WO2015085973A1 - Modifications of 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt - Google Patents

Abstract

Crystal modifications and amorphous form of ponatinib hydrochloride. Formula (I)

Description

Modifications of 3-(2-imidazo[l,2-b]pyridazin-3-Ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

Background of the invention

1. Field of the invention

The present invention relates to a novel modifications of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt of Formula I

(I)

in crystalline or amorphous phase, the processes for the preparation thereof as well as said modification for use in phamaceutically compositions.

2. Background information

3-(2-lmidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-IM-[4-[(4-methyl-l-piperazinyl)methyl]-3-

(trifluoromethyl)phenyl] benzamide compound which is also known as ponatinib (CAS no.: 943319- 70-8) has a tyrosine kinase inhibitor activity which is effectively used for the treatment of chronic myeloid leukaemia (CML) as well as Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL).

The enzyme tyrosine kinase is a subclass of protein kinase and it plays an important role in the phosphate group transfer in form adenosine triphosphate (ATP) to a protein in the cell. The phosphate group is attached to the appropriate amino acid, tyrosine on the protein. Tyrosine kinases act as an "on" and "off' switch, however, can easily undergo mutation by sticking in the "on" position resulting in uncontrolled growth of the cell that leads to the development of cancer. Consequently, tyrosine kinase inhibitors are often used as effective agents for cancer treatments.

WO2007075869 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases. One example of the compounds disclosed is 3-(2-imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide; preparation of the base and the hydrochloride salt thereof are described.

Many pharmaceutical solid compounds can exist in various crystalline forms regarded as polymorphs and hydrates/solvates. Salts, like ponatinib hydrochloride 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 disticnt 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 modification having desirable physicochamical properties and processability and improve the characteristics of the pharmaceutical product. For this reason there is an explicit need for new solid forms (polymoprhs, solvates, hydrates) of ponatinib hydrochloride.

Summary of the invention The object of the present invention is to provide novel modifications of 3-(2-imidazo[l,2-b]pyridazin- 3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt suitable for oral administration which meet the pharmaceutical requirements.

The present invention further relates to a pharmaceutical formulations containing the modifications of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt and the use thereof for the treatment of cancer.

It has now surprisingly been found that the compound of formula I can be prepared in 10 different crystal modifications as well as in amorphous phase. These 11 solid phase modifications, referred to herein as Crystal modification 1, Crystal modification 2, Crystal modification 3, Crystal modification 4, Crystal modification 5, Crystal modification 6, Crystal modification 7, Crystal modification 8, Crystal modification 9, Crystal modification 10 and amorphous phase, have different physico- chemical properties. Each solid phases were identified by characteristic X-Ray Powder diffractograms and Raman spectra and Fourier Transformed Infrared spectra; Crystal modification 1, Crystal modification 2, Crystal modification 3, Crystal modification 4, Crystal modification 5 and the amorphous phase were identified furthermore by solid state NMR spectra and differ in their Differential Scanning Calorimetry and Thermal Gravimetric Analysis curves, too.

Brief description of the figures

The figures depict the following spectra of the various salts prepared according to the invention. Figure 1 is an XRPD pattern of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 2 is a FTIR spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 3 is a Raman spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 4 is a ssNMR spectra of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt; Figure 5 is a DSC curve of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 6 is a TGA curve of the Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 7 is an XRPD pattern of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 8 is a FTIR spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 9 is a Raman spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 10 is a ssN R spectra of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 11 is a DSC curve of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 12 is a TGA curve of the Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 13 is an XRPD pattern of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 14 is a FTIR spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 15 is a Raman spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 16 is a ssNMR spectra of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 17 is a DSC curve of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 18 is a TGA curve of the Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 19 is an XRPD pattern of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt; Figure 20 is a FTIR spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 21 is a Raman spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 22 is a ssNMR spectra of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 23 is a DSC curve of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 24 is a TGA curve of the Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 25 is an XRPD pattern of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 26 is a FTIR spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 27 is a Raman spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 28 is a ssNMR spectra of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 29 is a DSC curve of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 30 is a TGA curve of the Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 31 is an XRPD pattern of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 32 is a FTIR spectra of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 33 is a Raman spectra of the Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 34 is an XRPD pattern of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt; Figure 35 is a FTIR spectra of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)- 4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 36 is a Raman spectra of the Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 37 is an XRPD pattern of the Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 38 is a Raman spectra of the Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 39 is an XRPD pattern of the Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 40 is a Raman spectra of the Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 41 is an XRPD pattern of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 42 is a FTIR spectra of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 43 is a Raman spectra of the Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 44 is an XRPD pattern of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 45 is a FTIR spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 46 is a Raman spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 47 is a ssN R spectra of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 48 is a DSC curve of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt;

Figure 49 is a TGA curve of the amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt. Detailed description of the invention

The aim of the present invention is to provide novel modifications of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride (ponatinib hydrochloride) of formula I with advantegous properties for pharmaceutical use regarding the physico-chemical properties and can be produced in a reproducible manner even in industrial scale.

(1)

The term„modification, modifications" of ponatinib hydrochloride, as used in this document, is synonymous to terms„solid state form, solid phase modification" of ponatinib hydrochloride and includes crystalline modifications, amorphous phases, hydrates and solvates of ponatinib hydrochloride.

The term„crystal modification" of ponatinib hydrochloride, as used in this document, is synonymous to commonly used expressions polymorphic form" or„crystalline form" of ponatinib hydrochloride.

The term„amorphous phase of ponatinib hydrochloride", as used in this document, is synonymous to commonly used expressions„amorphous ponatinib hydrochloride".

It has been surprisingly found that the above-mentioned crystalline modifications of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-

(trifluoromethyl)phenyl] benzamide hydrochloride can be prepared and have not been described in the literature and no solid state analytical data (X-Ray Powder Diffraction patterns, Single-Crystal X- Ray Diffraction data etc.) serving to characterize the crystalline phases have been provided.

The Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was prepared and indentified when the process of the patent application WO2007/075869 was reproduced. This crystalline modification has the characteristic XRPD pattern as shown in Figure 1. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:

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

5.80 15.231 29.6

6.98 12.653 42.7

9.97 8.864 27.3

12.40 7.134 67.4

13.53 6.538 26.8 14.12 6.268 15.4

14.84 5.965 14.5

15.72 5.634 10.2

16.31 5.430 36.5

17.58 5.040 14.2

18.56 4.776 12.9

19.22 4.614 100.0

20.23 4.387 18.4

21.78 4.078 33.0

22.23 3.996 17.3

23.73 3.746 35.3

24.97 3.563 14.0

25.45 3.498 9.6

25.95 3.431 72.2

26.76 3.329 10.6

27.39 3.254 8.7

28.34 3.146 7.5

29.42 3.033 6.2

30.08 2.969 6.8

31.75 2.816 8.0

34.95 2.565 8.5

Table 1

The Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 3 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2924, 2219, 1671, 1620, 1397, 1190, 1153, 1103, 903 and 468 cm^"1 wavenumbers and Figure 4 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 5 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 6 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively. The Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt shows a 0.9% weigth loss in the range of 20°C-to 100°C. The DSC measurement gives a melting process with T_onset=258.5°C and T_peak=261.5°C.

In one of the aspects of the invention, an alternative process for preparation of the crystalline modification 1 is provided. In this process, ponatinib hydrochloride is suspended in a suitable organic solvent by heating of the system to a temperature close to the boiling point of the solvent. The suspension is then stirred at this temperature for 10-15 minutes, then cooled back to room temperature and left for stirring overnight. After filtering off and drying at laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of ponatinib hydrochloride.

The suitable organic solvent is a solvent selected form the group of acetone, acetonitrile, butyl acetate, 2-butanone, cyclohexane, diethyl ether, toluene, xylene, dioxane, ethyl acetate, 4-methyl-2- pentanone, n-hexane and tetrahydrofurane.

The process of preparation of the Crystal modification 1 of ponatinib hydrochloride thus comprises the steps of: a/ suspending ponatinib hydrochloride in a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, cyclohexane, diethyl ether, toluene, xylene, dioxane, ethyl acetate, 4-methyl-2-pentanone, n-hexane and tetrahydrofurane by heating close to the boiling point of the respective solvent:

b/ stirring the suspension of the step a/ for 10-15 min at the temperature close to the boiling point of the respective solvent used in the step a/;

c/ cooling the suspension of the step b/ to a temperature of 15-29°C;

d/ stirring the suspension of the step c/ for 12-16 hours;

e/ isolating the ponatinib hydrochloride in Crystal modification 1.

The Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt 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). The Crystal modification 2 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-

(trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 3, below:

Table 3

The Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 9 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2967, 2214, 1655, 1617, 1524, 1155, 999, 912, 839 and 459 cm ¹ wavenumbers and Figure 10 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods. Figure 11 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 12 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 350°C and 20°C to 300°C, respectively. The crystalline Modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-t(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate that shows a 11.1% weigth loss in the range of 20°C-to 230°C. The rresponding to water loss),

The Crystal modification 2 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving ponatinib hydrochloride in a solvent selected form the group consisting of 75 v/v % ethanol-water mixture; water; and water-dioxane in 1:1 ratio by volume at room temperature; b/ evaporating the solvent at laboratory conditions.

Another process of preparation of the Crystal modification 2 of ponatinib hydrochloride comprises the steps of:

a/ suspending ponatinib hydrochloride in water at room temperature;

b/ stirring the suspension of the step a/ for one week;

c/ isolating the Crystal modification 2 of ponatinib hydrochloride.

The Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt 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). The Crystal modification 3 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride exhibits the following diffraction peaks in XRPD pattern, see Table 4, below:

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

5.98 14.771 75.0

12.14 7.286 25.3

13.54 6.533 37.9

13.92 6.359 34.8

15.20 5.824 23.9

15.61 5.671 27.1

16.01 5.532 18.7

16.32 5.426 18.8

16.98 5.217 100.0

17.90 4.952 85.8

18.31 4.841 65.4

19.14 4.634 31.8

20.08 4.418 96.5

21.84 4.067 65.0 22.60 3.931 25.5

24.60 3.616 29.5

25.14 3.539 67.8

25.95 3.431 49.7

26.37 3.377 37.2

27.05 3.294 30.4

28.69 3.109 17.8

Table 4

The Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 15 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3045, 2958, 2216, 1654, 1619, 1156, 1024, 1000, 888 and 471 cm-1 wavenumbers and Figure 16 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-t4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods. Figure 17 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 18 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 350°C and 20°C to 300°C, respectively. The crystalline Modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate and shows a 9.0% weigth loss in the range of 20°C-to 150°C. The DSC measurement gives a melting process with

and

The Crystal modification 3 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in water by heating to the boiling point;

b/ cooling the solution of the step a/ to a room temperature by exposing the solution of the step a/ to room temperature for a time period sufficient to achieve cooling of the system to the room temperature or by placing the test-tube / vial containing the solution of the step a/ into ice;

c/ isolating the crystal modification 3 of ponatinib hydrochloride.

The solution resulting from the step a/ can be optionally filtered in order to remove the possible undissolved solids prior to the cooling step b/.

Another process of preparation of the Crystal modification 3 of ponatinib hydrochloride comprises the steps of:

a/ dissolving the ponatinib hydrochloride in methanol at room temperature;

b/ isolating the Crystal modification 3 of ponatinib hydrochloride by evaporation of methanol at laboratory conditions.

The Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 19. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The Crystal modification 4 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 5, below: Pos. [^e2Th.] d-spacing [A] el. Int. [%]

6.84 12.905 40.1

7.25 12.178 100.0

8.01 11.036 58.1

10.32 8.569 5.0

11.28 7.839 3.5

13.37 6.619 2.5

14.70 6.020 10.3

16.24 5.453 14.4

16.67 5.313 4.2

17.78 4.983 3.0

21.65 4.101 4.2

22.65 3.923 6.9

23.93 3.715 4.8

24.59 3.617 4.6

25.88 3.439 2.3

28.30 3.151 4.0

29.68 3.007 4.1

33.09 2.705 3.7

Table 5

The Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 21 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2969, 2220, 1659, 1162, 1071, 1005, 910, 738, 555 and 463 cm^"1 wavenumbers and Figure 22 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods. Figure 23 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 24 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively. The crystalline Modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate and shows a 8.1% weigth loss in the range of 20°C-to 100°C. The DSC responding to water loss),

The Crystal modification 4 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 75 v/v% ethanol-water mixture by heating to the boiling point;

b/ cooling the solution of the step a/ to the room temperature by placing the test-tube / vial containing the the solution of the step a/ into ice;

c/ isolating the Crystal modification 4 of ponatinib hydrochloride.

The Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 25. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO PD PANalytical). The Crystal modification 5 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 6, below:

Table 6

The Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 27 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 2959, 2216, 1660, 1617, 1421, 1233, 1162, 1003, 903 and 460 cm ¹ wavenumbers and Figure 28 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The Crystal modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods. Figure 29 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 30 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively. The crystalline Modification 5 of 3-(2-imidazo[l,2-b]pyridazin-3- ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a solvate and shows a 11.1% weigth loss in the range of 20°C-to 230°C. The DSC measurement gives a melting process with

and

The Crystal modification 5 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ suspending ponatinib hydrochloride in toluene at room temperature;

b/ stirring the suspension of the step a/ for one week;

c/ isolating the Crystal modification 5 of ponatinib hydrochloride. The Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 31. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 6 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-

(trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 7, below:

Table 7

The Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy. Figure 33 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3067, 2960, 2214, 1672, 1313, 1269, 1053, 911, 765 and 436 cm^"1 wavenumbers.

The Crystal modification 6 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol or ethanol by heating to the boiling point; b/ cooling the solution of the step a/ to a room temperature by placing the test-tube / vial containing the the solution of the step a/ into ice or by exposing the solution of the step a/ to room temperature for a time period sufficient to achieve cooling of the system to the room temperature; c/ isolating the Crystal modification 6 of ponatinib hydrochloride.

In one embodiment of the invention the Crystal modification 6 of ponatinib hydrochloride is prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol or ethanol by heating to the boiling point; b/ cooling the solution of the step a/ to a room temperature by placing the test-tube / vial containing the the solution of the step a/ into ice;

c/ isolating the Crystal modification 6 of ponatinib hydrochloride.

In another embodiment of the invention the Crystal modification 6 of ponatinib hydrochloride is prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol by heating to the boiling point;

b/ cooling the solution of the step a/ to a room temperature by exposing the solution of the step a/ to room temperature for a time period sufficient to achieve cooling of the system to the room temperature;

c/ isolating the Crystal modification 6 of ponatinib hydrochloride.

Another process of preparation of the Crystal modification 6 of ponatinib hydrochloride comprises the steps of:

a/ dissolving the ponatinib hydrochloride in methanol at room temperature;

b/ isolating the Crystal modification 6 of ponatinib hydrochloride by evaporation of methanol in vacuum oven at 60°C using 500 mbar vacuum pressure.

The Crystal modification 7 of S-f -imidazofl^-bJpyridazin-B-ylethyny ^-methyl-N-f -ff^methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic X PD pattern as shown in Figure 34. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 7 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 8, below:

Table 8

The Crystal modification 7 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy. Figure 36 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3008, 2958, 2208, 1665, 1360, 1258, 1069, 1001, 771 and 460 cm^"1 wavenumbers.

The Crystal modification 7 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 75 v/v % ethanol-water mixture by heating to the boiling point;

b/ cooling the solution of the step a/ to a room temperature;

c/ isolating the Crystal modification 7 of ponatinib hydrochloride.

The Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 37. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The XRPD pattern of Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt corresponds to a semi- crystalline form and exhibits the following diffraction peaks in XRPD pattern, see Table 9, below:

Table 9

The Crystal modification 8 of 3-(2-imidazofl,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy. Figure 38 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 3962, 2215, 1656, 1310, 1263, 1067, 996, 762 and 456 cm^"1 wavenumbers.

The Crystal modification 8 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol by heating to the boiling point;

b/ cooling the solution of the step a/ to room temperature by placing the test-tube / vial containing the solution of the step a/ into ice;

c/ isolating the Crystal modification 8 of ponatinib hydrochloride.

The Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 39. XRPD pattern was recorded on an X- ay Powder Diffractometer (X^'PERT PRO MPD PANalytical). The XRPD pattern of Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt corresponds to a semi- crystalline form and exhibits the following diffraction peaks in XRPD pattern, see Table 10, below:

Table 10

The Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy. Figure 40 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3068, 2929, 2217, 1671, 1607, 1539, 1398, 1308, 1154 and 776 cm ¹ wavenumbers.

The Crystal modification 9 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol at room temperature;

b/ isolating the Crystal modification 9 of ponatinib hydrochloride by evaporation of methanol in vacuum oven at 60°C using 500 mbar vacuum pressure.

The Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 41. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 10 of 3-(2- imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide hydrochloride salt exhibits the following diffraction peaks in XRPD pattern, see Table 11, below:

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

6.71 13.155 4.5

8.39 10.535 100.0

10.72 8.245 10.0

13.52 6.542 5.6

15.02 5.892 4.5

16.61 5.333 37.8

17.71 5.004 12.2

18.22 4.866 13.4

21.96 4.045 6.2

22.95 3.871 11.6

24.19 3.676 6.0

24.92 3.571 16.2

25.38 3.506 7.9

26.24 3.393 5.3 28.66 3.112 6.7

29.90 2.986 6.3

32.64 2.741 6.3

33.41 2.680 6.9

Table 11

The Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy. Figure 43 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3965, 3922, 2217, 1659, 1606, 1478, 1359, 1313, 761 and 463 cm^"1 wavenumbers.

The Crystal modification 10 of ponatinib hydrochloride can be prepared by a process comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol at room temperature;

b/ isolating the Crystal modification 10 of ponatinib hydrochloride by evaporation of 2-propanol at laboratory conditions.

The amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt according to the invention has the characteristic XRPD pattern as shown in Figure 44. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).

The amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be characterized by Raman spectroscopy and solid-state NMR invesitgations. Figure 46 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3069, 2963, 2216, 1667, 1606, 1399, 1154, 1000, 904 and 463 cm ¹ wavenumbers and Figure 47 shows the ssNMR (Bruker AVANCE 250 MHz) spectrum.

The amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt can be further described by thermal analytical methods. Figure 48 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 49 shows the TGA (Perkin Elmer TGA 6) curves measured in the range of 50°C to 300°C and 20°C to 300°C, respectively. The amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4- methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt is a hydrate that shows a 8.2% weigth loss in the range of 20°C-to 160°C. The DSC measurement gives a melting process with T_{peak l}=86.7°C (corresponding to water loss), T_{onset 2}=128.7°C,

The amorphous ponatinib hydrochloride can be prepared by a process comprising the steps of: a/ dissolving ponatinib hydrochloride in a solvent selected form the group of consisting of water; ethanol; and water-dioxane in 1:1 ratio by volume at room temperature;

b/ isolating the amorphous ponatinib hydrochloride by evaporation of the solvent in vacuum oven at 60°C using 500 mbar vacuum pressure.

Another process for preparation of the amorphous ponatinib hydrochloride comprisese the steps of: a/ dissolving the ponatinib hydrochloride in ethanol at room temperature;

b/ isolating the amorphous ponatinib hydrochloride by evaporation of ethanol at laboratory conditions. Yet another process of preparation of the amorphous ponatinib hydrochloride comprises the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol by heating to the boiling point;

b/ isolating the amorphous ponatinib hydrochloride by evaporation of the 2-propanol under pressure 50 mbar at 40°C;

c/ optionally, drying of the product of the step b/ at laboratory conditions until the constant weight of the product is reached.

The term„room temperature" is defined as a temperature between 15°C and 29°C for the purpose of this document; preferably it is between 20-23°C.

The term„overnight" as used in this patent application is related to the duration of the given process step. The process that is to be carried out„overnight" has to be performed for at least 10 hours, preferably 12-16 hours.

The term„drying at laboratory condition", as used in this patent application, means drying at room temperature and relative humidity 20-60%.

The expression „heating to the boiling" or „heating to the boiling point" or „heating to a temperature close to the boiling point" of the solvent means heating to a temperature that lies between the temperature of the boiling point and the temperature of 5 °C lower than the temperature of the boiling point of the respective solvent, including the limit values.

lower than the boiling point of the respective solvent.

Analysis - XRPD (X-Ray Powder Diffractometry)

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

Generator settings:

excitation voltage 45 kV

anodic current 40 mA.

Scan description:

scan type - gonio

- measurement range 2 - 40^ 2Θ

- step size 0.012 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. 1/42 anti-scatter fixed slit, 0.02 rad Soller slits.

Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122⁵. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.

Analysis - Raman spectroscopy

FTIR spectra were recorded by FT-Raman Bruker RFS 100/S Spectrometer

General settings: Excitation source: Nd-YAG laser (1064 nm)

Applied spectral domain: 3600-200 cm^"1

Applied laser power: 250 mW

Detector: liquid nitrogen cooled Ge-diode detector (D418-T)

Resolution: 4 cm^"1

Number of accumulations: 128

Scattering geometry: 180° (back scattering)

Aperture: 3.5 mm Analysis - FTIR (Fourier-Transformed Infra-Red) spectroscopy

FTIR 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 - Solid State NMR spectroscopy

¹³C CP-MAS ss NMR spectra were meausred 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 coformer.

Analysis - DSC (Differential Scanning Calorimetry)

DSC measurements were performed on a Perkin Elmer Pyris 1 DSC.

The sample were weighed in aluminium pans and covers (20 μί) and measured in a nitrogen flow. Investigations were performed in a temperature range of 50°C to 300-350°C with a heating rate of 10°C/min. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima and onset temperature of peaks.

The peak temperature is obviously the temperature at the maximum/minimum of the thermal event.

The onset temperature is defined as the intersection of the tangents of the peak with the extrapolated baseline.

The weight sample was about 3.5 mg. Analysis - TGA (ThermoGravimetric Analysis)

TGA were performed on a Perkin Elmer TGA 6.

The samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 20°C to 300°C with a heating rate of 10°C/min.

The weight sample was about 3-21 mg.

Example

Example 1 - reproduction of the prior art (Crystal modification 1)

Preparation of Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

Process described in the patent application WO2007/075869 was reproduced. 2 g (3.755 mmol) of 3- (2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-IM-[4-[(4-methyl-l-piperazinyl)methyl]-3- (trifluoromethyl)phenyl] benzamide was suspended in 40 mL of acetonitrile and heated to 50°C with stirring. 360 pL (4.057 mmol) of hydrochloric acid was dissolved in 4 mL of ethanol at room temperature and the solution of the counterion was drop-wise added to the solution of the API of 50°C while complete dissolution occured. Within a few minutes a precipitate was formed.

The suspension was cooled back to room temperature and was filtered off, washed with 6 mL of mother liqour and 6 mL of fresh acetonitrile. The solids were dried at 50°C under vacuum overnight. Yield: 1.63 g (76%)

FTIR spectra confirmed the structure. The XRPD pattern was measured (Figure 1) and showed that the compound is in a crystalline state that was designated as Crystal modification 1.

Example 2

Preparation of Crystal modification 1 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

Alternative process for crystal modification 1 is provided. 60 mg (0.105 mmol) of 3-(2-imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was suspended in acetone by heating to the boiling of the solvent. The suspension was stirred at this temperature for 10-15 minutes then cooled back to room temperature and left for stirring overnight. The solid was filtered off and dried at laboratory condition.

Similarly, the same result was obtained using any of the solvents listed in the table 10.

Table 10 Example 3

Preparation of Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.070 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 0.8 mL of water-dioxane mixture of 1:1 ratio by volume at room temperature. The solvent was completely evaporated at laboratory condition.

FTI spectra confirmed the structure. Example 4

Preparation of Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.070 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 1.4 mL of 75% ethanol-water mixture at room temperature. The solvent was completely evaporated at laboratory condition.

FTIR spectra confirmed the structure.

Example 5

Preparation of Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.070 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 12 mL of water at room temperature. The solvent was completely evaporated at laboratory condition. FTIR spectra confirmed the structure. Example 6

Preparation of Crystal modification 2 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt 300 mg (0.527 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was suspended in 3 mL water. The slurry was stirred for one week at laboratory condition. Finally the resulting suspension was filtered off and dried at laboratory condition.

Yield: 220 mg (73%)

FTIR spectra confirmed the structure. Example 7

Preparation of Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.070 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 4.5 mL of methanol at room temperature. The solvent was completely evaporated at laboratory condition.

FTIR spectra confirmed the structure. Example 8

Preparation of Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 0.2 mL of dimethyl sulfoxide by heating to the boiling point of the solvent. The hot solution was slowly cooled back to room temperature and the resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 9

Preparation of Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [{4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenylJ benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 2.5 mL of water by heating to the boiling point of the solvent. The hot solution was slowly cooled back to room temperature and the resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 10

Preparation of Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 2.5 mL of water by heating to the boiling point of the solvent. The test-tube / vial containing the hot solution was placed into ice and left to cool down to room temperature. The resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 11

Preparation of Crystal modification 3 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

150 mg (0.264 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was charged into a micro test tube and 6.3 mL of water was dispensed into the tube. The vial was agitated during heating to the boiling point (95°C) to ensure adequate dissolution of the 3-(2-imidazo[l,2- b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt. Then the solution was filtered to remove the remaining solid particles and it was left to cool slowly down to room temperature. Finally the resulting precipitate was filtered off and dried at laboratory condition.

Yield: 105 mg (70%)

FTIR spectra confirmed the structure. Example 12

Preparation of Crystal modification 4 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

100 mg (0.176 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was charged into a micro test tube and 0.5 mL of 75% ethanol-water mixture was dispensed into the tube. The vial was agitated during heating close to the boiling point of the solvent (75°C) to ensure adequate dissolution of the API. Then the vial with the solution was placed into ice and was left to cool down to room temperature. Finally the resulting precipitate was filtered off and dried at laboratory condition.

Yield: 52 mg (52%)

FTIR spectra confirmed the structure.

Example 13

Preparation of Crystal modification 5 of 3-{2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

100 mg (0.176 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was suspended in 3 mL toluene. The slurry was stirred for one week at ambient condition. Finally the resulting suspension was filtered off and dried at laboratory condition.

Yield: 69 mg (69%)

FTIR spectra confirmed the structure.

Example 14

Preparation of Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-t4-((4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 3.5 mL of methanol by heating to the boiling point of the solvent. The hot solution was slowly cooled back to room temperature and the resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure.

Example 15

Preparation of Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 3.5 mL of methanol by heating to the boiling point of the solvent. The test-tube / vial containing the hot solution was placed into ice and left to cool down to room temperature. The resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 16

Preparation of Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 4 mL of anhydrous ethanol by heating to the boiling point of the solvent. The test-tube / vial containing the hot solution was placed into ice and left to cool down to room temperature. The resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 17

Preparation of Crystal modification 6 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazotl_/2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 4.5 mL of methanol at room temperature. The solvent was evaporated in vacuum oven at 60°C.

FTIR spectra confirmed the structure.

Example 18

Preparation of Crystal modification 7 of 3-{2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 0.3 mL of 75% ethanol-water mixture by heating to the boiling point of the solvent. The hot solution was slowly cooled back to room temperature and the resulting precipitate was filtered off and dried at laboratory condition.

FTIR spectra confirmed the structure. Example 19

Preparation of Crystal modification 8 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

60 mg (0.105 mmol) of 3-(2-imidazo[l_;2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 8 mL of 2-propanol by heating to the boiling point of the solvent. The test-tube / vial containing the hot solution was placed into ice and left to cool down to room temperature. The resulting precipitate was filtered off and dried at laboratory condition.

Example 20

Preparation of Crystal modification 9 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 25 mL of 2-propanol at room temperature. The solvent was evaporated in vacuum oven at 60°C.

Example 21

Preparation of Crystal modification 10 of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4- [(4-methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 25 mL of 2-propanol at room temperature. The solvent was evaporated at laboratory condition.

FTIR spectra confirmed the structure.

Example 22

Preparation of amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 11 mL of ethanol at room temperature. The solvent was evaporated at laboratory condition.

FTIR spectra confirmed the structure.

Example 23

Preparation of amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethyny!)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 0.8 mL of water-dioxane mixture of 1:1 ratio by volume at room temperature. The solvent was evaporated in vacuum oven at 60°C.

FTIR spectra confirmed the structure. Example 24

Preparation of amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phertyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 11 mL of ethanol at room temperature. The solvent was evaporated in vacuum oven at 60°C.

FTIR spectra confirmed the structure.

Example 25

Preparation of amorphous phase of 3-{2-imidazoIl,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

40 mg (0.105 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 12 mL of water at room temperature. The solvent was evaporated in vacuum oven at 60°C.

FTIR spectra confirmed the structure.

Example 26

Preparation of amorphous phase of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4- methyl-l-piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt

100 mg (0.176 mmol) of 3-(2-imidazo[l,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-l- piperazinyl)methyl]-3-(trifluoromethyl)phenyl] benzamide hydrochloride salt was dissolved in 42 mL of 2-propanol by heating to the boiling point. The vial was agitated during heating to ensure adequate dissolution of the API. The solvent was almost completely evaporated under reduced pressure at 40°C and 50 mbar. Finally the resulting suspension was dried at laboratory condition. Yield: 99 mg (99%)

FTIR spectra confirmed the structure.

Claims

Claims:

1. A process of preparation of the Crystal modification 1 of ponatinib hydrochlorid comprising the steps of:

a/ suspending ponatinib hydrochloride in a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, cyclohexane, diethyl ether, toluene, xylene, dioxane, ethyl acetate, 4-methyl-2-pentanone, n-hexane and tetrahydrofurane by heating to a temperature close to the boiling point of the respective solvent;

b/ stirring the suspension of the step a/ for 10-15 min at a temperature close to the boiling point of the respective solvent used in the step a/;

c/ cooling the suspension of the step b/ to a temperature of 15-29°C;

d/ stirring the suspension of the step c/ for 12-16 hours;

e/ isolating the ponatinib hydrochloride in Crystal modification 1.

2. Crystal modification 2 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKot (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 7.0, 13.4, 16.5, 21.0, 22.2 and 25.9°.

3. Crystal modification 2 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm ¹ at 2967, 2214, 1655, 1617, 1524 1155, 999, 912, 839 and 459 cm^"1 wavenumbers.

4. Crystal modification 2 of ponatinib hydrochloride, characterised by a melting process which gives endothermic maxima at 94.2°C, 152.0°C and 255.7°C, which occur during thermal analysis using DSC in the range of 50-350°C.

5. Crystal modification 2 of ponatinib hydrochloride, characterised by a TGA thermal analysis measured by a in the range of 20-300°C shown in the Figure 12.

6. Crystal modification 2 of ponatinib hydrochloride, characterised by a solid-state ¹³C NMR spectrum depicted in Figure 10.

7. Process of preparation of the Crystal modification 2 of ponatinib hydrochloride comprising the ste s of:

a/ dissolving ponatinib hydrochloride in a solvent selected form the group consisting of 75 v/v % ethanol-water mixture; water; and water-dioxane in 1:1 ratio by volume at room temperature; b/ evaporating the solvent at laboratory conditions.

8. Process of preparation of the Crystal modification 2 of ponatinib hydrochloride comprising the steps of:

a/ suspending ponatinib hydrochloride in water at room temperature;

b/ stirring the suspension of the step a/ for one week;

c/ isolating the crystal modification 2 of ponatinib hydrochloride.

9. Crystal modification 3 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 6.0, 13.5, 17.0, 20.1, 21.8 and 25.1°.

10. Crystal modification 3 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm ¹ at 3045, 2958, 2216, 1654, 1619, 1156, 1024, 1000, 888 and 471 cm^"1 wavenumbers.

11. Crystal modification 3 of ponatinib hydrochloride, characterised by a melting process which gives endothermic maxima at 124.1°C, 143.7°C, 249.7°C and 254.3°C, which occur during thermal analysis using DSC in the range of 50-350°C.

12. Crystal modification 3 of ponatinib hydrochloride, characterised by a TGA thermal analysis measured by a in the range of 20-300°C shown in the Figure 18.

13. Crystal modification 3 of ponatinib hydrochloride, characterised by a solid-state ¹³C NMR spectrum depicted in Figure 16.

14. Process of preparation of the Crystal modification 3 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in water by heating to the boiling point;

b/ cooling the solution of the step a/ to a room temperature;

c/ isolating the crystal modification 3 of ponatinib hydrochloride.

15. The process according the claim 14, characterised in that the cooling in the step b/ is performed by exposing the solution of the step a/ to room temperature for a time period sufficient to achieve cooling of the system to the room temperature.

16. The process according the claim 14, characterised in that the cooling in the step b/ is performed by placing the test-tube / vial containing the the solution of the step a/ into ice.

17. The process according to any of the claims 14-16, wherein the solution of the step a/ is filtered prior to the cooling step b/.

18. Process of preparation of the Crystal modification 3 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol at room temperature;

b/ isolating the Crystal modification 3 of ponatinib hydrochloride by evaporation of methanol at laboratory conditions.

19. Crystal modification 4 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 7.3, 8.0, 14.7, 16.2 and 22.6°.

20. Crystal modification 4 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm ¹ at 2969, 2220, 1659, 1162, 1071, 1005, 910, 738, 555 and 463 cm^"1 wavenumbers.

21. Crystal modification 4 of ponatinib hydrochloride, characterised by a melting process which gives endothermic maxima at 81.5⁰C, 214.7°C and 253.6 °C, which occur during thermal analysis using DSC in the range of 50-300°C.

22. Crystal modification 4 of ponatinib hydrochloride, characterised by a TGA thermal analysis measured by a in the range of 20-300°C shown in the Figure 24.

23. Crystal modification 4 of ponatinib hydrochloride, characterised by a solid-state ¹³C NMR spectrum depicted in Figure 22.

24. Process of preparation of the Crystal modification 4 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 75 v/v % ethanol-water mixture by heating to the boiling point;

b/ cooling the solution of the step a/ to the room temperature by placing the test-tube / vial containing the the solution of the step a/ into ice;

c/ isolating the Crystal modification 4 of ponatinib hydrochloride.

25. Crystal modification 5 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 7.8, 10.3, 15.4, 20.0, 23.6 and 25.1°.

26. Crystal modification 5 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm^"1 at 2959, 2216, 1660, 1617, 1421, 1233, 1162, 1003, 903 and 460 cm^"1 wavenumbers.

27. Crystal modification 5 of ponatinib hydrochloride, characterised by a melting process which gives endothermic maxima at 179.8°C, 198.5°C and 257.8°C,which occur during thermal analysis using DSC in the range of 50-300°C.

28. Crystal modification 5 of ponatinib hydrochloride, characterised by a TGA thermal analysis measured by a in the range of 20-300°C shown in the Figure 30.

29. Crystal modification 5 of ponatinib hydrochloride, characterised by a solid-state ¹³C NMR spectrum depicted in Figure 28.

30. Process of preparation of the Crystal modification 5 of ponatinib hydrochloride comprising the steps of:

a/ suspending ponatinib hydrochloride in toluene at room temperature;

b/ stirring the suspension of the step a/ for one week;

c/ isolating the Crystal modification 5 of ponatinib hydrochloride.

31. Crystal modification 6 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 10.3, 14.4, 15.9, 19.1, 20.7 and 26.2°.

32. Crystal modification 6 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm^"1 at 3067, 2960, 2214, 1672, 1313, 1269, 1053, 911, 765 and 436 cm^"1 wavenumbers.

33. Process of preparation of the crystal modification 6 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol or ethanol by heating to the boiling point; b/ cooling the solution of the step a/ to a room temperature;

c/ isolating the Crystal modification 6 of ponatinib hydrochloride.

34. The process according the claim 33, characterised in that the cooling in the step b/ is performed by placing the test-tube / vial containing the the solution of the step a/ into ice.

35. The process according the claim 33, characterised in that the cooling in the step b/ is performed by exposing the solution of the step a/ to room temperature for a time period sufficient to achieve cooling of the system to the room temperature.

36. The process of claim 35, wherein the used solvent is methanol.

37. Process of preparation of the crystal modification 6 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in methanol at room temperature,

b/ isolating the Crystal modification 6 of ponatinib hydrochloride by evaporation of methanol in vacuum oven at 60°C using 500 mbar vacuum pressure.

38. Crystal modification 7 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKoc (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 6.7, 9.1, 15.0, 17.7, 18.2 and 25.5°.

39. Crystal modification 7 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm ¹ at 3008, 2958, 2208, 1665, 1360, 1258, 1069, 1001,

771 and 460 cm^"1 wavenumbers.

40. Process of preparation of the crystal modification 7 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 75 v/v % ethanol-water mixture by heating to the boiling point;

b/ cooling the solution of the step a/ to a room temperature;

c/ isolating the Crystal modification 7 of ponatinib hydrochloride.

41. Crystal modification 8 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKcc (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 5.5, 6.7 and 11.2°.

42. Crystal modification 8 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm^'1 at 3066, 3962, 2215, 1656, 1310, 1263, 1067, 996, 762 and 456 cm^"1 wavenumbers.

43. Process of preparation of the crystal modification 8 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol by heating to the boiling point;

b/ cooling the solution of the step a/ to room temperature by placing the test-tube / vial containing the solution of the step a/ into ice;

c/ isolating the Crystal modification 8 of ponatinib hydrochloride.

44. Crystal modification 9 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKct (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 5.5, 7.5, 11.2, 19.5 and 24.0°.

45. Crystal modification 9 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm^"1 at 3068, 2929, 2217, 1671, 1607, 1539, 1398, 1308, 1154 and 776 cm^'1 wavenumbers.

46. Process of preparation of the Crystal modification 9 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol at room temperature;

b/ isolating the Crystal modification 9 of ponatinib hydrochloride by evaporation of methanol in vacuum oven at 60°C using 500 mbar vacuum pressure.

47. Crystal modification 10 of ponatinib hydrochloride, characterised by a XRPD pattern having the characteristic diffraction peaks, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) of 8.4, 16.6, 18.2, 23.0 and 24.9°.

48. Crystal modification 10 of ponatinib hydrochloride, showing the characteristic peaks of the FT- Raman spectrum with spectral resolution 4 cm ¹ at 3965, 3922, 2217, 1659, 1606, 1478, 1359, 1313, 761 and 463 cm^"1 wavenumbers.

49. Process of preparation of the Crystal modification 10 of ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in 2-propanol at room temperature;

b/ isolating the Crystal modification 10 of ponatinib hydrochloride by evaporation of methanol at laboratory conditions.

50. Amorphous ponatinib hydrochloride.

51. Amorphous ponatinib hydrochloride, exhibiting a XRPD pattern, using radiation CuKa (λ = 1.542A), at reflection angle 2Θ (± 0.2° 2Θ) shown in the Figure 43.

52. Amorphous ponatinib hydrochloride, showing the characteristic peaks of the FT-Raman spectrum with spectral resolution 4 cm^"1 at 3069, 2963, 2216, 1667, 1606, 1399, 1154, 1000, 904 and 463 cm^"1 wavenumbers.

53. Amorphous ponatinib hydrochloride, characterised by a melting process which gives endothermic maxima at 86.7°C and 247.4°C,which occur during thermal analysis using DSC in the range of 50-300°C.

54. Amorphous ponatinib hydrochloride, characterised by a TGA thermal analysis measured by a in the range of 20-300°C shown in the Figure 49.

55. Amorphous ponatinib hydrochloride, characterised by a solid-state ¹³C NMR spectrum depicted in Figure 47.

56. Process of preparation of the amorphous ponatinib hydrochloride comprising the steps of:

a/ dissolving ponatinib hydrochloride in a solvent selected form the group of consisting of water; ethanol; and water-dioxane in 1:1 ratio by volume at room temperature

b/ isolating the amorphous ponatinib hydrochloride by evaporation of the solvent in vacuum oven at 60°C using 500 mbar vacuum pressure.

57. Process of preparation of the amorphous ponatinib hydrochloride comprising the steps of:

a/ dissolving the ponatinib hydrochloride in ethanol at room temperature;

b/ isolating the amorphous ponatinib hydrochloride by evaporation of ethanol at laboratory conditions.

58. Process of preparation of the amorphous ponatinib hydrochloride comprising the steps of: a/ dissolving the ponatinib hydrochloride in 2-propanol by heating to the boiling point; b/ isolating the amorphous ponatinib hydrochloride by evaporation of the 2-propanol under pressure 50mbar at 40°C;

c/ optionally, drying of the product of the step b/ at laboratory conditions until the constant weight of the product is reached.