The invention provides new solid forms of abiraterone acetate of formula I

in a crystalline or amorphous form, a process for the preparation thereof and use thereof for the preparation of a pharmaceutical composition. The use of these new salts for the preparation of abiraterone acetate in the free base form or in the form of any other pharmaceutical salt of abiraterone acetate is also provided by the invention.

Background Art

The compound 3 -acetoxy-17-(3-pyridyl)-androsta-5,16-diene, known under the name abiraterone acetate (CAS 154229-18-2), is an inhibitor of biosynthesis of androgens. It selectively inhibits the enzyme 17a-hydroxylase/C17,20-lyase (CYP17), which catalyses the conversion of pregnenolone and progesterone to the precursors of testosterone, DHEA, or androstenedione by 17a-hydroxylation and cleaving of the CI 7,20 bond. Abiraterone acetate is used together with prednisone or prednisolone for treatment of metastatic castration- resistant prostate cancer in adult men. Abiraterone acetate is in vivo metabolized to abiraterone.

Preparation of salts of abiraterone acetate and tartaric, acetic, malic, methanesulfonic, ditoluoyl tartaric, hydrochloric and sulphuric acids is described in international application WO2006021776. Further disclosed is a method for the preparation of abiraterone acetate or its pharmaceutically acceptable salt, comprising isolation of the abiraterone acetate salt, e.g. methanesulfonate, of from methyl tert-butyl ether. A method of purification of abiraterone acetate using the trifluoromethanesulfonate salt of abiraterone acetate is further described in the patent document CN 102030798.

Some salts of abiraterone acetate described in WO2006021776 are prepared in a low to medium yield and the purification effect is not sufficient To achieve the required purity the crystallization must be repeated.

Disclosure of Invention

The invention provides new pharmaceutically acceptable salts of abiraterone acetate of formula I

and an acid selected from the group comprising benzenesulfonic, p-toluenesulfonic and fumaric acids, either in a crystalline or amorphous form, a process for the preparation thereof and use thereof for the preparation of a pharmaceutical composition. The use of these new salts for the preparation of abiraterone acetate in the free base form or in the form of any other pharmaceutical salt of abiraterone acetate is also provided by the invention.

Brief Description of Drawings

Figure 1 XRPD pattern of the salt of abiraterone acetate and benzenesulfonic acid

Figure 2 DSC curve of the salt of abiraterone acetate and benzenesulfonic acid

Figure 3 TGA curve of the salt of abiraterone acetate and benzenesulfonic acid

Figure 4 DVS curve of the salt of abiraterone acetate and benzenesulfonic acid

Figure 5 IR spectrum of the salt of abiraterone acetate and benzenesulfonic acid

Figure 6 1H-NMR spectrum of the salt of abiraterone acetate and benzenesulfonic acid Figure 7 Solid-state NMR spectrum - of abiraterone acetate (top) and the salt of

abiraterone acetate with benzenesulfonic acid (bottom)

Figure 8 XRPD pattern of the salt of abiraterone acetate and p-toluenesulfonic acid Figure 9 DSC curve of the salt of abiraterone acetate and p-toluenesulfonic acid

Figure 10 TGA curve of the salt of abiraterone acetate and p-toluenesulfonic acid

Figure 11 DVS curve of the salt of abiraterone acetate and p-toluenesulfonic acid

Figure 12 IR spectrum of the salt of abiraterone acetate and p-toluenesulfonic acid

Figure 13 1 H-NMR spectrum of the salt of abiraterone acetate and p-toluenesulfonic

acid

Figure 14 Solid-state NMR spectrum - of abiraterone acetate (top) and the salt of

abiraterone acetate with p-toluenesulfonic acid (bottom)

Figure 15 XRPD pattern of the salt of abiraterone acetate and fumaric acid

Figure 16 DSC curve of the salt of abiraterone acetate and fumaric acid

Figure 17 TGA curve of the salt of abiraterone acetate and fumaric acid

Figure 18 DVS curve of the salt of abiraterone acetate and fumaric acid

Figure 19 IR spectrum of the salt of abiraterone acetate and fumaric acid

Figure 20 1 H-NMR spectrum of the salt of abiraterone acetate and fumaric acid

Figure 21 Solid-state NMR spectrum of the salt of abiraterone acetate and fumaric acid

Detailed Description of Invention

This invention provides salts of abiraterone acetate from the group of benzenesulfonate, p- toluenesulfonate and fumarate. These salts have proven to be suitable for pharmaceutical application, especially for their convenient physical-chemical properties and an easily reproducible preparation procedure, which is suitable even for industrial-scale production. The advantage of these solid forms also includes their good processability during the preparation of a pharmaceutical composition and high yield and high purity achievable during their preparation.

The invention comprises the salts of abiraterone acetate with benzenesulfonic, p- toluenesulfonic and fumaric acids in a crystalline or amorphous form.

The invention further comprises the salts of abiraterone acetate with benzenesulfonic, p- toluenesulfonic and fumaric acids in a non-solvated form, solvated form and in the form of hydrates.

The salts in accordance with the invention can exist in several solid forms depending on the selected preparation conditions. These forms differ in their internal structure (polymorphism) and may exhibit different physical-chemical characteristics. The invention comprises these individual polymorphs as well as their mixtures in any proportion. All the salts in accordance with the invention were prepared by reaction of abiraterone acetate with an acid from the group comprising benzenesulfonic, p-toluenesulfonic and fumaric acids in a solvent selected from the group of C1-C4 alkyl alcohols. These solvents have proven to be suitable for the preparation of the salts of abiraterone acetate in accordance with this invention in a high yield and high purity. In addition, the solvents from the group of C1-C4 alkyl alcohols are suitable from the safety point of view during the preparation of pharmaceutically suitable substances. In a preferable embodiment, 2-propanol is used out of the group of C1-C4 alkyl alcohols.

The reaction of abiraterone acetate with benzenesulfonic, p-toluenesulfonic or fumaric acid is conducted at a temperature of 40 to 60 °C, preferably at a temperature of about 50 °C. The resulting salt is isolated from the reaction mixture after cooling to the room temperature, or to a temperature of 20 °C to -10 °C.

The crystalline salt of abiraterone acetate and benzenesulfonic acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 1. The XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).

An overview of the most prominent peaks of the X-ray diffraction pattern is presented in Table 1.

Table 1:

Interplanar Relative

Position distance intensity

[°2Θ] [nm] [%]

540 1.6362 5.2

6.50 1.3584 11.8

8.04 1.0987 9.2

10.10 0.8751 15.1

12.23 0.7234 42.4

13.11 0.6749 7.1

14.50 0.6105 15.1

15.44 0.5735 12.3

16.43 0.5392 19.2 18.14 0.4887 100.0

18.82 0.4711 21.6

19.76 0.4489 13.3

21.06 0.4216 7.1

22.64 0.3924 7.5

23.17 0.3836 26.5

23.66 0.3757 21.6

24.16 0.3681 4.8

24.74 0.3596 3.3

25.07 0.3549 3.6

25.47 0.3494 2.4

26.36 0.3378 2.6

28.64 0.3114 3.3

29.31 0.3044 3.4

30.23 0.2954 2.7

The crystalline salt of abiraterone acetate and benzenesulfonic acid can be further characterized by means of thermal analytical techniques. The DSC curve (Perkin Elmer Pyris 1 DSC) in Figure 2, measured in the range of 50 to 220 °C, shows the following characteristic values: 205.1 °C. The TGA curve (Perkin Elmer TGA 6) in Figure 3 shows a weight loss of abiraterone acetate benzenesulfonate of 0.39 in the temperature range of 20 to 250 °C.

The DVS analysis in Figure 4 shows a slight change in the weight of crystalline abiraterone acetate benzenesulfonate of 1.1 % in the range of the ambient relative humidity of 0 to 90 %. This salt is hence slightly hygroscopic.

The crystalline salt of abiraterone acetate and benzenesulfonic acid, obtained by the above mentioned method in accordance with the invention, was isolated in a high yield (62.6 %) and in excellent purity (99.8 %).

The amorphous salt of abiraterone acetate and -toluenesulfonic acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 8. The XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical). The amorphous salt of abiraterone acetate and p-toluenesulfonic acid can be further characterized by means of thermal analytical techniques. The DSC curve (Perkin Elmer Pyris 1 DSC) in Figure 9, measured in the range of 50 to 220 °C, shows the following characteristic values: T _peak, i = 76.4 °C (water), T _g = 96.6 °C, Τ _οη5¾ ,2 = 109.8 °C and T _peak , ₂ =132.0 °C. The TGA curve (Perkin Elmer TGA 6) in Figure 10 shows a weight loss of abiraterone acetate p- toluenesulfonate of 2.91% in the temperature range of 20 to 240 °C.

The DVS analysis in Figure 11 shows the change in the weight of crystalline abiraterone acetate -toluenesulfonate in the range of the ambient relative humidity of 0 to 90 %. The established water absorption is 15.5 % and water loss during desorption is 13.8 %, i.e., water is retained in the amount of 1.7 %. This means that the amorphous salt of abiraterone acetate and -toluenesulfonic acid is hygroscopic.

The amorphous salt of abiraterone acetate and p-toluenesulfonic acid, obtained by the above mentioned method in accordance with the invention, was isolated in a high yield (72.3 %)

The crystalline salt of abiraterone acetate and fumaric acid in accordance with the invention exhibits a characteristic XPRD pattern, which is shown in Figure 15. The XRPD pattern was recorded using an X-Ray Powder Diffractometer (X'PERT PRO MPD PANalytical).

An overview of the most prominent peaks of the X-ray diffraction pattern is presented in Table

2.

Table 2:

Interplanar Relative

Position distance intensity

[°2Θ] [nm] [%]

6.09 1.4510 100.0

6.75 1.3076 16.8

8.95 0.9869 6.4

1.15 0.7926 8.7

12.23 0.7232 35.6

13.14 0.6733 20.8

13.93 0.6350 5.6

14.94 0.5924 12.2 16.54 0.5356 19.2

17.68 0.5013 13.8

18.33 0.4835 39.1

19.63 0.4519 14.8

19.93 0.4451 21.2

21.33 0.4162 36.7

22.53 0.3943 14.8

25.44 0.3498 9.7

27.22 0.3274 10.3

27.91 0.3194 14.7

The crystalline salt of abiraterone acetate and fumaric acid can be further characterized by means of thermal analytical techniques. The DSC curve (Perkin Elmer Pyris 1 DSC) in Figure 16 measured in the range of 50 to 250 °C shows the following characteristic values: T _on set ⁼ 162.9 °C and T _pea k = 165.1 °C. The TGA curve (Perkin Elmer TGA 6) in Figure 17 shows a weight loss of abiraterone acetate fumarate of 0.19 % in the temperature range of 20 to 250 °C. The DVS analysis in Figure 18 shows a negligible change in the weight of crystalline fumarate of abiraterone acetate of 0.1 % in the range of the ambient relative humidity of 0 to 90 %. This means that this salt is not hygroscopic.

The crystalline salt of abiraterone acetate and fumaric acid, obtained by the above mentioned method in accordance with the invention, exhibited an excellent purity of 99.9 %.

The new salts of abiraterone acetate in accordance with the invention are easy to prepare using a single-stage process in the environment of a solvent or a mixture of solvents from the group of C1-C4 alcohols, preferably 2-propanol, namely in a good to excellent yield and chemical purity.

Examples

Example 1

Preparation of a salt of abiraterone acetate and benzenesulfonic acid

250 mg (0.662 mmol) of abiraterone acetate was dissolved in 2.5 mol of 2-propanol at 50 °C. 105 mg (0.662 mmol) of benzenesulfonic acid was dissolved in 2-propanol at the room temperature and the solution prepared this way was added dropwise to the API solution at 50 °C.

The solution was agitated at the temperature of 50°C in a closed ampoule for at least 1 hour, then cooled down to the room temperature and stirred overnight. The obtained suspension was filtered and vacuum dried at room temperature. Yield: 222 mg (62.6 %)

The stoichiometric proportion of abiraterone acetate and benzenesulfonic acid was determined to be approximately 1:1 using the 'H-NMR technique.

Example 2

Preparation of the salt of abiraterone acetate and j?-toluenesulfonic acid

250 mg (0.662 mmol) of abiraterone acetate was dissolved in 2.5 mol of 2-propanol at 50 °C.

126 mg (0.662 mmol) of -toluenesulfonic acid was dissolved in 2-propanol at the room temperature and the solution prepared this way was added dropwise to the API solution at 50

°C.

The solution was agitated at the temperature of 50°C in a closed ampoule for at least 1 hour, then cooled down to the room temperature and stirred overnight. The obtained suspension was filtered and vacuum-dried at the room temperature. Yield: 272 mg (72.3 %)

The stoichiometric proportion of abiraterone acetate and j-toluenesulfonic acid was determined to be approximately 1:1 using the 1H-NMR technique.

Example 3

Preparation of the salt of abiraterone acetate and fumaric acid

250 mg (0.662 mmol) of abiraterone acetate was dissolved in 2.5 mol of 2-propanol at 50 °C. 154 mg (1.324 mmol) of fumaric acid was dissolved in 2-propanol at the room temperature and the solution prepared this way was added dropwise to the API solution at 50 °C.

The solution was agitated at the temperature of 50°C in a closed ampoule for at least 1 hour, then it was cooled down to the room temperature and stirred overnight. The obtained suspension was filtered and vacuum-dried at the room temperature. Yield: 205 mg (50.8 %) The stoichiometric proportion of abiraterone acetate and fumaric acid was determined to be approximately 1:1.5 using the Ή-NMR technique. List of analytical techniques

Analysis - NMR (Nuclear magnetic resonance)

The 1H NMR spectra were recorded with an AVANCE 500 MHz device and with the use of dimethyl sulfoxide (DMSO) as the solvent. The stoichiometry of the salts was determined based on the integrals of the respective signals for the API and the corresponding acid.

The ¹³ C CP-MAS ss NMR spectra were recorded using a Bruker 400 WB spectrometer (4 mm rotors, frequency 13 kHz). The spectra of the salts were compared to the spectrum of the original API.

Analysis - XRPD (X-ray diffraction)

The diffraction patterns were recorded with an X'PERT PRO MPD PANalytical

diffractometer, used radiation CuKoc (λ = 0,1542 nm (1.542A)),

Generator settings:

excitation voltage 45 kV

anode current 40 mA.

Scanning description:

- measurement range 2 - 40° 2Θ

- increment 0.01° 2Θ

increment time: 0.5 s.

The measurement was carried out with a flat powder sample placed on a Si plate.

For setting of the primary optics programmable divergence slits with the irradiated sample area of 10 mm, 0.02 rad Soller slits and a ¼ anti-dispersion slit were used. For setting of the secondary optics the X'Celerator detector with the maximum opening of the detection slit, 0.02 rad Soller slits and a 5.0mm anti-dispersion slit were used.

Analysis - DSC (Differential scanning calorimetry)

The DSC measurement was carried out using a Perkin Elmer Pyris 1 DSC device.

The charge of the sample in a standard Al pot was approximately 3.5 mg and the heating up rate was 10 °C/min. The temperature program that was used consists of 1 stabilization minute at the temperature of 50 °C and then heating to 250 °C at the heating up rate of 10 °C/min. 4.0N2 at a flow rate of 20 ml/min was used as the carrier gas.

Analysis - TGA (Thermogravimetric analysis)

The TGA measurement was conducted using a Perkin Elmer TGA 6 device. The samples were weighed (19 to 22 mg) and dosed into a ceramic pot, nitrogen was used as the carried gas. The measurement was carried out in the temperature range of 20 to 250 °C at the heating up rate of 10 °C/min.

Analysis - DVS (Dynamic vapour sorption)

The dynamic vapour sorption records were obtained using a DVS Advantage 1 device from Surface Measurement Systems. The charge of a sample in a quartz dish was between 18.5 and 20.1 mg and the temperature in the device varied in the range of 25.3 to 25.4 °C.

Measurement program used: the sample was loaded with two sorption and desorption cycles, wherein the sample is first exposed to increasing relative humidity in the range of 0 % to 90 % (sorption) and then to decreasing relative humidity of 90 % to 0 % (desorption) and the whole process is repeated again. Nitrogen was used as the carrier gas.

Overview of the results of the analytical techniques for individual salts in accordance with the invention:

A) Salt of abiraterone acetate and benzenesulfonic acid

B) Salt of abiraterone acetate and j?-toluenesulfonic acid

C) Salt of abiraterone acetate and fumaric acid