Technical Field

The invention relates to a novel solid form of l-[(3i?)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl] iperidin-l-yl]prop-2-en-l-one of formula (I),

(I)

known as ibrutinib and to methods of its preparation. Background Art

l-[(3i?)-3-[4-Amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d ]pyrimidin-l-yl]piperidin-l- yl]prop-2-en-l-one, which is known as ibrutinib (CAS no. 936563-96-1) ,belongs to the group of kinase inhibitors that can be used for the treatment of lymphomas. Under the trade name Imbruvica, Ibrutinib was approved by The Food and Drug Administration (FDA) for the treatment of centrocytic lymphoma.

Preparation of this molecule and its isolation with the use of chromatography was described in the patent WO2008/039218. Preparation of crystalline forms of ibrutinib in solvated or non- solvated forms was described in the patents WO2013/184572 and CN 103694241. Use of ibrutinib in the treatment of lymphomas together with other pharmaceutically active ingredients was described in the patent WO2013/113841 and the patent WO2013/155347, which also mentions pharmaceutically acceptable salts of this drug without any further description or. The patent WO2013/184572 deals, besides preparation methods, with the pharmaceutical composition of crystalline and solvated forms of ibrutinib for oral administration and mentions pharmaceutically acceptable salts of this drug without any further description or example of production thereof. Further use of ibrutinib for the treatment of cancer, inflammatory and autoimmune diseases, together with a description of pharmaceutical compositions mentioning its pharmaceutically acceptable salts without further description or example of production thereof is mentioned in the patent WO2014/004707. The solubility of the crystalline free base of ibrutinib in water is very low, even if aqueous solutions with different pH are used. It is clear that novel solid forms of this active pharmaceutical ingredient are needed for the preparation of dosage forms with higher solubility and bioavailability.

Disclosure of Invention

The invention provides a novel crystalline solid form of ibrutinib in the form of a pharmaceutically acceptable salt with sulphuric acid and methods of its preparation. This salt is prepared by a reaction of ibrutinib in the free base form (formula I) with sulphuric acid in a suitable solvent or mixtures of solvents. The prepared novel crystalline solid form has suitable physical-chemical characteristics for use in the pharmaceutical industry and formulation of new dosage forms. The salt of ibrutinib with sulphuric acid is in the solid phase and in crystalline form; in the DSC record it exhibits the melting point of approximately 121°C. The ibrutinib sulphate is ibrutinib hemisulphate exhibiting the following characteristic diffraction peaks with the use of CuKct radiation: 4.18; 7.96; 14.51; 17.69; and 21.2 ± 0.2° 2-theta. The molar ratio of ibrutinib : sulphuric acid is in the range of 10:1 to 1:3, preferably 2:1.

Brief Description of Drawings

Figure 1. X-ray powder pattern of ibrutinib hemisulphate (according to Example 2).

Figure 2. IR spectrum of ibrutinib hemisulphate (according to Example 2).

Detailed description of the invention

Salts of pharmaceutically active substances generally have higher solubility and bioavailability values than their corresponding basic forms.

Although preparation of a salt by a reaction of an acid and a base is a well-known method, it is always a problem to obtain the desired salts in the solid phase and in purity corresponding to the demands for their pharmaceutical use. Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily soluble, it cannot often be obtained in the corresponding quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable and its purity is easier to achieve. This invention provides a salt of ibrutinib in a crystalline solid phase. The invention consists in a novel solid form of ibrutinib with sulphuric acid that can be prepared in a crystalline form in adequate yields with high chemical purity.

The prepared novel solid form of ibrutinib may have various internal arrangements (polymorphism) with different physical-chemical properties depending on the conditions of its preparation. Therefore, the invention relates to a crystalline or amorphous form of ibrutinib sulphate in any ratio.

This novel solid form is suitable for preparation of ibrutinib with high chemical and optical purity. The preparation of the novel form of ibrutinib (formula (I)) is based on a reaction of the free base of ibrutinib with sulphuric acid. The reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof. Aliphatic C1-C4 alcohols, esters or their mixtures are preferred. The most commonly used solvents are acetone, ethanol, isopropanol, acetonitrile, tetrahydrofuran or mixtures thereof.

The final product is typically precipitated or crystallized at temperatures in the range of - 30°C to the boiling point of the solvent.

The free base of ibrutinib was prepared according to the procedure mentioned in the patent (WO2008/039218).

The crystalline form of ibrutinib hemisulphate (according to Example 2) is characterized by the reflections presented in Table 1. Table 1 includes reflections whose relative intensity value is higher than 1 percent. The characteristic diffraction peaks of ibrutinib hemisulphate according to this invention are: 4.18; 7.96; 14.51; 17.69; and 21.2 ± 0.2° 2-theta. An example of the X-ray powder pattern is shown in Figure 1.

Table 1

Pos.

[°2Th.] d [A] Rel. Int. [%]

4.18 21.139 100.0

4.73 18.672 44.9

5.92 14.930 12.7

7.96 11.098 40.6

10.61 8,335 9.5

11.92 7.420 4.0 14.13 6.262 8.1

14.51 6.098 12.5

16.20 5.468 6.5

17.69 5.011 13.6

20.69 4.289 6.7

21.02 4.222 4.9

21.31 4.166 6.5

22.08 4.022 2.8

23.25 3.823 3.0

24.36 3.651 2.2

26.70 3.336 2.2

28.73 3.104 1.7

The melting point of the crystalline form of ibrutinib hemisulphate, prepared according to Example 2, is 121°C (DSC).

The infrared spectrum of ibrutinib sulphate (prepared according to Example 2) is shown in Fig. 2. The molar ratio of ibrutinib: sulphuric acid can be in the range of 10:1 to 1:3, preferably 2:1.

The invention is clarified in a more detailed way using the working examples below. These examples, which illustrate the preparation of the novel solid forms of ibrutinib according to the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.

Experimental part

X-ray powder diffraction

The diffraction patterns were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 20, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti- dispersion slit were used. The irradiated area of the sample is 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad SoUer slits and a 5.0 anti-dispersion slit were used. Infrared spectroscopy

ATR (Ge - single reflection) infrared spectra of the powder samples were measured with an infrared spectrometer (Nicolet Nexus, Thermo, USA) equipped with a DTGS KBr detector, in the measurement range of 600-4000 cm ^"1 and the spectral resolution of 4.0 cm ^"1 . The data were obtained at 64 spectrum accumulations. The OMNIC 6.2 software was used to process the spectra.

Differential Scanning Calorimetry (DSC)

The record of the novel solid form of ibrutinib hemisulphate was measured using a Discovery DSC device made by TA Instruments. The sample charge in a standard Al pot (40 was between 4-5 and 5 mg and the heating rate was 5°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 0°C and then of heating up to 220°C at the heating rate of 5°C/min (Amplitude = 0.8°C and Period = 60 s). As the carrier gas 5.0 N ₂ was used at the flow of 50 ml/min.

Examples

Example 1 The free base of ibrutinib was prepared according to the procedure mentioned in the patent (WO2008/039218).

Example 2 Preparation of ibrutinib hemisulphate l-[(3i?)-3-[4-Amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidin- 1- yl]prop-2-en-l-one (Ibrutinib) in the amount of 2.124 g (4.82-10 ^"3 mol) was dissolved in 110 ml of acetone. 0.134 ml (2.41 -10 ^"3 mol) of sulphuric acid (96 %) was added to this solution. After 30 min, the originally clear solution turned into a white suspension. The obtained suspension was further stirred at the room temperature for 2 hours. The separated solid fraction was then collected by filtration and dried at 30 to 50°C in a vacuum drier at the pressure of 20 kPa for 16 hours. Reaction yield 92 % by weight. HPLC purity 99.7 %. Melting point 121°C (DSC). XRPD: Fig. 1.