abstract

Sel comprenant un composé de formule (I) et au moins un constituant acide (HA).
PCT/CZ2014/000049 2014-05-05 2014-05-05 Sels de 2-chloro-n- (4-chloro -3- (pyridin -2-yl)phényl)-4- (méthylsulfonyl)benzamide WO2015169269A1 (fr)

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