WO2017032349A1

WO2017032349A1 - Salts of 5-fluoro-3-phenyl-2-[(1s)-1-(9h-purin-6-ylamino)propyl]quinazolin-4-one and preparation thereof

Info

Publication number: WO2017032349A1
Application number: PCT/CZ2016/000087
Authority: WO
Inventors: Violetta Kiss; Hana TOZICKOVA; Eszter TIEGER; Marcela Tkadlecova; Ondrej Dammer; Tomáš GURGUT
Original assignee: Zentiva , K.S.
Priority date: 2015-08-26
Filing date: 2016-08-10
Publication date: 2017-03-02
Also published as: CZ2015575A3

Abstract

The present invention relates to salts of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I and at least one acid component wherein the acid component is preferably selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid and wherein the salt of Formula I and acid component is presented in a crystalline or an amorphous form. The invention also relates to processes of preparation of salts as well as to their use in pharmaceutical compositions. (I)

Description

Salts of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-Ylamino)propyl]quinazolin-4-one and preparation thereof

Field of the Invention The present invention relates to salts of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I

(I) and at least one acid component wherein the acid component is preferably selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid and wherein the salt of Formula I and acid component is presented in a crystalline or an amorphous form. The invention also relates to processes of preparation of salts as well as to their use in pharmaceutical compositions.

Background Art

5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one compound which is also known as ideialisib (CAS no.: 870281-82-6) has a phosphoinositide 3-kinase (PI3K) inhibitor activity, which is effectively used for the treatment of chronic lymphocytic leukemia (CLL).

The enzymes phosphoinositide 3-kinases (PBKs) are a family of enzymes that are involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking and which are involved in cancer development.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and it affects B-cell lymphocytes, which originate in the bone marrow, develop in the lymph nodes and normally fight infection by producing antibodies.

Ideialisib blocks P1105, the delta isoform of the enzyme phosphoinositide 3-kinase and acts as a selective inhibitor of adenosine 5'-triphosphate (ATP) by binding to the catalytic domain of P13K5 and results in the inhibition of the phosphorylation of the key lipid second messenger phosphatidylinositol and prevention of Akt (protein kinase B) phosphorylation. WO2005113556 describes selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes with valuable pharmacological effect in the treatment of related diseases. One example of the compounds disclosed is 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and preparation of its base is also provided.

Various crystalline forms of idelalisib are disclosed in WO2013134288 and WO2015014315. Further is described process for the preparation of idelalisib anhydrous crystalline forms designated as Form I, Form II, solvated forms designated as Form III, Form IV, Form V, Form VI and Form VII, as well as crystalline Form II, IV and VI, polymorph II and hydrated crystalline forms designated as Form IX and VIII, respectively.

Many pharmaceutical solid compounds can exist in various crystalline forms regarded as polymorphs and hydrates/solvates having different crystal units and hence different physicochemical properties including melting point, solubility, dissolution rate and finally, bioavailability. In order to distinguish the distinct solid phases of a compound several solid state analytical techniques can be used, e.g. X-Ray Powder Diffraction, solid state NMR, Raman spectroscopy, thermoanalytical methods.

Detection of novel salts of an active pharmaceutical compound and novel solid phases (polymorphs, solvates and hydrates) thereof offers the opportunity to select the appropriate candidates having desirable physicochemical properties and processability and improve the characteristics of the pharmaceutical product. For these reasons there was an explicit need for new salts of idelalisib and its solid forms (polymorphs, solvates, hydrates).

Disclosure of the Invention

The object of the present invention is to provide salts of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I suitable for oral administration which meet the pharmaceutical requirements.

In some embodiments of this invention, the solid forms are characterized by a variety of solid state analytical data, including for example X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) curve. Provided is the amorphous phase of the benzenesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X- ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKct radiation. In some embodiments the amorphous phase of the benzensulfonic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 29.8°C (corresponding to the water loss) and T_onSet,recrystaiiization = 123.0°C. In some embodiments the amorphous phase of the benzensulfonic acid salt is characterised by the thermal gravimetric curve having a 3.3% weight loss in the range of 25°C to 95°C and 3.5% weight loss in the range of 95°C to 150°C.

It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrumental and analytical procedures and settings used to obtain the spectrum.

Provided is a process for the preparation of the amorphous phase of the benzensulfonic acid salt wherein idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Benzenesulfonic acid is added to the solution and then the solution is left to cool. After complete evaporation of the solvent, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib benzenesulfonic acid salt.

In some embodiments the process for the preparation of the amorphous phase of the benzensulfonic acid salt further comprises the steps of: a/ dissolving of idelalisib free base in methanol at temperature of 50°C; b/ addition of benzenesulfonic acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ at room temperature for additional 2 hours; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelaiisib benzenesulfonic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the benzensulfonic acid salt, further comprises the steps of drying of the product of the step g) under laboratory conditions until the constant weight of the product is reached.

Provided is the Crystal modification 1 of the benzenesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l- (9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.0; 10.3; 17.5; 20.2 and 20.9 ± 0.2° 2-theta measured by CuKa radiation. In some embodiments the Crystal modification 1 of the benzenesulfonic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onseU = 108.3°C T_peak = 151.0°C. In some embodiments the Crystal modification 1 of the benzenesulfonic acid salt is characterised by the thermal gravimetric curve having a 8.7% weight loss in the range of 25°C to 160°C.

Provided is a process for the preparation of the Crystal modification 1 of the benzenesulfonic acid salt wherein idelaiisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Benzenesulfonic acid is added to the suspension and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelaiisib benzenesulfonic acid salt. In some embodiments the process for the preparation of the Crystal modification 1 of the benzenesulfonic acid salt comprises the steps of: a/ suspending of idelaiisib free base in acetone at temperature of 50°C; b/ addition of benzenesulfonic acid to the suspension of step a/ while complete dissolution occurs; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the suspension of step d/ for 2 hours at room temperature while precipitation occurs and f/ isolating the idelaiisib benzenesulfonic acid salt in Crystal modification 1.

In some embodiments the process for the preparation of the Crystal modification 1 of benzensulfonic acid salt further comprises the step of drying of the product of the step f) under laboratory conditions until the constant weight of the product is reached.

The present invention further relates to the use of the amorphous of the benzenesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In another embodiment the present invention further relates to the use of the Crystal modification 1 of the benzenesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin- 4-one of Formula I for the preparation of a pharmaceutical compositions.

Provided is the amorphous phase of the methanesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the methanesulfonic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 81.1°C and T_peakii = 100.9°C. In some embodiments the amorphous phase of the methanesulfonic acid salt is characterised by the thermal gravimetric curve having a 7.4% weight loss in the range of 25°C to 175°C. It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrumental and analytical procedures and settings used to obtain the spectrum.

Provided is a process for the preparation of the amorphous phase of the methanesulfonic acid salt wherein idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Methanesulfonic acid is added to the suspension and then left to cool. After complete evaporation of the solvent, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib methanesulfonic acid salt.

In some embodiments the process for the preparation of the amorphous phase of the methanesulfonic acid salt further comprises the steps of: a/ dissolving of idelalisib free base in methanol at temperature of 50°C; b/ addition of methanesulfonic acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib methanesulfonic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the methanesulfonic acid salt, further comprises the step of drying of the product of the step g) under laboratory conditions until the constant weight of the product is reached.

In other embodiments an alternative process of preparation of amorphous phase of idelalisib methanesulfonic acid salt comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of methanesulfonic acid to the suspension of step a/ while complete dissolution occurs; c/ cooling the solution of step b/ to room temperature; d/ keeping the solution of step c/ for 2 hours at room temperature; e/ evaporating the solvent completely of the solution of step d/ and f/ isolating the idelalisib methanesulfonic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the methanesulfonic acid salt, further comprises the step of drying of the product of the step f) under laboratory conditions until the constant weight of the product is reached.

The present invention further relates to the use of the amorphous of the methanesulfonic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

Provided is the amorphous phase of the hydrobromic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the hydrobromic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset = 47.TC (corresponding to the water loss); T_{onset 2} = 158.6°C and T_peak;2 = 172.0°C. In some embodiments the amorphous phase of the hydrobromic acid salt is characterised by the thermal gravimetric curve having a 7.7% weight loss in the range of 25°C to 155°C and a 0.8% weight loss in the range of 155°C to 225°C.

Provided is a process for the preparation of the amorphous phase of the hydrobromic acid salt wherein idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydrobromic acid is added to the solution and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydrobromic acid salt.

In some embodiments the process for the preparation of the amorphous phase of the hydrobromic acid salt further comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of hydrobromic acid to the solution of the step a/; c/ agitation of the solution of the step b/ at 50°C for additional 30 minutes while precipitation occurs; d/ cooling the solution of the step c/ to room temperature; e/ keeping the suspension of the step d/ for 2 hours at room temperature and f/ isolating the idelalisib hydrobromic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the hydrobromic acid salt, further comprises the step of drying of the product of step d) under laboratory conditions until the constant weight of the product is reached.

In other embodiments an alternative process of preparation of amorphous phase of idelalisib hydrobromic acid salt comprises the steps of: a/ dissolving of idelalisib free base in acetonitrile at temperature of 50°C; b/ addition of hydrobromic acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib hydrobromic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the hydrobromic acid salt, further comprises the step of drying of the product of step g) under laboratory conditions until the constant weight of the product is reached.

Provided is the Crystal modification 1 of the hydrobromic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.0; 11.7; 16.7; 18.2; 21.1 and 23.2 ± 0.2° 2-theta measured by CuKct radiation. In some embodiments the Crystal modification 1 of the hydrobromic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 31.4°C (corresponding to the water loss); T_onset;2 = 93.1°C and T_peak;2 = 100.5°C; T_onsetj3 = 151.1°C and T ea_k,3 = 168.6°C; T_onseti4 = 182.6°C and T_peakj4 = 210.3°C. In some embodiments the Crystal modification 1 of the hydrobromic acid salt is characterised by the thermal gravimetric curve having a 2.1% weight loss in the range of 25°C to 190°C and a 0.7% weight loss in the range of 190°C to 215°C.

Provided is a process for the preparation of the Crystal modification 1 of the hydrobromic acid salt wherein amorphous phase of idelalisib hydrobromic acid salt is suspended in a suitable organic solvent at room temperature and then left for stirring. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib hydrobromic acid salt

In some embodiments the process for the preparation of the Crystal modification 1 of the hydrobromic acid salt comprises the steps of: a/ suspending of amorphous phase of idelalisib hydrobromic acid salt in ethyl acetate at room temperature; b/ stirring the suspension of step a/ at room temperature for 3 days and c/ isolating the Crystal modification 1 of idelaisib hydrobromic acid salt.

In some embodiments the process for the preparation of the Crystal modification 1 of hydrobromic acid salt further comprises the step of drying of the product of step c) under laboratory conditions until the constant weight of the product is reached. Provided is the Crystal modification 2 of the hydrobromic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.8; 15.2; 19.5; 21.8 and 23.9 ± 0.2° 2-theta measured by CuKa radiation. In some embodiments the Crystal modification 2 of the hydrobromic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 40.4°C (corresponding to the water loss); T_onset;2 = 151.2°C; and Tp_eak,2 = 171.3°C. In some embodiments the Crystal modification 2 of the hydrobromic acid salt is characterised by the thermal gravimetric curve having a 3.1% weight loss in the range of 25°C to 150°C and a 3.3% weight loss in the range of 150°C to 210°C.

Provided is a process for the preparation of the Crystal modification 2 of the hydrobromic acid salt wherein amorphous phase of idelalisib hydrobromic acid salt is suspended in a suitable organic solvent at room temperature and then left for stirring. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 2 of idelalisib hydrobromic acid salt

In some embodiments the process for the preparation of the Crystal modification 2 of the hydrobromic acid salt comprises the steps of: a/ suspending of amorphous phase of idelalisib hydrobromic acid salt in n-heptane or dichloromethane at room temperature; b/ stirring the suspension of step a/ at room temperature for 3 days and c/ isolating the Crystal modification 2 of idelaisib hydrobromic acid salt.

In some embodiments the process for the preparation of the Crystal modification 2 of hydrobromic acid salt further comprises the step of drying of the product of step c) under laboratory conditions until the constant weight of the product is reached.

The present invention further relates to the use of the amorphous of the hydrobromic acid salt of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In another embodiment the present invention further relates to the use of the Crystal modification 1 of the hydrobromic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4- one of Formula I for the preparation of pharmaceutical compositions.

In yet another embodiment the present invention further relates to the use of the Crystal modification 2 of the hydrobromic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions. Provided is the amorphous phase of the hydrochloric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the hydrochloric acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 28.7°C (corresponding to the water loss); T_{onset 2} = 140.8°C and T_peak,2 = 164.3°C; T_0nset = 169.8°C and T_peaki3 = 188.4°C. In some embodiments the amorphous phase of the hydrochloric acid salt is characterised by the thermal gravimetric curve having a 6.0% weight loss in the range of 25°C to 140°C and a 2.4% weight loss in the range of 140°C to 190°C.

It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrumental and analytical procedures and settings used to obtain the spectrum. Provided is a process for the preparation of the amorphous phase of the hydrochloric acid salt wherein idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Hydrochloric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydrochloric acid salt.

In some embodiments the process for the preparation of the amorphous phase of the hydrobromic acid salt further comprises the steps of: a/ dissolving of idelalisib free base in acetonitrile at temperature of 50°C; b/ addition of hydrochloric acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for additional 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib hydrochloric acid salt in amorphous phase.

Provided is the Crystal modification 1 of the hydrochloric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 9.9; 12.2; 15.1; 19.8; 21.6 and 24.1 ± 0.2° 2-theta measured by CuKa radiation. In some embodiments the Crystal modification 1 of the hydrochloric acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onsetil = 43.7°C (corresponding to the water loss); T_{onset 2} = 137.9°C and T_peak>2 = 169.8°C and T_onset,3 = 178.3°C and T_peak,3 = 193.0°C. In some embodiments the Crystal modification 1 of the hydrobromic acid salt is characterised by the thermal gravimetric curve having a 7.4% weight loss in the range of 25°C to 135°C and a 2.3% weight loss in the range of 135°C to 190°C.

Provided is a process for the preparation of the Crystal modification 1 of the hydrochloric acid salt wherein amorphous phase of idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydrochloric acid is added to the suspension and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib hydrochloric acid salt.

In some embodiments the process for the preparation of the Crystal modification 1 of the hydrochloric acid salt comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of hydrobromic acid to the solution of step a/ while complete dissolution occurs; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes while precipitation occurs; d/ cooling the solution of step c/ to room temperature; e/ keeping the suspension of step d/ for 2 hours at room temperature and f/ isolating the idelalisib hydrochloric acid salt in Crystal modification 1.

In some embodiments the process for the preparation of the Crystal modification 1 of hydrochloric acid salt further comprises the step of drying of the product of step f) under laboratory conditions until the constant weight of the product is reached.

In other embodiments an alternative process for the preparation of the Crystal modification 1 of the hydrochloric acid salt comprises the steps of: a/ suspending of amorphous phase of idelalisib hydrochloric acid salt in dichloromethane, ethyl acetate, ethanol or n-heptane at room temperature; b/ stirring the suspension of step a/ at room temperature for 3 days and c/ isolating the Crystal modification 1 of idelaisib hydrochloric acid salt. In some embodiments the process for the preparation of the Crystal modification 1 of hydrochloric acid salt further comprises the step of drying of the product of step c) under laboratory conditions until the constant weight of the product is reached.

The present invention further relates to the use of the amorphous of the hydrochloric acid salt of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In another embodiment the present invention further relates to the use of the Crystal modification 1 of the hydrochloric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4- one of Formula I for the preparation of pharmaceutical compositions.

Provided is the amorphous phase of the hydroiodic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin- 6-ylamino)propyl]quinazolin-4-one of Formula 1 having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the hydroiodic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset;i = 29.8°C (corresponding to the water loss); T_{onset 2} = 126.1°C and J_peak,2 = 160.6°C. In some embodiments the amorphous phase of the hydroiodic acid salt is characterised by the thermal gravimetric curve having a 3.2% weight loss in the range of 25°C to 130°C and a 3.0% weight loss in the range of 135°C to 205°C.

Provided is a process for the preparation of the amorphous phase of the hydroiodic acid salt wherein idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydroiodic acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydroiodic acid salt.

In some embodiments the process for the preparation of the amorphous phase of the hydroiodic acid salt further comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of hydroiodic acid to the solution of step a/ while complete dissolution occurs; c/ agitation of the solution of step b/ at 50°C for 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib hydroiodic acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the hydroiodic acid salt, further comprises the step of drying of the product of step g) under laboratory conditions until the constant weight of the product is reached.

In other embodiments the alternative process for the preparation of the amorphous phase of the hydroiodic acid salt further comprises the steps of: a/ dissolving of idelalisib free base in acetone at temperature of 50°C; b/ addition of hydroiodic acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib hydroiodic acid salt in amorphous phase.

Provided is the Crystal modification 1 of the hydroiodic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 7.2; 9.0; 17.0; 18.1 and 22.5 ± 0.2° 2-theta measured by CuKot radiation. In some embodiments the Crystal modification 1 of the hydroiodic acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 41.7°C (corresponding to the water loss); Τ_οη56ΐ;2 = 137.9°C and T_peak,₂ = 162.5°C; T_onset,₃ = 182.7°C and T_peak = 198.7°C. In some embodiments the Crystal modification 1 of the hydroiodic acid salt is characterised by the thermal gravimetric curve having a 0.9% weight loss in the range of 25°C to 140°C and a 1.6% weight loss in the range of 140°C to 205°C.

Provided is a process for the preparation of the Crystal modification 1 of the hydroiodic acid salt wherein the amorphous phase of the hydroiodic acid salt is suspended in a suitable organic solvent at room temperature and then left for stirring. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib hydroiodic acid salt.

In some embodiments the process for the preparation of the Crystal modification 1 of the hydroiodic acid salt comprises the steps of: a/ suspending amorphous phase of idelalisib hydroiodic acid salt in ethyl acetate at room temperature; b/ stirring the suspension of step a/ at room temperature for 3 days and c/ isolating the Crystal modification 1 of idelaisib hydroiodic acid salt.

In some embodiments the process for the preparation of the Crystal modification 1 of hydroiodic acid salt further comprises the step of drying of the product of step c) under laboratory conditions until the constant weight of the product is reached.

Provided is the amorphous phase of the phosphoric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin- 6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the phosphoric acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onse = 28.5°C (corresponding to the water loss); T_onseti2 = 117.5°C; and T_peak/2 = 125.2°C. In some embodiments the amorphous phase of the phosphoric acid salt is characterised by the thermal gravimetric curve having a 4.2% weight loss in the range of 20°C to HOT.

The present invention further relates to the use of the amorphous of the hydroiodic acid salt of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In another embodiment the present invention further relates to the use of the Crystal modification 1 of the hydroiodic acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

Provided is a process for the preparation of the amorphous phase of the phosphoric acid salt wherein idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Phosphoric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib phosphoric acid salt.

In some embodiments the process for the preparation of the amorphous phase of the phosphoric acid salt further comprises the steps of: a/ dissolving of idelalisib free base in acetone at temperature of 50°C; b/ addition of phosphoric acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib phosphoric acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the phosphoric acid salt, further comprises the step of drying of the product of step g) under laboratory conditions until the constant weight of the product is reached.

Provided is the Crystal modification 1 of the phosphoric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising characteristic peaks at about 5.4; 7.7; 9.3; 11.9; 21.2 and 24.8 ± 0.2° 2-theta measured by CuKa radiation. In some embodiments the Crystal modification 1 of the phosphoric acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 30.9°C (corresponding to the water loss); T_{onset 2} = 115.1°C and T_peak,2 = 136.2°C. In some embodiments the Crystal modification 1 of the phosphoric acid salt is characterised by the thermal gravimetric curve having a 2.0% weight loss in the range of 25°C to 85°C, a 2.3% weight loss in the range of 85°C to 145°C and a 3.0% weight loss in the range of 145°C to 240°C.

Provided is a process for the preparation of the Crystal modification 1 of the phosphoric acid salt wherein idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Phosphoric acid is added to the solution and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib phosphoric acid salt.

In some embodiments the process for the preparation of the Crystal modification 1 of the phosphoric acid salt comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of phosphoric acid to the solution of step a/ while complete precipitation occurs; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the suspension of step c/ to room temperature; e/ keeping the suspension of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the suspension of step e/; g/ adding of ethyl acetate to the residue of step f/; h/ keeping the suspension of step g/ for 2 hours at room temperature and i/ isolating the idelalisib phosphoric acid salt in amorphous phase.

In some embodiments the process for the preparation of the Crystal modification 1 of phosphoric acid salt further comprises the step of drying of the product of step i) under laboratory conditions until the constant weight of the product is reached.

The present invention further relates to the use of the amorphous of the phosphoric acid salt of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In yet another embodiment the present invention further relates to the use of the Crystal modification 1 of the phosphoric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

Provided is the amorphous phase of the sulfuric acid salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I having an X-ray powder diffraction pattern comprising an essentially amorphous phase measured by CuKa radiation. In some embodiments the amorphous phase of the sulfuric acid salt is characterised by differential scanning calorimetry curve having a melting process with T_onset,i = 30.0°C (corresponding to the water loss); T_onset,2 = 125.5°C and T_peak>2 = 141.9°C. In some embodiments the amorphous phase of the sulfuric acid salt is characterised by the thermal gravimetric curve having a 5.4% weight loss in the range of 20°C to 100°C and a 2.6% weight loss in the range of 100°C to 210°C.

Provided is a process for the preparation of the amorphous phase of the sulfuric acid salt wherein idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Sulfuric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib sulfuric acid salt.

In some embodiments the process for the preparation of the amorphous phase of the sulfuric acid salt further comprises the steps of: a/ dissolving of idelalisib free base in methanol at temperature of 50°C; b/ addition of sulfuric acid to the solution of step a/; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes; d/ cooling the solution of step c/ to room temperature; e/ keeping the solution of step d/ for 2 hours at room temperature; f/ evaporating the solvent completely of the solution of step e/ and g/ isolating the idelalisib sulfuric acid salt in amorphous phase.

In some embodiments the process for the preparation of the amorphous phase of the sulfuric acid salt, further comprises the step of drying of the product of step f) under laboratory conditions until the constant weight of the product is reached.

In other embodiments the alternative process for the preparation of the amorphous phase of the sulfuric acid salt further comprises the steps of: a/ suspending of idelalisib free base in acetone at temperature of 50°C; b/ addition of sulfuric acid to the solution of step a/ while complete dissolution occurs; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes while precipitation occurs; d/ cooling the suspension of step c/ to room temperature; e/ adding of ethyl acetate to the suspension of step d/; f/ keeping the suspension of step e/ for 2 hours at room temperature and g/ isolating the idelalisib sulfuric acid salt in amorphous phase.

The present invention further relates to the use of the amorphous of the sulfuric acid salt of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula I for the preparation of pharmaceutical compositions.

In yet another embodiment the present invention further relates to pharmaceutical formulations containing one or more solid forms of the salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I and benzenesulfonic acid, methanesulfonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid (any one or more of solid form modifications - Crystal modification 1, Crystal modification 2 and the amorphous phase) and a pharmaceutically acceptable carrier for the use thereof for the treatment of leukemia.

Provided is also the amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt as mentioned above and/or the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt as mentioned above and/or amorphous phase, Crystal modification 1 and Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt as mentioned above and/or amorphous phase and Crystal modification 1 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt as mentioned above and/or amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l- (9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt as mentioned above and/or amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one phosphoric acid salt as mentioned above and/or amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt as mentioned above for use for the treatement of cancer, by administering a composition comprising the amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt as mentioned above and/or the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt as mentioned above and/or amorphous phase, Crystal modification 1 and Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt as mentioned above and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l- (9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt as mentioned above and/or amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydroiodic acid salt as mentioned above and/or amorphous phase and Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4- one phosphoric acid salt as mentioned above and/or amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l- (9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt described herein and a pharmaceutically acceptable excipient.

In some embodiments, the cancer is a hematologic malignancy. In other embodiments, the hematologic malignancy is leukemia, wherein leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In particular embodiments, the hematologic malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplasia syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), indolent non-Hodgkin' s lymphoma (iNHL), refractory iNHL, non-Hodgkin' s lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macro globulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). The non-Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldestrom's macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). In one embodiment, the cancer is indolent non-Hodgkin' s lymphoma (iNHL).

It has now surprisingly been found that the salt of Formula I can be prepared in different crystal modifications as well as in amorphous phase. These solid phase modifications, referred to herein as amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt, Crystal modification of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt, amorphous phase of 5-fluoro-3-phenyl-2- [(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt, amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid, Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid, Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt, amorphous phase of 5-fluoro-3-phenyl-2- [(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt, Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt, amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt, Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydroiodic acid salt, amorphous phase of 5-fluoro-3-phenyl-2-[(lS)- l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt, Crystal modification 1 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt and amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt, have different physico-chemical properties. Each of the solid phases have been identified by characteristic X-Ray Powder diffractograms and Raman spectra and differ in their Differential Scanning Calorimetry and Thermal Gravimetric Analysis curves, too. Brief description of the Drawings

The figures depict the following spectra of the various solid forms prepared according to the invention.

Figure 1 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1; Figure 2 is a H-I-NMR spectra the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1;

Figure 3 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1;

Figure 4 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1;

Figure 5 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1;

Figure 6 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 1; Figure 7 is an FTIR spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2;

Figure 8 is a Hi- MR spectra the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2;

Figure 9 is an XRPD pattern of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2;

Figure 10 is a Raman spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2;

Figure 11 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2; Figure 12 is a TGA curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- y!amino)propyl]quinazolin-4-one and benzenesulfonic acid salt prepared according to Example 2;

Figure 13 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3;

Figure 14 is a ¹H-NMR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3;

Figure 15 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3;

Figure 16 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3; Figure 17 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3; Figure 18 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and methanesulfonic acid salt prepared according to Example 3;

Figure 19 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 5;

Figure 20 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 5;

Figure 21 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 5;

Figure 22 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 5;

Figure 23 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 5;

Figure 24 is an FTIR spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 7;

Figure 25 is an XRPD pattern of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 7;

Figure 26 is a Raman spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 7;

Figure 27 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 7;

Figure 28 is a TGA curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 7;

Figure 29 is an XRPD pattern of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 8;

Figure 30 is a Raman spectra of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 8;

Figure 31 is a DSC curve of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 8;

Figure 32 is a TGA curve of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrobromic acid salt prepared according to Example 8;

Figure 33 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 10;

Figure 34 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 10;

Figure 35 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 10;

Figure 36 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 10;

Figure 37 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 10;

Figure 38 is an FTIR spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 11; Figure 39 is an XRPD pattern of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 11;

Figure 40 is a Raman spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 11;

Figure 41 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 11;

Figure 42 is a TGA curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydrochloric acid salt prepared according to Example 11;

Figure 43 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 13;

Figure 44 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 13;

Figure 45 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 13;

Figure 46 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 13;

Figure 47 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 13;

Figure 48 is an FTIR spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 15;

Figure 49 is an XRPD pattern of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 15;

Figure 50 is a Raman spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 15;

Figure 51 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 15;

Figure 52 is a TGA curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and hydroiodic acid salt prepared according to Example 15;

Figure 53 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 16;

Figure 54 is a ^-NMR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 12;

Figure 55 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 16;

Figure 56 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 16;

Figure 57 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 16;

Figure 58 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 16;

Figure 59 is an FTIR spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17; Figure 60 is a ¹H-N R spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17;

Figure 61 is an XRPD pattern of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17;

Figure 62 is a Raman spectra of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17;

Figure 63 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17;

Figure 64 is a TGA curve of the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 17;

Figure 65 is an FTIR spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyf]quinazolin-4-one and phosphoric acid salt prepared according to Example 18;

Figure 66 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 18;

Figure 67 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 18;

Figure 68 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 18;

Figure 69 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one and phosphoric acid salt prepared according to Example 18.

Detailed description of the invention

The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various salts to the examples described herein will be readily apparent to those of average skill in the art, just as the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. The present invention provides salts of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one of formula I and one acid component selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid with advantegous properties for pharmaceutical use regarding the physico-chemical properties and which can be produced in a reproducible manner even in industrial scale.

(I)

The salts of idelalisib are as follows:

A) the salt of idelalisib and benzenesulphonic acid;

B) the salt of idelalisib and methanesulphonic acid;

C) the salt of idelalisib and hydrobromic acid

D) the salt of idelalisib and hydrochloric acid;

E) the salt of idelalisib and hydroiodic acid;

F) the salt of idelalisib and phosphoric acid;

G) the salt of idelalisib and sulfuric acid.

An advantage of the newly prepared forms of idelalisib salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form. In addition these salts are easily producible, with an excellent chemical purity, by a 1-step method in polar aprotic solvents, preferebly in acetone, acetonitrile and methanol.

Variations in the crystal structure of idelalisib novel salts may affect the dissolution rate (which may affect bioavailability etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical drug product, particularly when formulated in a solid oral dosage form (e.g., in a form of a tablet). The therapeutic use and manufacturing of idelalisib novel salts involves the development of a new solid form of idelalisib novel salt that is more bioavailable and stable.

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

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

The term „amorphous phase of idelalisib novel salt", as used in this document, is synonymous to commonly used expression„amorphous idelalisib novel salt".

The use of the term "about" includes and describes the value or parameter per se. For example, "about x" includes and describes "x" per se. In some embodiments, the term "about" when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/- 5 percent.

The term "substantially" or "substantially free/pure" with respect to a particular solid form of a compound means that the polymorphic form contains about less than 30%, about less than 20%, about less than 15%, about less than 10%, about less than 5%, or about less than 1% by weight of impurities. In other embodiments, "substantially" or "substantially free/pure" refers to a substance free of impurities. Impurities may, for example, include by-products or left over reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.

It has been surprisingly found that the above-mentioned salts of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-ylamino)propyl]quinazolin-4-one and solid forms thereof 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 amorphous or crystalline phases have been provided.

The invented salt formed from 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4- one and at least one pharmaceutically acceptable acid component can be present in a crystalline form or in an amorphous form.

The salts may be in an anhydrous and/or a solvent-free form; or they may be in a hydrated or solvated form.

All said salts can be prepared by the reaction of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one with an acid selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid in a solvent selected from the group consisting of C1-C4 alkyl alcohols, aldehydes, ketones, nitriles and water or in their mixtures, preferebly in acetone, acetonitrile and methanol.

The salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one with an acid selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid can be obtained by an alternative process comprising following steps:

a) dissolving the 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one in Cl- C4 alkyl alcohols, nitriles or their mixtures, preferably in methanol or acetonitrile at 50°C; b) addition of the acid component in solution in 1 equimolar ratio dissolved in the same solvent that was used in the step a) to the solution formed in the step a);

c) agitating the solution obtained in the step b) at 50°C for 30 minutes;

d) cooling of the solution obtained in the step c) to the room temperature;

e) agitating the solution obtained in the step d) at room temperature;

f) evaporating the solvent completely of the solution obtained in the step e);

g) collecting of the precipitated solid obtained in the step f);

h) analyzing the solid phase obtained in the step g).

a) suspending the 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one in aldehydes, ketones or any of their mixtures, preferably in acetone at 50°C;

b) addition of the acid component in solution in 1 equimolar ratio dissolved in the same solvent that was used in the step a) to the suspension formed in the step a), while complete dissolution occurs;

c) agitating the solution obtained in the step b) at 50°C for 30 minutes; d) cooling of the solution obtained in the step c) to the room temperature;

e) agitating the solution obtained in the step d) at room temperature for additional 2 hours; f) evaporationg the solvent completely of the solution obtained in the step e);

g) collecting of the precipitated solid obtained in the step f);

h) analyzing the solid phase obtained in the step g).

The salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one with an acid selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid can be obtained by another alternative process comprising following steps:

b) addition of the acid component in 1 equimolar ratio to the solution formed in the step a) while complete dissolution occurs;

c) agitating the solution obtained in the step b) at 50°C for 1 hour;

d) cooling of the solution obtained in the step c) to the room temperature while precipitation occurs;

e) agitating the suspension obtained in the step d) at room temperature for 16 hours;

f) collecting of the precipitated solid from the suspension obtained in the step e) by filtration and drying under laboratory conditions;

g) analyzing the solid phase obtained in the step g).

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one with an acid selected from the group consisting of benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid can be obtained by a process comprising following steps:

a) suspending the amorphous phase of salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one in alcohols, aldehydes, ketones, C1-C7 alkanes, halogenated hydrocarbons and any of their mixtures, preferably in ethanol, ethyl acetate, n-heptane and DCM at room tepmerature;

b) agitating the suspension obtained in the step a) at room temperature for 3 days;

c) collecting of the precipitated solid from the suspension obtained in the step b) by filtration and drying under laboratory conditions;

d) analyzing the solid phase obtained in the step c).

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and benzenesulfonic acid can be characterized by FTIR and ¹H-IM R spectroscopy investigations. Figure 1 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3242; 3062; 2972; 1738; 1650; 1122; 1034; 1015; 692 and 608 cm^"1 wavenumbers. Figure 2 shows the ¹H-N R (Bruker AVANCE 500) spectrum.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 3. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyllquinazolin-4-one benzenesulfonic acid salt can be characterized by Raman spectroscopy. Figure 4 shows the Raman spectrum (Bruker RFS 100/s) comprising characteristic peaks at 3066; 2935; 2876; 1571; 1297; 999; 681; 617; 316 and 270 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 5 shows the DSC (Mettler- Toledo 822e DSC) and Figure 6 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt shows a 3.3% weight loss in the range of 25°C to 95°C and 3.5% weight loss in the range of 95°C to 150°C. The DSC measurement gives a melting process with T_onse = 29.8°C (corresponding to the water loss); T_onset;recrYStaiiization ⁼ 123.0°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt is provided. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Benzenesulfonic acid is added to the solution and then left to cool. After complete evaporation of the solvent, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib benzenesulfonic acid salt.

The suitable organic solvent is methanol.

The process of preparation of the amorphous phase of idelalisib benzenesulfonic acid salt thus comprises the steps of:

a/ dissolving of idelalisib free base in methanol at temperature of 50°C;

b/ addition of benzenesulfonic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solutionof the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib benzenesulfonic acid salt in an amorphous phase;

h/ optionally, drying of the product of step f/ under laboratory conditions until the constant weight of the product is reached.

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and benzenesulfonic acid can be characterized by FTIR and ^-NMR spectroscopy investigations. Figure 7 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3244; 2975; 1716; 1656; 1486; 1219; 1125; 1036; 694 and 604 cm^"1 wavenumbers. Figure 8 shows the ¹H-N R (Bruker AVANCE 500) spectrum.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 9. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 1, below: Pos. [°2Th.] d-spacing [A] Rel. Int. [%]

5.77 15.312 8.2

9.02 9.794 100.0

10.34 8.545 26.4

11.22 7.879 2.8

11.63 7.602 3.7

12.65 6.990 3.4

14.48 6.112 10.0

16.22 5.460 12.4

17.46 5.076 43.5

18.19 4.874 24.9

18.40 4.819 21.3

19.06 4.654 5.6

19.36 4.582 9.5

19.57 4.533 8.5

20.17 4.399 27.1

20.55 4.319 8.9

20.87 4.254 31.8

21.65 4.102 11.5

22.24 3.995 3.6

22.67 3.919 12.1

23.41 3.797 6.3

24.66 3.607 7.0

25.16 3.536 7.6

26.37 3.377 6.4

26.66 3.342 6.8

26.93 3.308 11.9

27.67 3.222 3.8

28.60 3.119 3.6

29.85 2.991 7.8

30.13 2.964 3.8

Table 1

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt can be characterized by Raman spectroscopy. Figure 10 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3131; 2953; 2919; 2873; 1683; 1608; 1354; 617; 272 and 240 cm^"1 wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 11 shows the DSC (Mettler- Toledo 822e DSC) and Figure 12 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt shows a 8.7% weight loss in the range of 25°C to 160°C. The DSC measurement gives a melting process with T_onset,i = 108.3°C T_peak = 151.0°C. In one of the aspects of the invention, a process for preparation of the Crystal modification 1 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt is provided. In this process, idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Benzenesulfonic acid is added to the suspension and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib benzenesulfonic acid salt.

The suitable organic solvent is acetone.

The process of preparation of the Crystal modification 1 of idelalisib benzenesulfonic acid salt thus comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of benzenesulfonic acid to the suspension of step a/ while complete dissolution occurs; c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the suspension of the step d/ for 2 hours at room temperature while precipitation occurs; f/ isolating the idelalisib benzenesulfonic acid salt in Crystal modification 1;

g/ optionally, drying of the product of step e/ under laboratory conditions until the constant weight of the product is reached.

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and methanesulfonic acid can be characterized by FTI and ¹H-NMR spectroscopy investigations. Figure 13 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3242; 2974; 2935; 2876; 1737; 1650; 1149; 1035; 772 and 613 cm^"1 wavenumbers. Figure 14 shows the ^XH-NMR (Bruker AVANCE 500) spectrum.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 15. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical).

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt can be characterized by Raman spectroscopy. Figure 16 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3063; 2886; 1695; 1508; 1352; 1003; 617; 501; 270 and 2413cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 17 shows the DSC (Mettler- Toledo 822e DSC) and Figure 18 shows the TGA (TA Instruments DSC Discovery) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt shows a 7.4% weight loss in the range of 25°C to 175°C. The DSC measurement gives a melting process with T_onseU = 81.rC and T_peak/1 = 100.9°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one methanesulfonic acid salt is provided. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Methanesulfonic acid is added to the suspension and then left to cool. After complete evaporation of the solvent, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib methanesulfonic acid salt. The suitable organic solvent is methanol.

The process of preparation of the amorphous phase of idelalisib methanesulfonic acid salt thus comprises the steps of:

a/ dissolving of idelalisib free base in methanol at temperature of 50°C;

b/ addition of methanesulfonic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solutionof the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib methanesulfonic acid salt in amorphous phase;

Another process of preparation of amorphous phase of idelalisib methanesulfonic acid salt comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of methanesulfonic acid to the suspension of step a/ while complete dissolution occurs; c/ cooling the solution of the step b/ to room temperature;

d/ keeping the solution of the step c/ for 2 hours at room temperature;

e/ evaporating the solvent completely of the solution of step d/;

f/ isolating the idelalisib methanesulfonic acid salt in amorphous phase;

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydrobromic acid can be characterized by FTIR spectroscopy investigations. Figure 19 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3177; 2972; 2940; 2879; 1712; 1650; 1035; 847; 695 and 606 cm^"1 wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 20. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X'PERT PRO PD PANalytical).

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be characterized by Raman spectroscopy. Figure 21 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3074; 2985; 2935; 2878; 1607; 1297; 1003; 618; 270 and 250 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 22 shows the DSC (Mettler-Toledo 822e DSC) and Figure 23 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt shows a 7.7% weight loss in the range of 25°C to 155°C and a 0.8% weight loss in the range of 155°C to 225°C. The DSC measurement gives a melting process with T_onSe_t|i = 47.1°C (corresponding to the water loss); T_onset,₂ = 158.6°C and T_peak,2 = 172.0°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt is provided. In this process, idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydrobromic acid is added to the solution and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydrobromic acid salt.

The suitable organic solvent is acetone.

The process of preparation of the amorphous phase of idelalisib hydrobromic acid salt thus comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of hydrobromic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C while complete precipitation occurs;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the suspension of the step d/ for 2 hours at room temperature;

f/ isolating the idelalisib hydrobromic acid salt in amorphous phase;

Another process of preparation of the amorphous phase of idelalisib hydrobromic acid salt comprises the steps of:

a/ dissolving of idelalisib free base in acetonitrile at temperature of 50°C;

b/ addition of hydrobromic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solution of the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib hydrobromic acid salt in amorphous phase;

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydrobromic acid can be characterized by FTIR spectroscopy investigations. Figure 24 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3213; 3139; 3072; 2932; 2788; 1694; 1651; 1231; 816 and 610 cm^"1 wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid 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 MPD PANalytical). The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 2, below: Pos. [°2Th.] d-spacing [A] el. Int. [%]

7.01 12.607 25.5

7.50 11.785 30.4

8.22 10.748 22.6

9.03 9.783 100.0

10.00 8.816 5.0

11.72 7.544 27.0

12.77 6.926 4.5

14.31 6.184 5.5

16.67 5.312 20.3

18.20 4.871 20.4

18.86 4.701 10.2

19.65 4.513 10.0

21.05 4.218 16.7

22.49 3.950 6.3

23.15 3.839 32.2

23.65 3.759 9.4

24.46 3.636 10.8

25.51 3.489 14.5

27.45 3.247 6.8

28.22 3.160 6.3

28.67 3.111 4.5

29.41 3.034 4.1

30.79 2.902 4.2

Table 2

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be characterized by Raman spectroscopy. Figure 26 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3068; 2965; 2878; 2746; 1698; 1397; 1459; 1303; 617 and 273 cm^"1 wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 27 shows the DSC (Mettler-Toledo 822e DSC) and Figure 28 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 1 of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt shows a 2.1% weight loss in the range of 25°C to 190°C and a 0.7% weight loss in the range of 190°C to 215°C. The DSC measurement gives a melting process with T_{onset l} = 31.4°C (corresponding to the water loss); T_{onset 2} = 93.1°C and T_peak;2 - 100.5°C; T_onset,₃ = 151.1°C and T_pea = 168.6°C; T_onset,₄ = 182.6°C and Tpea = 210.3°C.

The process of preparation of the Crystal modification 1 of idelalisib hydrobromic acid salt comprises the steps of:

a/ suspending of amorphous phase of idelalisib hydrobromic acid salt in ethyl acetate at room temperature;

b/ stirring the suspension of step a/ at room temperature for 3 days; c/ isolating the Crystal modification 1 of idelaisib hydrobromic acid salt;

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

The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt according to the invention has the characteristic X PD pattern as shown in Figure 29. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 3, below:

Table 3

The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be characterized by Raman spectroscopy and FT. Figure 30 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3066; 2936; 2878; 1608; 1324; 1231; 1003; 770; 618 and 314cm ¹ wavenumbers.

The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 31 shows the DSC (Mettler-Toledo 822e DSC) and Figure 32 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 2 of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrobromic acid salt shows a 3.1% weight loss in the range of 25°C to 150°C and a 3.3% weight loss in the range of 150°C to 210°C. The DSC measurement gives a melting process with T_onset = 40.4°C (corresponding to the water loss); T_onset,₂ = 151.2°C; and T_peak,₂ = 171.3°C.

The process of preparation of the Crystal modification 2 of idelalisib hydrobromic acid salt comprises the steps of: a/ suspending of amorphous phase of idelalisib hydrobromic acid salt in n-heptane at room temperature;

b/ stirring the suspension of step a/ at room temperature for 3 days;

c/ isolating the Crystal modification 2 of idelaisib hydrobromic acid salt;

Another process of preparation of the Crystal modification 2 of idelalisib hydrobromic acid salt comprises the steps of:

a/ suspending of amorphous phase of idelalisib hydrobromic acid salt in dichloromethane at room temperature;

b/ stirring the suspension of step a/ at room temperature for 3 days;

c/ isolating the Crystal modification 2 of idelaisib hydrobromic acid salt;

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydrochloric acid can be characterized by FTIR spectroscopy investigations. Figure 33 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3059; 2875; 1688; 1650; 1505; 1230; 1035; 818; 695 and 612 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 34. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO PD PAIMalytical).

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt can be characterized by Raman spectroscopy. Figure 35 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3065; 2935; 2878; 1694; 1609; 1326; 1208; 1003; 618 and 315 cm^"1 wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 36 shows the DSC (Mettler-Toledo 822e DSC) and Figure 37 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt shows a 6.0% weight loss in the range of 25°C to 140°C and a 2.4% weight loss in the range of 140°C to 190°C. The DSC measurement gives a melting process with T_onSet,i = 28.7°C (corresponding to the water loss); T_onset,2 = 140.8°C and T_peak,₂ = 164.3°C; T_onset,₃ = 169.8°C and T_peak,₃ = 188.4°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt is provided. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Hydrochloric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydrochloric acid salt.

The suitable organic solvent is acetontirile.

The process of preparation of the amorphous phase of idelalisib hydrochloric acid salt thus comprises the steps of: a/ dissolving of idelalisib free base in acetonitrile at temperature of 50°C;

b/ addition of hydrochloric acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solution of the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib hydrochloric acid salt in amorphous phase;

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydrochloric acid can be characterized by FTI spectroscopy investigations. Figure 38 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3175; 2971; 2879; 1713; 1605; 1321; 1024; 821; 695 and 611cm ¹ wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 39. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO PD PANalytical). The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrochloric acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 4, below:

Table 4

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt can be characterized by Raman spectroscopy. Figure 40 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3074; 2956; 2936; 2878; 1683; 1654; 1323; 1004; 437 and 270 cm ¹ waven umbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 41 shows the DSC (Mettler-Toledo 822e DSC) and Figure 42 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 1 of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt shows a 7.4% weight loss in the range of 25°C to 135°C and a 2.3% weight loss in the range of 135°C to 190°C. The DSC measurement gives a melting process with T_onse = 43.7°C (corresponding to the water loss); Tonset,2 = 137.9°C and T_pea = 169.8°C and T_onseti3 = 178.3°C and T_peak|3 = 193.0°C.

In one of the aspects of the invention, a process for preparation of the Crystal modification 1 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydrochloric acid salt is provided. In this process, idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydrochloric acid is added to the suspension and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib hydrochloric acid salt.

The suitable organic solvent is acetone.

The process of preparation of the Crystal modification 1 of idelalisib hydrochloric acid salt thus comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of hydrobromic acid to the solution of step a/ while complete dissolution occurs;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes while precipitation occurs; d/ cooling the solution of the step c/ to room temperature;

e/ keeping the suspension of the step d/ for 2 hours at room temperature;

f/ isolating the idelalisib hydrochloric acid salt in Crystal modification 1;

Another process of preparation of the Crystal modification 1 of idelalisib hydrochloric acid salt comprises the steps of:

a/ suspending of amorphous phase of idelalisib hydrochloric acid salt in dichloromethane, ethyl acetate, ethanol or n-heptane at room temperature;

b/ stirring the suspension of step a/ at room temperature for 3 days;

c/ isolating the Crystal modification 1 of idelaisib hydrochloric acid salt;

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydroiodic acid can be characterized by FTIR spectroscopy investigations. Figure 43 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3180; 2968; 2874; 1688; 1606; 1558; 1473; 817; 719 and 641 cm ¹ wavenumbers. The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt according to the invention has the characteristic X PD 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 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt can be characterized by Raman spectroscopy. Figure 45 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3061; 2934; 2877; 1608; 1454; 1382; 1295; 1002; 618 and 269 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 46 shows the DSC (Mettle r-Toledo 822e DSC) and Figure 47 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt shows a 3.2% weight loss in the range of 25°C to 130°C and a 3.0% weight loss in the range of 130°C to 205°C. The DSC measurement gives a melting process with T_onseU = 29.8°C (corresponding to the water loss); T_onset,₂ = 126.1°C and T_peak,₂ = 160.6°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt is provided. In this process, idelalisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Hydroiodic acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib hydroiodic acid salt.

The suitable organic solvent is acetone.

The process of preparation of the amorphous phase of idelalisib hydroiodic acid salt thus comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of hydroiodic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solution of the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib hydroiodic acid salt in amorphous phase;

h/ optionally, drying of the product of step e/ under laboratory conditions until the constant weight of the product is reached.

a/ dissolving of idelalisib free base in acetone at temperature of 50°C;

b/ addition of hydroiodic acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of the step c/ to room temperature;

e/ keeping the solution of the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/; g/ isolating the idelalisib hydroiodic acid salt in amorphous phase;

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and hydroiodic acid can be characterized by FTIR spectroscopy investigations. Figure 48 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3207; 3138; 3074; 2974; 1697; 1645; 1230; 1211; 815 and 604 cm ¹ wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 49. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 5, below:

Table 5

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt can be characterized by Raman spectroscopy. Figure 50 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3072; 2932; 2891; 1699; 1458; 1379; 1091; 1002; 818 and 616 cm ¹ wavenumbers. The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 51 shows the DSC (Mettler-Toledo 822e DSC) and Figure 52 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 1 of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one hydroiodic acid salt shows a 0.9% weight loss in the range of 25°C to 140°C and a 1.6% weight loss in the range of 140°C to 205°C. The DSC measurement gives a melting process with T_{onset l} = 41.7°C (corresponding to the water loss); Tonset.2 = 137.9'C and T_peakj2 = 162.5°C; T_onset,₃ = 182.7°C and T_peak,3 = 198.7°C.

The process of preparation of the Crystal modification 1 of idelalisib hydroiodic acid salt comprises the steps of:

a/ suspending amorphous phase of idelalisib hydroiodic acid salt in ethyl acetate at room temperature;

b/ stirring the suspension of step a/ at room temperature for 3 days;

c/ isolating the Crystal modification 1 of idelaisib hydroiodic acid salt;

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and phosphoric acid can be characterized by FTIR and NMR spectroscopy investigations. Figure 53 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3061; 2970; 2875, 1687; 1650; 1473; 1230; 817; 719 and 613 cm^"1 wavenumbers. Figure 54 shows the ¹H-N R (Bruker A VANCE 500) spectrum.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 55. XRPD pattern was recorded on an X-Ray Powder Diffracto meter (X^'PERT PRO MPD PANalytical).

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt can be characterized by Raman spectroscopy. Figure 56 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3069; 2938; 2878; 1697; 1607; 1456; 1327; 1003; 618 and 270 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 57 shows the DSC (Mettler-Toledo 822e DSC) and Figure 58 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt shows a 4.2% weight loss in the range of 20°C to 110°C. The DSC measurement gives a melting process with T_onsetl = 28.5°C (corresponding to the water loss); T_onset,2 ⁼ 117.5°C; and T_pe^ = 125.2°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt is provided. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Phosphoric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib phosphoric acid salt.

The suitable organic solvent is methanol.

The process of preparation of the amorphous phase of idelalisib phosphoric acid salt thus comprises the steps of: a/ dissolving of idelalisib free base in acetonitrile at temperature of 50°C;

b/ addition of phosphoric acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of step c/ to room temperature;

e/ keeping the solution of the step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib phosphoric acid salt in amorphous phase;

The crystalline salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and phosphoric acid can be characterized by FTI and NMR spectroscopy investigations. Figure 59 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 2972; 2875; 1730; 1652; 1608; 1232; 950; 817; 718 and 614 cm^"1 wavenumbers. Figure 60 shows the ¹H-NMR (Bruker AVANCE 500) spectrum.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 61. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt exhibits the following diffraction peaks in XRPD pattern, see Table 6, below:

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

2.71 32.611 74.4

5.40 16.365 100.0

6.07 14.545 17.9

7.14 12.363 10.4

7.69 11.487 35.5

8.58 10.295 4.9

9.29 9.508 27.1

9.75 9.061 18.0

10.52 8.404 7.9

11.58 7.637 17.9

11.91 7.423 28.3

12.37 7.149 15.7

14.15 6.256 6.9

15.08 5.872 4.5

16.40 5.400 8.3

17.41 5.090 13.8

17.86 4.963 7.3

18.95 4.680 9.5

19.75 4.493 10.1

21.24 4.180 12.0

22.46 3.956 8.8

23.53 3.777 8.8 1 24.75 1 3.594 | 9.3 |

Table 6

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt can be characterized by Raman spectroscopy. Figure 62 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3070; 2938; 2878; 1702; 1608; 1564; 1327; 618; 272 and 242 cm ¹ wavenumbers.

The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 63 shows the DSC (Mettler-Toledo 822e DSC) and Figure 64 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The Crystal modification 1 of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt shows a 2.0% weight loss in the range of 25°C to 85°C, a 2.3% weight loss in the range of 85°C to 145°C and a 3.0% weight loss in the range of 145°C to 240°C. The DSC measurement gives a melting process with T_onseU = 30.9°C (corresponding to the water loss); T_onset,2 = 115.1°C and T_peak,2 = 136.2°C.

In one of the aspects of the invention, a process for preparation of the Crystal modification 1 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one phosphoric acid salt is provided. In this process, ideialisib free base is suspended in a suitable organic solvent by heating of the system to an elevated temperature. Phosphoric acid is added to the solution and then left to cool. After filtering off and drying under laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of ideialisib phosphoric acid salt.

The suitable organic solvent is acetone.

The process of preparation of the Crystal modification 1 of ideialisib phosphoric acid salt thus comprises the steps of:

a/ suspending of ideialisib free base in acetone at temperature of 50°C;

b/ addition of phosphoric acid to the solution of step a/ while complete dissolution occurs;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes while precipitation occurs; d/ cooling the suspension of step c/ to room temperature;

e/ keeping the suspension of step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the suspension of step e/;

g/ addition of ethyl acetate to the residue of step f/;

h/ keeping the suspension of step g/ for 2 hours at room temperature;

i/ isolating the Crystal modification 1 of ideialisib phosphoric acid salt;

j/ optionally, drying of the product of step e/ under laboratory conditions until the constant weight of the product is reached.

The amorphous salt of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one and sulfuric acid can be characterized by FTIR spectroscopy investigations. Figure 65 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3180; 2968, 1683; 1650; 1473; 1295; 1230; 817; 694 and 606 cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt according to the invention has the characteristic XRPD pattern as shown in Figure 66. XRPD pattern was recorded on an X-Ray Powder Diffractometer (X^'PERT PRO MPD PANalytical). The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt can be characterized by Raman spectroscopy. Figure 67 shows the Raman spectrum (Bruker RFS 100/S) comprising characteristic peaks at 3065; 3070; 2936; 2879; 1739; 1611; 1594; 1296; 1003; 617 and 2714cm ¹ wavenumbers.

The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt can be further described by thermoanalytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 68 shows the DSC (Mettler-Toledo 822e DSC) and Figure 69 shows the TGA (NETZSCH TG 209 thermogravimetric analyser) curves measured in the range of 25°C to 350°C and 25°C to 400°C, respectively. The amorphous phase of 5-fluoro-3- phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt shows a 5.4% weight loss in the range of 20°C to 100°C and a 2.6% weight loss in the range of 100°C to 210°C. The DSC measurement gives a melting process with T_onse = 30.0°C (corresponding to the water loss); T_onset,2 = 125.5°C and T_peak,2 = 141.9°C.

In one of the aspects of the invention, a process for preparation of the amorphous phase of 5-fluoro- 3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one sulfuric acid salt is provided. In this process, idelalisib free base is dissolved in a suitable organic solvent by heating of the system to an elevated temperature. Sulfuric acid is added to the solution and then left to cool. After complete evaporation of the solvent the product was analysed by the methods described above and characterised as the amorphous phase of idelalisib sulfuric acid salt.

The suitable organic solvent is methanol.

The process of preparation of the amorphous phase of idelalisib sulfuric acid salt thus comprises the steps of:

a/ dissolving of idelalisib free base in methanol at temperature of 50°C;

b/ addition of sulfuric acid to the solution of step a/;

c/ agitation of the solution of step b/ at 50°C for additional 30 minutes;

d/ cooling the solution of step c/ to room temperature;

e/ keeping the solution of step d/ for 2 hours at room temperature;

f/ evaporating the solvent completely of the solution of step e/;

g/ isolating the idelalisib sulfuric acid salt in amorphous phase;

Another process of preparation of the amorphous phase of idelalisib sulfuric acid salt comprises the steps of:

a/ suspending of idelalisib free base in acetone at temperature of 50°C;

b/ addition of sulfuric acid to the solution of step a/ while complete dissolution occurs;

c/ cooling the suspension of step b/ to room temperature while complete precipitation occurs;

d/ keeping the suspension of step c/ for 2 hours at room temperature;

e/ addition of ethyl acetate to the suspension of step d/;

f/ keeping the suspension of the step e/ for 2 hours at room temperature;

g/ isolating the idelalisib sulfuric acid salt in amorphous phase;

h/ optionally, drying of the product of step e/ under 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„drying under laboratory conditions", 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. Analysis - NMR (Nuclear Magnetic Resonance)

For H NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts were determinated from integrals of corresponding signals of API and coformer.

In case of phosphates the stoichiometry was determined by means of an internal standard added to the measured sample. This standard was a compound containing in its molecule defined numbers of phosphorus and hydrogen atoms. Signal od this compound was compared with those of idelalisib phosphate both in ¹H and ³¹P NMR spectra.

Analysis - XRPD (X-Ray Powder Diffractometry)

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

Generator settings:

excitation voltage 45 kV

anodic current 40 mA.

Scan description:

scan type - go nio

measurement range 2 - 40 ° 2Θ

- step size 0.01 ° 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. 1/4 ° anti-scatter fixed slit, 0.02 rad Soller slits.

Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122 ° . 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.

Analysis - Raman spectroscopy

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

General settings:

Excitation source: Nd-YAG laser (1064 nm) Applied spectral domain: 4000-200 cm^"

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: 4000

Sample gain: 4.0

Optical velocity: 0.6329

Aperture: 100.00

Analysis - DSC (Differential Scanning Calorimetry)

DSC measurements were performed using a Mettler-Toledo 822e DSC.

Samples were placed into standard aluminum pans (40 μΙ_) sealed with a pierced lid. The sample cell was heated under a nitrogen purge at a rate of 10°C/min from 25°C up to a final temperature of 350°C with 50 mL/min nitrogen purge. The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima (T_peai_<) and onset temperature (T_onset) of peaks for the crystalline form. The enthalpy is given in J/g.

The weight sample was about 2.5-3 mg. Analysis - TGA (ThermoGravimetric Analysis)

TGA analyses were performed using a NETZSCH TG 209 thermogravimetric analyser (NETZSCH- Geratebau GmbH, Germany).

Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was heated under nitrogen purge at a rate of 10°C/min from 25°C up to a final temperature of 400°C.

The weight sample was about 5-15 mg. Examples

The following examples are intended to further illustrate the present invention without limiting its scope. Example 1

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propvl]quinazolin-4-one benzenesulfonic acid salt

250 mg (0.602 mmol) of idelalisib free base was dissolved in 2 mL of methanol by heating to 50°C applying a continuous stirring of 750 rpm.

95 mg (0.602 mmol; 1:1 molar ratio) of benzenesulfonic acid was dissolved in 1 mL of methanol at room temperature and the solution was drop-wise added to the methanol solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solution was further stirred at 50°C for additional 30 minutes, then cooled back to room temperature and stirred for additional 2 hours at that temperature.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 340 mg (0.593 mmol) off-white glassy solid

Yield: 98%

HPLC: 99.34%

Chiral HPLC: 99.53%

¹H-NMR was measured (Figure 2) and showed that the compound confirms the structure with an idelalisib : benzenesulfonic acid stoichiometry of 1:1.

XRPD pattern was measured (Figure 3) and showed that the compound is in an amorphous phase. Example 2

Preparation of Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one benzenesulfonic acid salt

250 mg ((0.602 mmol)of idelalisib was suspended in 2 mL of acetone by heating to 50°C applying a continuous stirring of 750 rpm.

95 mg (0.602 mmol; 1:1 molar ratio) of benzenesulfonic acid was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solution was further stirred at 50°C for additional 30 minutes and then cooled back to room temperature and stirred for additional 2 hours at that temperature. Crystallization occurred upon stirring at room temperature.

The solid precipitated is collected by filtration and dried on air by vacuum suction.

Product: 230 mg (0.401 mmol) off-white crystalline solid

Yield: 67%

HPLC: 99.95%

Chiral HPLC: 100%

¹H-NMR was measured (Figure 8) and showed that the compound confirms the structure with an idelalisib : benzenesulfonic acid stoichiometry of 1:1.

XRPD pattern was measured (Figure 9) and showed that the compound is in a crystalline state that was designated as Crystal modification 1. Example 3

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one methanesulfonic acid salt

250 mg (0.602 mmol) of idelalisib free base was dissolved in 5 mL of methanol by heating to 50°C applying a continuous stirring of 750 rpm.

58 μί (0.602 mmol; 1:1 molar ratio) of methanesulfonic acid was added to the methanol solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 298 mg (0.583 mmol) beige glassy solid

Yield: 97%

HPLC: 99.19%

Chiral HPLC: 99.55%

1H-NMR was measured (Figure 14) and showed that the compound confirms the structure with an idelalisib : methanesulfonic acid stoichiometry of 1:1.4.

XRPD pattern was measured (Figure 15) and showed that the compound is in an amorphous phase. Example 4

250 mg (0.602 mmol) of idelalisib free base was suspended in 2 mL of acetone by heating to 50°C applying a continuous stirring of 750 rpm.

58 μί (0.602 mmol; 1:1 molar ratio) of methanesulfonic acid was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 200 mg (0.391 mmol) yellowish glassy solid

Yield: 65%

HPLC: 98.5%

Chiral HPLC: 99.04%

Hi- MR was measured and showed that the compound confirms the structure with an idelalisib : methanesulfonic acid stoichiometry of 1:1.7.

XRPD pattern was measured and showed that the compound is in an amorphous phase. Example 5

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt

68 μί (0.602 mmol; 1:1 molar ratio) of hydrobromic acid (48% aqueous solution) was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solution was further stirred at 50°C for additional 30 minutes, then cooled back to room temperature and stirred for additional 2 hours at that temperature. Precipitation occurred upon stirring at 50°C.

The solid precipitated was collected by filtration and dried on air by vacuum suction.

Product: 270 mg (0.544 mmol) off-white glassy solid

Yield: 90%

HPLC: 99.97%

Chiral HPLC: 100%

Br-ion content: 14.4%

XRPD pattern was measured (Figure 20) and showed that the compound is in an amorphous phase.

Example 6

250 mg (0.602 mmol) of idelalisib free base was suspended in 2 mL of acetonitrile by heating to 50°C applying a continuous stirring of 750 rpm.

68 μί (0.602 mmol; 1:1 molar ratio) of hydrobromic acid (48% aqueous solution) was added to the acetonitrile solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 258 mg (0.521 mmol) off-white glassy solid

Yield: 87%

HPLC: 99.35%

Chiral HPLC: 99.58%

Br-ion content: 15.5%

XRPD pattern was measured and showed that the compound is in an amorphous phase. Example 7

Preparation of Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt

250 mg ((0.504 mmol) of amorphous phase of idelalisib hydrobromic acid salt was suspended in 0.5 mL of ethyl acetate at room temperature and started to agitate with a stirring rate of 750 rpm.

The suspension was agitated for 3 days at room temperature and then the solid was collected by filtration and dried under laboratory conditions by vacuum suction.

Product: 188 mg (0.379 mmol) white crystalline solid

Yield: 75%

HPLC: 99.97%

Chiral HPLC: 100%

Br-ion content: 15.9%

XRPD pattern was measured (Figure 25) and showed that the compound is in a crystalline state that was designated as Crystal modification 1.

Example 8

Preparation of Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrobromic acid salt

250 mg ((0.504 mmol) of amorphous phase of idelalisib hydrobromic acid salt was suspended in 0.5 mL of r?-heptane at room temperature and started to agitate with a stirring rate of 750 rpm.

Product: 210 mg (0.423 mmol) white crystalline solid

Yield: 84%

HPLC: 99.97%

Chiral HPLC: 100%

Br-ion content: 15.8%

XRPD pattern was measured (Figure 29) and showed that the compound is in a crystalline state that was designated as Crystal modification 2.

Example 9

250 mg ((0.504 mmol) of amorphous phase of idelalisib hydrobromic acid salt was suspended in 0.5 mL of dichloromethane at room temperature and started to agitate with a stirring rate of 750 rpm.

Product: 193 mg (0.389 mmol) white crystalline solid Yield: 77%

HPLC: 99.97%

Chiral HPLC: 100%

Br-ion content: 16.0%

XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as Crystal modification 2.

Example 10

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrochloric acid salt

250 mg (0.602 mmol) of idelalisib free base was dissolved in 2 mL of acetonitrile by heating to 50°C applying a continuous stirring of 750 rpm.

53 μί (0.602 mmol; 1:1 molar ratio) of hydrochloric acid (35% aqueous solution) was added to the acetonitrile solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. The solution was further stirred at 50°C for additional 30 minutes, then cooled back to room temperature and stirred for additional 2 hours at that temperature.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 230 mg (0.509 mmol) off-white glassy solid

Yield: 85%

HPLC: 99.45%

Chiral HPLC: 99.63%

Cl-ion content: 7.6%

XRPD pattern was measured (Figure 34) and showed that the compound is in an amorphous phase. Example 11

Preparation of Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydrochloric acid salt

53 μΐ (0.602 mmol; 1:1 molar ratio) of hydrochloric acid (35% aqueous solution) was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

Product: 240 mg (0.531 mmol) off-white crystalline solid

Yield: 88%

HPLC: 99.89% Chiral HPLC: 100%

Cl-ion content: 7.45%

XRPD pattern was measured (Figure 39) and showed that the compound is in an amorphous phase. Example 12

250 mg ((0.553 mmol) of amorphous phase of idelalisib hydrochloric acid salt was suspended in 0.5 mL of ethyl acetate at room temperature and started to agitate with a stirring rate of 750 rpm. The suspension was agitated for 3 days at room temperature and then the solid was collected by filtration and dried under laboratory conditions by vacuum suction.

Product: 197 mg (0.436 mmol) white crystalline solid

Yield: 79%

HPLC: 99.97%

Chiral HPLC: 100%

Cl-ion content: 7.7%

XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as Crystal modification 1.

Similarly, same results were obtained using any of the solvents listed in the Table 7.

Solvent

ethyl acetate

n-heptane

dichloromethane

Table 7

Example 13

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydroiodic acid salt

80 μί (0.602 mmol; 1:1 molar ratio) of hydroiodic acid (57% aqueous solution) was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 320 mg (0.589 mmol) yellowish glassy solid

Yield: 98% HPLC: 99.33%

Chiral HPLC: 99.56%

Hon content: 22.2%

XRPD pattern was measured (Figure 44) and showed that the compound is in an amorphous phase.

Example 14

80 μί (0.602 mmol; 1:1 molar ratio) of hydroiodic acid (57% aqueous solution) was added to the acetonitrile solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 183 mg (0.337 mmol) brownish glassy solid

Yield: 56%

HPLC: 99.38%

Chiral HPLC: 99.61%

l-ion content: 22.4%

XRPD pattern was measured and showed that the compound is in an amorphous phase.

Example 15

Preparation of Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one hydroiodic acid salt

250 mg (0.553 mmol) of amorphous phase of idelalisib hydroiodic acid salt was suspended in 0.5 mL of ethyl acetate at room temperature and started to agitate with a stirring rate of 750 rpm.

Product: 180 mg (0.331 mmol) white crystalline solid

Yield: 72%

HPLC: 99.97%

Chiral HPLC: 100%

l-ion content: 23.2%

XRPD pattern was measured (Figure 49) and showed that the compound is in a crystalline state that was designated as Crystal modification 1. Example 16

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one phosphoric acid salt

41 [il (0.602 mmol; 1:1 molar ratio) of phosphoric acid (85% aqueous solution) was added to the methanol solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 300 mg (0.584 mmol) grey glassy solid

Yield: 97%

HPLC: 99.30%

Chiral HPLC: 99.55%

XH-NMR was measured (Figure 54) and showed that the compound confirms the structure with an idelalisib : phosphoric acid stoichiometry of 1:1.

XRPD pattern was measured (Figure 55) and showed that the compound is in an amorphous phase. Example 17

Preparation of Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one phosphoric acid salt

41 μΐ (0.602 mmol; 1:1 molar ratio) of phosphoric acid (85% aqueous solution) was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solution was further stirred at 50°C for additional 30 minutes, then cooled back to room temperature while precipitation occurred forming a sticky substance.

2 mL of ethyl acetate was added to the sticky substance and stirred for additional 2 hours at room temperature.

The solid was collected by filtration and dried on air by vacuum suction.

Product: 297 mg (0.578 mmol) grey glassy solid

Yield: 96%

HPLC: 99.31%

Chiral HPLC: 99.28%

¹H-NMR was measured (Figure 60) and showed that the compound confirms the structure with an idelalisib : methanesulfonic acid stoichiometry of 1:1.3.

XRPD pattern was measured (Figure 61) and showed that the compound is in a crystalline state that was designated as Crystal modification 1. Example 18

Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one sulfuric acid salt

34 μί (0.602 mmol; 1:1 molar ratio) of sulfuric acid (96% aqueous solution) was added to the methanol solution of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm.

The solvent was fully evaporated and the solid precipitated was collected.

Product: 305 mg (0.594 mmol) beige glassy solid

Yield: 99%

HPLC: 99.14%

Chiral HPLC: 99.52%

XRPD pattern was measured (Figure 66) and showed that the compound is in an amorphous phase. Example 19

34 ί (0.602 mmol; 1:1 molar ratio) of sulfuric acid (96% aqueous solution) was added to the acetone suspension of idelalisib at 50°C, while continuously stirred with a stirring rate of 750 rpm. Complete dissolution occurred.

The solid was collected by filtration and dried on air by vacuum suction.

Product: 297 mg (0.578 mmol) off-white glassy solid

Yield: 97%

HPLC: 99.28%

Chiral HPLC:99.44%

Claims

C LA I M S

1. A salt comprising compound of Formula I:

(I)

and at least one acid component (HA) selected from the group consisting of hydrobromic acid, hydrochloric acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulphonic acid and benzenesulphonic acid.

2. The salt according to claim 1, wherein HA is hydrobromic acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 9.0; 11.7; 16.7; 18.2; 21.1 and 23.2 ± 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 1.

3. The salt according to claim 1, wherein HA is hydrobromic acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 9.8; 15.2; 19.5; 21.8 and 23.9 ± 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 2.

4. The salt according to claim 1, wherein HA is hydrobromic acid, characterized in that with using CuKa radiation it reveals an amorphous form.

5. The salt according to claim 1, wherein HA is hydrochloric acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 9.9; 12.2; 15.1; 19.8; 21.6 and 24.1 + 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 1.

6. The salt according to claim 1, wherein HA is hydrochloric acid, characterized in that with using CuKa radiation it reveals an amorphous form.

7. The salt according to claim 1, wherein HA is hydroiodic acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 7.2; 9.0; 17.0; 18.1 and 22.5 ± 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 1.

8. The salt according to claim 1, wherein HA is hydroiodic acid, characterized in that with using CuKa radiation it reveals an amorphous form.

9. The salt according to claim 1, wherein HA is sulfuric acid, characterized in that with using CuKa radiation it reveals an amorphous form.

10. The salt according to claim 1, wherein HA is phosphoric acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 5.4; 7.7; 9.3; 11.9; 21.2 ± 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 1.

11. The salt according to claim 1, wherein HA is phosphoric acid, characterized in that with using CuKa radiation it reveals an amorphous form.

12. The salt according to claim 1, wherein HA is methanesulphonic acid, characterized in that with using CuKa radiation it reveals an amorphous form.

13. The salt according to claim 1, wherein HA is benzenesulphonic acid, characterized by X-ray powder diffraction pattern comprising characteristic peaks at about 9.0; 10.3; 17.5; 20.2 and 20.9 ± 0.2° 2-theta measured by CuKa radiation, herein reffered as the Crystal modification 1.

14. The salt according to claim 1, wherein HA is benzenesulphonic acid, characterized in that with using CuKa radiation it reveals an amorphous form.

15. A process of preparation of salt according to any of preceeding claims, characterized in that it comprises dissolution or suspending of the 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one in an organic solvent, addition of the acid component, followed by agitating and cooling of the solution.

16. The process of claim 15, wherein the organic solvent is selected from range of C1-C4 alkyl alcohols, aldehydes, ketones, nitriles and water or their mixture, preferebly methanol, ethanol, acetone or acetonitrile or their mixture.

17. The process of claim 15, wherein the acid component is selected from benzenesulphonic acid, methanesulphonic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, phosphoric acid and sulfuric acid.

18. The process as claimed in claim 15, wherein the acid component in a solution is added in 1 equimolar ratio.

19. The process as claimed in claim 15, wherein the obtained solution is agitated at the temperature of 50°C.

20. The process as claimed in claim 15, wherein the addition of the acid component is in a solution, that is dissolved in the same organic solvent as 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one.

21. Use of salt according to any of preceeding claims in the preparation of 5-fluoro-3-phenyl-2-[(lS)- l-(9H-purin-6-ylamino)propyl]quinazolin-4-one base or in preparation of other salts.

22. A pharmaceutical composition comprising a salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile of Formula I

H-X (I)

23. The pharmaceutical composition as claimed in claim 21, further comprising one or more pharmaceutically acceptable carriers or excipients.

24. The pharmaceutical composition as claimed in claims 21 and 22, which is in a pharmaceutical form suitable for oral administration.

25. The pharmaceutical composition of claims 21 to 23, wherein the pharmaceutical composition is in a form of a tablet.

26. The salt as claimed in any one of claims 1 to 14 for use in treating of a disease in a patient wherein said disease is associated with JAK activity.

27. The salt as claimed in any one of claims 1 to 14 for use in the treatment of cancer.

28. The salt as claimed in claim 26, wherein the cancer is a hematological cancer.

29. The salt as claimed in any one of claims 1 to 14 for use for treating chronic myelogenous leukemia (CML) in a patient comprising administering to a patient a therapeutically effective amount of the said crystalline salt.

30. The salt as claimed in any one of claims 1 to 14 for use for treating acute lymphoblastic leukemia (ALL) in a patient comprising administering to a patient therapeutically effective amount of the said crystalline salt.

31. The salt as claimed in any one of claims 1 to 14 for use for treating chronic myelomonocytic leukemia (CMML) in a patient comprising administering to a patient therapeutically effective amount of the said crystalline salt.