WO2016188506A1 - Solid forms of 5-fluoro-3-phenyl-2-[(1s)-1-(9h-purin-6-ylamino)propyl]quinazolin-4-one and preparation thereof - Google Patents

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

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WO2016188506A1
WO2016188506A1 PCT/CZ2016/000056 CZ2016000056W WO2016188506A1 WO 2016188506 A1 WO2016188506 A1 WO 2016188506A1 CZ 2016000056 W CZ2016000056 W CZ 2016000056W WO 2016188506 A1 WO2016188506 A1 WO 2016188506A1
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Prior art keywords
crystal modification
purin
fluoro
ylamino
quinazolin
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PCT/CZ2016/000056
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French (fr)
Inventor
Violetta Kiss
Eszter TIEGER
Hana TOZICKOVA
Ondrej Dammer
Lukas KREJCIK
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Zentiva, K.S.
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Publication of WO2016188506A1 publication Critical patent/WO2016188506A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to solid forms of 5-fluoro-3-phenyl-2-[ ⁇ lS)-l- ⁇ 9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I
  • PI3K phosphoinositide 3-kinase
  • CLL chronic lymphocytic leukaemia
  • PI3Ks phosphoinositide 3-kinases
  • 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.
  • Idelaiisib blocks ⁇ , 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 PI3K6 and results in the inhibition of the phosphorylation of the key lipid second messenger phosphatidylinositol and prevention of Akt (protein kinase B) phosphorylation.
  • ATP adenosine 5'-triphosphate
  • WO2005113556 describes selective inhibitors of phosphoinositide 3-kinase (PI3K) enzymes with valuable pharmacological effect in the treatment of related diseases.
  • PI3K phosphoinositide 3-kinase
  • 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 the base is also provided.
  • idelaiisib Various crystalline forms of idelaiisib are disclosed in WO2013134288 and WO2015014315. Further is described process for the preparation of idelaiisib anhydrous crystalline forms designated as Form I, Form II, solvated forms designated as Form HI, Form IV, Form V, Form VI and Form VII, as well as crystalline Form M, IV and VI, polymorph II and hydrated crystalline forms designated as Form IX and VIII, respectively.
  • the object of the present invention is to provide solid forms 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.
  • 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.
  • Crystal modification 1 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 10.4; 11.9 and 15.7 ⁇ 0.2° 2-theta, measured by CuKa radiation.
  • the Crystal modification 1 further comprises characteristic peaks at about 8.2; 9.1; 14.7; 18.8 and 23.7 ⁇ 0.2° 2-theta, measured by CuKa radiation.
  • the Crystal modification 1 is characterised by the thermal gravimetric curve having a 4.3 % weight loss in the range of 20 °C to 150 °C.
  • the Crystal modification 1 is substantially a hydrate.
  • idelaiisib is dissolved in suitable organic solvent, preferably a polar aprotic solvent, more preferably tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethylsulfoxide or a mixture thereof, in particular in acetonitrile, by heating of the system to a temperature close to the boiling point of the solvent.
  • suitable organic solvent preferably a polar aprotic solvent, more preferably tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethylsulfoxide or a mixture thereof, in particular in acetonitrile
  • the process for the preparation of the Crystal modification 1 comprises the steps of: a) dissolution of idelaiisib in acetonitrile at the temperature close to the boiling point of the respective solvent; b) cooling the solution of the step a) to a temperature of 0 - 5 °C to form a suspension; c) keeping the suspension of the step b) at a temperature of 0 - 5 °C for about 4 hours; and d) isolating the idelaiisib free base in Crystal modification 1.
  • the process for the preparation of the Crystal modification 1 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
  • the process for the preparation of the Crystal modification 1 further illustrates that the heated solution is cooled to a temperature of at least about 0 °C In yet another embodiment the process for the preparation of the Crystal modification 1 further illustrates that the heated solution is kept cooled for about 4 hours.
  • the present invention further lists the process for the preparation of the Crystal modification 1, wherein clergyalisib is dissolved in a suitable organic solvent, preferably a polar aprotic solvent, more preferably in tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethy!sulfoxide or a mixture thereof, in particular in acetonitrile, by heating of the system to a temperature dose to the boiling point of the solvent.
  • a suitable organic solvent preferably a polar aprotic solvent, more preferably in tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethy!sulfoxide or a mixture thereof, in particular in acetonitrile
  • Crystal modification 2 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 10.8; 11.8; 18.3; 20.0; 23.7 and 25.5+ 0.2° 2-theta, measured by CuKa radiation.
  • the Crystal modification 2 is characterised by the thermal gravimetric curve having a 14.3 % weight loss in the range of 20 °C to 180 °C. in one variation, the Crystal modification 2 is substantially a solvate.
  • the process for the preparation of the Crystal modification 2 comprises the steps of: a) suspending sacredalisib in ⁇ /,/V-dimethyl formamide at room temperature; b) heating up the suspension of step a) to 40 to 60 e C; c) stirring the suspension of step b); d) isolating the Crystal modification 2 of sacredalisib.
  • the process for the preparation of the Crystal modification 2 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
  • the process for the preparation of the Crystal modification 2 comprises the steps of: a) suspending idelalisib in W,A/-dim ethyl formamide at room temperature; b) stirring the suspension of the step a); c) isolating the Crystal modification 2 of idelalisib.
  • the process for the preparation of the Crystal modification 2 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
  • the process for the preparation of the Crystal modification 2 further provides that the suspension is heated to a temperature of at least about 40 to 60 e C, preferably 50 °C. in another embodiment the process for the preparation of the Crystal modification 2 further relates that the suspension is stirred for at least 48 hours. In another embodiment the process for the preparation of the Crystal modification 2 further provides that the suspension is stirred for at least 2 weeks.
  • the present invention further relates to the use of the Crystal modification 1 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 composition.
  • the present invention further relates to the use of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula ⁇ for the preparation of a pharmaceutical composition.
  • the present invention further relates to a pharmaceutical formulations containing one or more solid forms of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one (any one or more of solid form modifications of Crystal form 1, Crystal form 2 and the amorphous phase) and a pharmaceutically acceptable carrier for the use thereof for the treatment of cancer.
  • the cancer is a hematologic malignancy.
  • the hematologic malignancy is leukemia, wherein leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL).
  • leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the hematologic malignancy is leukemia or lymphoma.
  • the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplasia syndrome (MDS), myeloproliferative disease ⁇ PD), chronic myeloid leukemia (CIVIL), 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-ceil lymphoma, and diffuse large B-cell lymphoma (DLBCL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL
  • the cancer is T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL).
  • T-ALL T-cell acute lymphoblastic leukemia
  • B-ALL B-cell acute lymphoblastic leukemia
  • the non- Hodgkin lymphoma encompasses the indolent B-cell diseases that include, for example, follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).
  • the cancer is indolent non-Hodgkin's lymphoma (iNHL).
  • Crystal modification 1 can be prepared in 2 different crystal modifications as well as in amorphous phase.
  • These 3 solid phase modifications referred to herein as Crystal modification 1, Crystal modification 2, and amorphous phase, have different physico-chemical properties.
  • Each solid phases were identified by characteristic X-Ray Powder diffractograms and Raman spectra and differ in their Differential Scanning Calorimetry and Thermal Gravimetric Analysis curves, too.
  • Figure 1 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;
  • Figure 2 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;
  • Figure 3 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyI-2-[(lS)-l-(9H-purin- 6-ylamino)propy!]quinazolin-4-one;
  • Figure 4 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;
  • Figure 5 is an XRPD pattern of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-yIamino ⁇ propyl]quinazolin-4-one;
  • Figure 6 is a Raman spectra of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H- purin-6-ylamino)propyl3quinazolin-4-one;
  • Figure 7 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;
  • Figure 8 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;
  • Figure 9 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin- 6-ylamino)propyl]quinazo[in-4-one;
  • Figure 10 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyi-2-[(lS)-l-(9H- purin-6-ylamino)propy[]quinazolin-4-one;
  • Figure 11 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one;
  • Figure 12 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one.
  • the present invention provides novel solid forms of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one (ideialisib) of formula I
  • Variations in the crystal structure of sacredalisib 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 sacredalisib involves the development of a new solid form of sacredalisib that is more bioavailable and stable.
  • 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 percent, about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent, or about less than 1 percent by weight of impurities.
  • 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.
  • the Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propy!]- quinazolin-4-one has the characteristic XRPD pattern as shown in Figure 1.
  • 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 exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:
  • Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]- quinazoiin-4-one can be characterized by Raman spectroscopy.
  • Figure 2 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3067, 2933, 1690, 1612, 1568, 1324, 1002, 760, 268 and 235 cm '1 wavenumbers.
  • Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H-purin-6-ylamino)propyl]- quinazolin-4-one can be further described by thermoanaiytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA).
  • Figure 3 shows the DSC ⁇ Perkin Elmer Pyris 1 DSC)
  • Figure 4 shows the TGA (Perkin Elmer TGA 6 ⁇ curves measured in the range of 20 °C to 300 °C and 20 e C to 300 "C, respectively.
  • Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one is a hydrate shows a 4.3 % weight loss in the range of 20 °C to 150 "C
  • the DSC measurement gives a melting process with °C (corresponding to the water loss);
  • a process for preparation of the Crystal modification 1 is provided.
  • idelalisib is dissolved in a suitable organic solvent by heating of the system to a temperature close to the boiling point of the solvent. The solution is then placed onto ice for cooling. After filtering off and drying at laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib.
  • the suitable organic solvent is acetonitrile.
  • the process of preparation of the Crystal modification 1 of idelalisib thus comprises the steps of: a/ dissolution of idelalisib in acetonitrile at the temperature close to the boiling point of the respective solvent; b/ cooling the suspension of the step a/ to a temperature of 0-5°C; c/ keeping the suspension of the step b/ at a temperature of 0-5°C for 4 hours; d/ isolating the idelalisib free base in Crystal modification 1; e/ optionally, drying of the product of step d/ at laboratory condition 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 according to the invention has the characteristic XRPD pattern as shown in Figure 5.
  • 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 exhibits the following diffraction peaks in XRPD pattern, see Table 2, below: Pos. [°2Th.] d-spacing [ ⁇ ] Rel. Int. [%]
  • Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H-purin-6-ylam ' ino)propyl]- quinazolin-4-one can be characterized by Raman spectroscopy.
  • Figure 6 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3069, 2956, 2930, 2875, 1684, 1612, 1328, 1290, 1004 and 616 cm "1 wavenumbers.
  • Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]- quinazolin-4-one can be further described by thermal analytical methods.
  • Figure 7 shows the DSC (Perkin Elmer Pyris 1 DSC) and
  • Figure 8 shows the TGA (TA Instruments DSC Discovery) curves measured in the range of 20 e C to 300 "C and 20 e C to 300 °C, respectively.
  • the crystalline Modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H-purin-6-ylamino)propyl]- quinazolin-4-one is a solvate that shows a 14.3 % weight loss in the range of 20 "C to 180 e C.
  • the Crystal modification 2 of idelalisib can be prepared by a process comprising the steps of: a/ suspending idelalisib in N,N-d ⁇ methyl formamide at room temperature; b/ heating up the suspension of step a/ to 50°C applying a continuous agitation; c/ stirring the suspension of step b/ for 2 weeks; d/ isolating the Crystal modification 2 of idelalisib; e/ optionally, drying of the product of step d/ at laboratory condition until the constant weight of the product is reached.
  • Another process of preparation of the Crystal modification 2 of idelalisib comprises the steps of: a/ suspending idelalisib in ⁇ /,/V-dimethyl formamide at room temperature; b/ stirring the suspension of the step a/ for 48 hours; c/ isolating the Crystal modification 2 of idelalisib; d/ optionally, drying of the product of step c/ at laboratory condition until the constant weight of the product is reached.
  • the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H-purin-6-ylamino)propyl]quinazolin- 4-one 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 amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l- ⁇ 9H-purin-6-ylamino)propyl]quinazolin- 4-one can be characterized by Raman spectroscopy.
  • Figure 10 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 2938, 2874, 1695, 1454, 1326, 1003, 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 shows a 3.5 % weight loss in the range of 20 °C to 200 °C.
  • the DSC measurement gives a melting process with °C.
  • the amorphous idelalisib can be prepared by a process comprising the steps of: a/ dissolving idelalisib in a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate, ethanol, 2-propanol, methanol, 4-methyl-2-pentanone or a mixture thereof, water-dioxane in 1:1 ratio by volume and water-ethanol in 25:75 ratio by volume at room temperature; b/ isolating the amorphous idelalisib by evaporation of the solvent in vacuum oven at 60 °C using 500 mbar vacuum pressure.
  • a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate
  • Another process for preparation of the amorphous idelalisib comprises the steps of: a/ dissolving idelalisib in a solvent selected from the group of consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate, ethanol, 2-propanol, methanol, 4-methyl-2-pentanone or a mixture thereof, water-dioxane in 1:1 ratio by volume and water-ethanol in 25:75 ratio by volume at room temperature; b/ isolating the amorphous idelalisib by evaporation of the solvent in vacuum oven at laboratory condition.
  • a solvent selected from the group of consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate, ethanol, 2-propanol,
  • Yet another process of preparation of the amorphous idelalisib comprises the steps of: a/ dissolving idelalisib in a solvent selected from the group of consisting of chloroform, dichloromethane, tetrahydrofuran and xylenes or a mixture thereof at the temperature close to the boiling point of the respective solvent or at room temperature; b/ cooling the solution of the step a/ to room temperature; c/ isolating the amorphous idelalisib; d/ optionally, drying of the product of step c/ at laboratory condition until the constant weight of the product is reached.
  • the term “bulroom 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.
  • Incident beam optics programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/42 anti-scatter fixed slit, 0.02 rad Soller slits.
  • Diffracted beam optics X'Celerator detector, scanning mode, active length 2.122 s . 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
  • the sample were weighed in aluminium pans and covers (20 ⁇ ) and measured in a nitrogen flow. Investigations were performed in a temperature range of 20 °C to 300 e C with a heating rate of 10 °C/min
  • the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima O ) and onset temperature (T on set) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form.
  • the enthalpy is given in J/g.
  • the weight sample was about 2.5-3 mg.
  • the temperatures specified in relation to DSC analyses are the temperatures of the peak maxima ( ⁇ ⁇ 3 ⁇ ) and onset temperature (T Qrise t) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form.
  • the enthalpy is given in J/g.
  • the weight sample was about 3.5-5 mg.
  • the samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 20 °C to 300 °C with a heating rate of 10 "C/min.
  • the weight sample was about 6-22 mg.
  • the solid obtained was collected by filtration, washed with a few drops of pre-cooled acetonitrile and then dried by vacuum suction at laboratory condition.
  • the suspension was heated up to 50 "C and kept at that temperature applying a continuous stirring for 2 weeks.
  • the solid obtained was collected by filtration and then dried by vacuum suction at laboratory condition.
  • the solid obtained was collected by filtration, washed with a few drops of pre-cooled dimethylformamide and then dried by vacuum suction at laboratory condition.
  • XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
  • idelalisib 60 mg (0.144 mmol) of idelalisib was dissolved in dichloromethane by heating to the boiling of the solvent. The solution was stirred at this temperature for 10-15 minutes then placed onto ice to cool. The solid obtained was placed into fridge overnight, then filtered off and dried at laboratory condition. XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
  • the solvent was completely evaporated in vacuum oven at 60°C using 500 mbar vacuum pressure.
  • XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
  • XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.

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Abstract

Solid forms of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4-one of formula (I), suitable for oral administration, which comply with pharmaceutical requirements. Preparation and characterization of Crystal Form 1 and Crystal Form 2.

Description

Solid forms of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-yiamino)propyl]quinazolin-4-one and preparation thereof
Technical Field
The present invention relates to solid forms of 5-fluoro-3-phenyl-2-[{lS)-l-{9H-purin-6- ylamino)propyl]quinazolin-4-one of Formula I
Figure imgf000003_0001
H
(I) in crystalline or amorphous phase, the processes for the preparation thereof as well as 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 idelalisib (CAS no.: 870281-82-6), has a phosphoinositide 3-kinase (PI3K) inhibitor activity, which is effectively used for the treatment of chronic lymphocytic leukaemia (CLL). The enzymes phosphoinositide 3-kinases (PI3Ks) 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.
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. Idelaiisib blocks ΡΙΙΟδ, 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 PI3K6 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 the base is also provided.
Various crystalline forms of idelaiisib are disclosed in WO2013134288 and WO2015014315. Further is described process for the preparation of idelaiisib anhydrous crystalline forms designated as Form I, Form II, solvated forms designated as Form HI, Form IV, Form V, Form VI and Form VII, as well as crystalline Form M, 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 physico- chemical 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 and Raman spectroscopy, as well as thermoanalytical methods. Discovery of new solid phases (polymorphs, solvates and hydrates) of an active pharmaceutical compound offers the opportunity to select the appropriate modification having desirable physico-chemical properties and processability and improve the characteristics of the pharmaceutical product. For this reason there is an explicit need for new solid forms (polymorphs, solvates, hydrates) of idelaiisib.
Disclosure of Invention
The object of the present invention is to provide solid forms 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 Crystal modification 1 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 10.4; 11.9 and 15.7 ± 0.2° 2-theta, measured by CuKa radiation. In some embodiments the Crystal modification 1 further comprises characteristic peaks at about 8.2; 9.1; 14.7; 18.8 and 23.7 ± 0.2° 2-theta, measured by CuKa radiation. In some embodiments the Crystal modification 1 is characterised by differential scanning calorimetry curve having a melting process with Tonset(1= 67 °C corresponding to the water loss; Tor)set,2 = 141.3 °C; Tre_ryStaiirzation = 205 °C and Tonset,3 = 245.5 "C. In some embodiments the Crystal modification 1 is characterised by the thermal gravimetric curve having a 4.3 % weight loss in the range of 20 °C to 150 °C. In one variation, the Crystal modification 1 is substantially a hydrate.
It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum.
Provided further is a process for the preparation of the Crystal modification 1 wherein idelaiisib is dissolved in suitable organic solvent, preferably a polar aprotic solvent, more preferably tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethylsulfoxide or a mixture thereof, in particular in acetonitrile, by heating of the system to a temperature close to the boiling point of the solvent.
In some embodiments the process for the preparation of the Crystal modification 1 comprises the steps of: a) dissolution of idelaiisib in acetonitrile at the temperature close to the boiling point of the respective solvent; b) cooling the solution of the step a) to a temperature of 0 - 5 °C to form a suspension; c) keeping the suspension of the step b) at a temperature of 0 - 5 °C for about 4 hours; and d) isolating the idelaiisib free base in Crystal modification 1. In some embodiments, the process for the preparation of the Crystal modification 1 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached. In yet another embodiment the process for the preparation of the Crystal modification 1 further illustrates that the heated solution is cooled to a temperature of at least about 0 °C In yet another embodiment the process for the preparation of the Crystal modification 1 further illustrates that the heated solution is kept cooled for about 4 hours. In some embodiments the present invention further lists the process for the preparation of the Crystal modification 1, wherein ideialisib is dissolved in a suitable organic solvent, preferably a polar aprotic solvent, more preferably in tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethy!sulfoxide or a mixture thereof, in particular in acetonitrile, by heating of the system to a temperature dose to the boiling point of the solvent. Provided further is the Crystal modification 2 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 10.8; 11.8; 18.3; 20.0; 23.7 and 25.5+ 0.2° 2-theta, measured by CuKa radiation. In some embodiments the Crystal modification 2 is characterised by differential scanning calorimetry curve having a melting process with 109 °C corresponding to a solvent loss and Tonset,2 = 249,4 °C. In some embodiments the Crystal modification 2 is characterised by the thermal gravimetric curve having a 14.3 % weight loss in the range of 20 °C to 180 °C. in one variation, the Crystal modification 2 is substantially a solvate.
It should be understood that relative intensities can vary depending on a number of factors, including sample preparation, mounting, and the instrument and analytical procedure and settings used to obtain the spectrum.
Provided further is a process for the preparation of the Crystal modification 2, wherein ideialisib is suspended in Λ/,ΛΖ-dimethyl formamide at room temperature. In some embodiments the process for the preparation of the Crystal modification 2 comprises the steps of: a) suspending ideialisib in Λ/,/V-dimethyl formamide at room temperature; b) heating up the suspension of step a) to 40 to 60 eC; c) stirring the suspension of step b); d) isolating the Crystal modification 2 of ideialisib. In some embodiments the process for the preparation of the Crystal modification 2 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached. In another embodiment the process for the preparation of the Crystal modification 2 comprises the steps of: a) suspending idelalisib in W,A/-dim ethyl formamide at room temperature; b) stirring the suspension of the step a); c) isolating the Crystal modification 2 of idelalisib. In some embodiments the process for the preparation of the Crystal modification 2 further comprises the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
In yet another embodiment the process for the preparation of the Crystal modification 2 further provides that the suspension is heated to a temperature of at least about 40 to 60 eC, preferably 50 °C. in another embodiment the process for the preparation of the Crystal modification 2 further relates that the suspension is stirred for at least 48 hours. In another embodiment the process for the preparation of the Crystal modification 2 further provides that the suspension is stirred for at least 2 weeks.
The present invention further relates to the use of the Crystal modification 1 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 composition.
In another embodiment the present invention further relates to the use of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one of Formula ί for the preparation of a pharmaceutical composition.
In yet another embodiment the present invention further relates to a pharmaceutical formulations containing one or more solid forms of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one (any one or more of solid form modifications of Crystal form 1, Crystal form 2 and the amorphous phase) and a pharmaceutically acceptable carrier for the use thereof for the treatment of cancer.
Provided is also the Crystal modification 1 of 5-fluoro-3-phenyl-2-[{lS)-l-(9H-purin-6- y!amino)propy!3quinazolin-4-one as mentioned above and/or the Crystal modification 2 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one as mentioned above, for use for the treatment of cancer, by administering to the patient a composition comprising the Crystal modification 1 and/or the Crystal modification 2 described herein and a pharmaceutically acceptable excipients. 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 { PD), chronic myeloid leukemia (CIVIL), 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-ceil 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, Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well as the aggressive lymphomas that include, for example, Burkitt 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 compound of formula 1 can be prepared in 2 different crystal modifications as well as in amorphous phase. These 3 solid phase modifications, referred to herein as Crystal modification 1, Crystal modification 2, and amorphous phase, have different physico-chemical properties. Each solid phases were 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 Drawings
The figures depict the following spectra of the various solid forms prepared according to the invention.
Figure 1 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;
Figure 2 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; Figure 3 is a DSC curve of the Crystal modification 1 of 5-fluoro-3-phenyI-2-[(lS)-l-(9H-purin- 6-ylamino)propy!]quinazolin-4-one;
Figure 4 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; Figure 5 is an XRPD pattern of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H- purin-6-yIamino}propyl]quinazolin-4-one;
Figure 6 is a Raman spectra of the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-{9H- purin-6-ylamino)propyl3quinazolin-4-one;
Figure 7 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;
Figure 8 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;
Figure 9 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin- 6-ylamino)propyl]quinazo[in-4-one; Figure 10 is a Raman spectra of the amorphous phase of 5-fluoro-3-phenyi-2-[(lS)-l-(9H- purin-6-ylamino)propy[]quinazolin-4-one;
Figure 11 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one;
Figure 12 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one.
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 modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
The present invention provides novel solid forms of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6- ylamino)propyl]quinazolin-4-one (ideialisib) of formula I
Figure imgf000010_0001
H
(I)
with advantageous properties for pharmaceutical use regarding the physico-chemical properties and can be produced in a reproducible manner even in industrial scale.
Variations in the crystal structure of ideialisib 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 ideialisib involves the development of a new solid form of ideialisib that is more bioavailable and stable. The term„modiftcation, modifications" of ideialisib, as used in this document, is synonymous to terms„soiid state form, solid phase modification" of ideialisib and includes crystalline modifications, amorphous phases, hydrates and solvates of ideialisib.
The term „crystal modification" of ideialisib, as used in this document, is synonymous to commonly used expressions„polymorphic form" or„crystaliine form" of ideialisib. The term „amorphous phase of ideialisib", as used in this document, is synonymous to commonly used expressions„amorphous ideialisib". 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 percent, about less than 20 percent, about less than 15 percent, about less than 10 percent, about less than 5 percent, or about less than 1 percent 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 solid forms of 5-fluoro-3-phenyl-2- [(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one can be prepared and have not been described in the literature and no solid state analytical data {X-Ray Powder Diffraction patterns, Single-Crystal X-Ray Diffraction data etc.) serving to characterize the crystalline phases have been provided.
The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propy!]- quinazolin-4-one according to the invention has the characteristic XRPD pattern as shown in Figure 1. 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 exhibits the following diffraction peaks in XRPD pattern, see Table 1, below:
Pos. [°2Th.] d-spacing [Λ] Rel. Int. [%]
2.87 30.778 9.2
6.45 13.704 16.3
8.18 10.803 35.0
8.66 10.203 31.4
9.13 9.679 32.7
10.43 8.478 100.0
11.93 7.410 43.0
14.71 6.019 34.5
15.69 5.643 41.3
16.36 5.414 21.0
17.51 5.061 10.2
18.84 4.706 16.2
20.40 4.350 6.6
22.02 4.034 11.9
23.71 3.749 15.4
24.92 3.570 3.6
2.8.61 3.117 3.9
Table 1
The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]- quinazoiin-4-one can be characterized by Raman spectroscopy. Figure 2 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3067, 2933, 1690, 1612, 1568, 1324, 1002, 760, 268 and 235 cm'1 wavenumbers.
The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylamino)propyl]- quinazolin-4-one can be further described by thermoanaiytical methods (Differential Scanning Calorimetry, DSC; Thermal Gravimetric Analysis, TGA). Figure 3 shows the DSC {Perkin Elmer Pyris 1 DSC) and Figure 4 shows the TGA (Perkin Elmer TGA 6} curves measured in the range of 20 °C to 300 °C and 20 eC to 300 "C, respectively. The Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one is a hydrate shows a 4.3 % weight loss in the range of 20 °C to 150 "C The DSC measurement gives a melting process with
Figure imgf000013_0001
°C (corresponding to the water loss);
Figure imgf000013_0002
in one of the aspects of the invention, a process for preparation of the Crystal modification 1 is provided. In this process, idelalisib is dissolved in a suitable organic solvent by heating of the system to a temperature close to the boiling point of the solvent. The solution is then placed onto ice for cooling. After filtering off and drying at laboratory conditions, the product was analysed by the methods described above and characterised as the Crystal modification 1 of idelalisib. The suitable organic solvent is acetonitrile.
The process of preparation of the Crystal modification 1 of idelalisib thus comprises the steps of: a/ dissolution of idelalisib in acetonitrile at the temperature close to the boiling point of the respective solvent; b/ cooling the suspension of the step a/ to a temperature of 0-5°C; c/ keeping the suspension of the step b/ at a temperature of 0-5°C for 4 hours; d/ isolating the idelalisib free base in Crystal modification 1; e/ optionally, drying of the product of step d/ at laboratory condition 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 according to the invention has the characteristic XRPD pattern as shown in Figure 5. 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 exhibits the following diffraction peaks in XRPD pattern, see Table 2, below: Pos. [°2Th.] d-spacing [Λ] Rel. Int. [%]
8.15 10.840 13.4
10.85 8.151 26.2
11.26 7.849 34.5
11.80 7.492 55.8
12.27 7.206 18.5
14.22 6.223 9.7
14.57 6.077 5.4
14.94 5.926 3.1
16.44 5.388 6.8
16.76 5.285 5.6
17.62 5.030 25.2
18.30 4.843 100.0
18.86 4.703 18.1
19.14 4.632 7.3
19.70 4.503 18.8
20.04 4.427 45.7
20.49 4.331 9.6
21.45 4.139 27.1
22.72 3.911 12.4
23.74 3.745 30.3
24.59 3.618 5.2
25.47 3.495 23.2
26.11 3.411 8.0
27.54 3.236 7.4
27.73 3.214 8.1
28.51 3.128 15.2
28.79 3.098 17.4
29.03 3.073 8.6
29.32 3.044 8.5 29.93 2.983 10.1
34.16 2.623 4.1
37.19 2.416 4.1
38.09 2.360 6.1
Table 2
The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylam'ino)propyl]- quinazolin-4-one can be characterized by Raman spectroscopy. Figure 6 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3069, 2956, 2930, 2875, 1684, 1612, 1328, 1290, 1004 and 616 cm"1 wavenumbers.
The Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]- quinazolin-4-one can be further described by thermal analytical methods. Figure 7 shows the DSC (Perkin Elmer Pyris 1 DSC) and Figure 8 shows the TGA (TA Instruments DSC Discovery) curves measured in the range of 20 eC to 300 "C and 20eC to 300 °C, respectively. The crystalline Modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylamino)propyl]- quinazolin-4-one is a solvate that shows a 14.3 % weight loss in the range of 20 "C to 180 eC. The DSC measurement gives a melting process with Tonset,i=109 °C {corresponding to a solvent loss) and Tonset(2=249.4 °C. The Crystal modification 2 of idelalisib can be prepared by a process comprising the steps of: a/ suspending idelalisib in N,N-d\ methyl formamide at room temperature; b/ heating up the suspension of step a/ to 50°C applying a continuous agitation; c/ stirring the suspension of step b/ for 2 weeks; d/ isolating the Crystal modification 2 of idelalisib; e/ optionally, drying of the product of step d/ at laboratory condition until the constant weight of the product is reached.
Another process of preparation of the Crystal modification 2 of idelalisib comprises the steps of: a/ suspending idelalisib in Λ/,/V-dimethyl formamide at room temperature; b/ stirring the suspension of the step a/ for 48 hours; c/ isolating the Crystal modification 2 of idelalisib; d/ optionally, drying of the product of step c/ at laboratory condition until the constant weight of the product is reached.
The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylamino)propyl]quinazolin- 4-one 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 amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylamino)propyl]quinazolin- 4-one can be characterized by Raman spectroscopy. Figure 10 shows the Raman (Bruker RFS 100/S) spectrum comprising characteristic peaks at 3066, 2938, 2874, 1695, 1454, 1326, 1003, 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 can be further described by thermal analytical methods. Figure 11 shows the DSC (TA Instruments DSC Discovery) and Figure 12 shows the TGA {Perkin Elmer TGA 6) curves measured in the range of 0 eC to 300 aC and 20 eC to 300 °C, respectively. The amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]quinazolin-4-one shows a 3.5 % weight loss in the range of 20 °C to 200 °C. The DSC measurement gives a melting process with
Figure imgf000016_0001
°C.
The amorphous idelalisib can be prepared by a process comprising the steps of: a/ dissolving idelalisib in a solvent selected from the group consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate, ethanol, 2-propanol, methanol, 4-methyl-2-pentanone or a mixture thereof, water-dioxane in 1:1 ratio by volume and water-ethanol in 25:75 ratio by volume at room temperature; b/ isolating the amorphous idelalisib by evaporation of the solvent in vacuum oven at 60 °C using 500 mbar vacuum pressure.
Another process for preparation of the amorphous idelalisib comprises the steps of: a/ dissolving idelalisib in a solvent selected from the group of consisting of acetone, acetonitrile, butyl acetate, 2-butanone, chloroform, dioxane, dichloromethane, ethyl acetate, ethanol, 2-propanol, methanol, 4-methyl-2-pentanone or a mixture thereof, water-dioxane in 1:1 ratio by volume and water-ethanol in 25:75 ratio by volume at room temperature; b/ isolating the amorphous idelalisib by evaporation of the solvent in vacuum oven at laboratory condition.
Yet another process of preparation of the amorphous idelalisib comprises the steps of: a/ dissolving idelalisib in a solvent selected from the group of consisting of chloroform, dichloromethane, tetrahydrofuran and xylenes or a mixture thereof at the temperature close to the boiling point of the respective solvent or at room temperature; b/ cooling the solution of the step a/ to room temperature; c/ isolating the amorphous idelalisib; d/ optionally, drying of the product of step c/ at laboratory condition 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 at laboratory condition", as used in this patent application, means drying at room temperature and relative humidity 20-60 %. The expression„heating to the boiling" or„heating to the boiling point" or„heating to a temperature close to the boiling point" of the solvent means heating to a temperature that lies between the temperature of the boiling point and the temperature of 5 °C lower than the temperature of the boiling point of the respective solvent, including the limit values.
Analysis - XRPD (X-Ray Powder Diffractometry)
Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ = 1.542 A). Generator settings:
- excitation voltage 45 kV
anodic current 40 mA.
Scan description: scan type - gonio
measurement range 2 - 409 2Θ
- step size 0.0122Θ
- step time: 0.5 s.
Samples were measured as received on Si plate (zero background holder). Incident beam optics: programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/42 anti-scatter fixed slit, 0.02 rad Soller slits.
Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122s. 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.
Analysis - Raman spectroscopy
FTIR spectra were recorded by FT-Raman Bruker RFS 100/S Spectrometer General settings:
Excitation source: Nd-YAG laser (1064 nm)
Applied spectral domain: 4000-200 cm"1
Applied laser power: 250 mW
Detector: liquid nitrogen cooled Ge-diode detector (D418-T)
Resolution: 4 cm -1
Number of accumulations: 128
Scattering geometry: 180° (back scattering)
Aperture: 3.5 mm Analysis - DSC (Differential Scanning Calorimetry)
Crystalline modifications:
DSC measurements were performed on a Perkin Elmer Pyris 1 DSC.
The sample were weighed in aluminium pans and covers (20 μΐ) and measured in a nitrogen flow. Investigations were performed in a temperature range of 20 °C to 300 eC with a heating rate of 10 °C/min The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima O ) and onset temperature (Tonset) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form. The enthalpy is given in J/g. The weight sample was about 2.5-3 mg.
Amorphous phase:
DSC measurements were performed on a TA Instruments DSC Discovery.
The sample were weighed in aluminium pans and covers (40 mL) and measured in a nitrogen flow. Investigations were performed in a temperature range of 0 °C to 300 eC with a heating rate of 5 °C/min (Amplitude = 0,8 °C and Period = 60 s). The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima (Τρβ3ι<) and onset temperature (TQriset) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form. The enthalpy is given in J/g.
The weight sample was about 3.5-5 mg.
Analysis - TGA (ThermoGravimetric Analysis)
TGA measurements were performed on a Perkin Elmer TGA 6.
The samples were weighed in ceramic pans and measured in nitrogen flow. TGA investigations were performed in a temperature range of 20 °C to 300 °C with a heating rate of 10 "C/min.
The weight sample was about 6-22 mg. Examples
The following examples are intended to further illustrate the present invention without limiting its scope.
Example 1
Preparation of Crystal modification 1 of 5-fluoro-3-pheny[-2-[(lS)-l-(9H-purin-6-ylamino)- propyllquinazolin-4-one
300 mg (0.722 mmol) of idelalisib was dissolved 10 mL of acetonitrile at the boiling point. The hot solution was filtered to get rid of any insoluble particles. The clear solution was placed into fridge (5 °C) to apply quick cooling. The suspension was kept at fridge for 4 hours.
The solid obtained was collected by filtration, washed with a few drops of pre-cooled acetonitrile and then dried by vacuum suction at laboratory condition.
Product: 172 mg (0.414 mmol) white crystalline solid Yield: 57 %
HPLC: 99.67 %
Chiral HPLC: 100 %
XRPD pattern was measured (Figure 1) and showed that the compound is in a crystalline state that was designated as Crystal modification 1.
Example 2
Preparation of Crystal modification 2 of 5-fiuoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)- propyl]quinazolin-4-one
150 mg (0.361 mmol) of idelalisib was suspended in 0.1 mL of dimethylformamide at room temperature.
The suspension was heated up to 50 "C and kept at that temperature applying a continuous stirring for 2 weeks. The solid obtained was collected by filtration and then dried by vacuum suction at laboratory condition.
Product: 150 mg (0.361 tmmol) white crystalline solid Yield: 100 % HPLC: 99.60 %
Chiral HPLC: 99.56 %
XRPD pattern was measured (Figure 2) and showed that the compound is in a crystalline state that was designated as Crystal modification 2.
Example 3
Preparation of Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)- propy I] q u in azol in-4-on e
300 mg (0.722 mmol) of rdelalisib was suspended in 0.2 mL of dimethylformamide at room temperature. The suspension was kept at room temperature applying a continuous stirring for 48 hours.
The solid obtained was collected by filtration, washed with a few drops of pre-cooled dimethylformamide and then dried by vacuum suction at laboratory condition.
Product: 238 mg (0.573 mmol) white crystalline solid
Yield: 79 % XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as Crystal modification 2.
Example 4
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)- propyl]quinazolin-4-one
300 mg (0.722 mmol) of idelalisib was dissolved 6.75 mL of dichloromethane at room temperature. The solvent was fully evaporated by rotadest applying a continuous stirring rate and a 40 °C of water bath and 50 mbar vacuum.
Product: 267 mg (0.643 mmol) greyish crystalline solid
Yield: 89 % HPLC: 99.21 %
Chiral HPLC: 99.59 %
XRPD pattern was measured (Figure 3) and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
Example 5
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)~ propyl]quinazolin-4-orte
300 mg (0.722 mmol) of idelalisib was dissolved S.25 mL of tetrahydrofurane at room temperature. The solvent was fully evaporated by rotadest applying a continuous stirring rate and a 40 °C of water bath and 50 mbar vacuum.
Product: 259 mg (0.623 mmol) greyish crystalline solid
Yield: 86 %
HPLC: 99.25 % Chiral HPLC: 99.59%
XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib. Example 6
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-{9H~purin-6-yfamino)- propyl]quinazolin-4-one
60 mg (0.144 mmoi) of idelalisib was dissolved in chloroform by heating to the boiling of the solvent.
The solution was stirred at this temperature for 10-15 minutes then cooled back to room temperature and left for stirring overnight. The solid was filtered off and dried at laboratory condition.
XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
Similarly, the same result was obtained using any of the solvents listed in the Table 3.
Solvent dichloromethane tetrahydrofurane
xylenes
Table 3
Example 7
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)- propyl]quinazolin-4-one
60 mg (0.144 mmol) of idelalisib was dissolved in dichloromethane by heating to the boiling of the solvent. The solution was stirred at this temperature for 10-15 minutes then placed onto ice to cool. The solid obtained was placed into fridge overnight, then filtered off and dried at laboratory condition. XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
Similarly, the same result was obtained using xylenes.
Example 8
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)- propyl]quinazolin-4-one
30 mg (0.072 mmol) of idelalisib was dissolved in chloroform at room temperature.
The solvent was completely evaporated in vacuum oven at 60°C using 500 mbar vacuum pressure.
XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
Similarly, the same result was obtained using any of the solvents listed in the Table 4.
Solvent butyl acetate ethyl acetate ethanol - water [75-25
v/v(%)]
2-propanol tetrahydrofuran
4-methyl-2-pentanone
Table 4 Example 9
Preparation of amorphous phase of 5-fluoro-3-phenyl-2-[{lS)-l-{9H-purin-6-ylamino)- propyl]quinazolin-4-one
30 mg (0.072 mmol) of idelalisib was dissolved in chloroform at room temperature. The solvent was completely evaporated laboratory condition.
XRPD pattern was measured and showed that the compound is in a crystalline state that was designated as amorphous idelalisib.
Similarly, the same result was obtained using any of the solvents listed in the Table 4.
Figure imgf000025_0001
Table 5

Claims

1. A Crystal modification 1 of 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino)propyl]- quinazolin-4-one of Formula [
Figure imgf000026_0001
H
(I) having an X-ray powder diffraction pattern comprising characteristic peaks at about 10.4; 11.9 and 15.7 ± 0.2° 2-theta measured by CuKoc radiation.
2. The Crystal modification 1 of claim 1, wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 8.2; 9.1; 14.7; 18.8 and 23.7 ± 0.2° 2- theta measured by CuKoc radiation.
3. The Crystal modification 1 of any one of claims 1 to 2, characterised by differential scanning calorimetry curve having a melting process with TonSet,i = 67 °C corresponding to the water loss; Tonse = 141.3 °C; TrecrYst_iiization = 205 °C and Tonset,3= 245.5 °C.
4. The Crystal modification 1 of any one of claims 1 to 3, characterised by the Thermal gravimetric curve having a 4.3 % weight loss in the range of 20 °Cto 150 °C
5. The Crystal modification 1 of any one of claims 1 to 4, wherein the crystal modification is substantially a hydrate.
6. A composition comprising the Crystal modification 1 of any one of claims 1 to 5, wherein the composition is substantially free of solid forms other than the Crystal modification 1 of 5-fluoro-3-phenyi-2-[(lS}-l-(9H-purin-6-ylamino)propyl3quinazolin-4-one.
7. A process for the preparation of the Crystal modification 1 of any one of claims 1 to 5, wherein idelalisib is dissolved in suitable organic solvent, preferably a polar aprotic solvent, by heating of the system to a temperature close to the boiling point of the solvent.
8. The process according to claim 7, wherein the polar aprotic solvent is tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethylsulfoxide or a mixture thereof, preferably acetonitrile.
9. The process according to claim 8, comprising the steps of: a) dissolution of idelalisib in acetonitrile at the temperature close to the boiling point of the respective solvent; b) cooling the solution of the step a) to a temperature of 0 - 5 °C to form a suspension; c) keeping the suspension of the step b) at a temperature of 0 - 5 °C for about 4 hours; d) isolating the idelalisib free base in Crystal modification 1.
10. The process according to claim 9, further comprising the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
11. The process according to any one of claims 7 to 10, wherein the heated solution is cooled to the temperature of 5 °C or lower.
12. The process according to any one of claims 7 to 11, wherein the heated solution is kept cooled for about 4 hours.
13. A Crystal modification 2 of 5-fluoro-3-phenyl-2-[{lS)-l-(9H-purin-6-ylamino)propyl]- quinazolin-4-one of Formula I
Figure imgf000028_0001
H
(I) having an X-ray powder diffraction pattern comprising characteristic peaks at about 10.8; 11.8; 18.3; 20.0; 23.7 and 25.5± 0.2" 2-theta measured by CuK radiation.
14. The Crystal modification 2 of claim 13, characterised by differential scanning calorimetry curve having a melting process with Tonsetjl= 109 °C corresponding to a solvent loss and Tonset,2 = 249.4 °C.
15. The Crystal modification 2 of any one of claims 13 or 14, characterised by the Thermal gravimetric curve having a 14.3 % weight loss in the range of 20 °C to 180 °C.
16. The Crystal modification 2 of any one of claims 13 to 15, wherein the solid form is substantially a solvate.
17. A process for the preparation of the Crystal modification 2 as claimed in claims 13 to 16, wherein idelalisib is suspended in /V,/V-dimethy! formamide at room temperature.
18. The process according to claim 17, comprising the steps of: a) suspending idelalisib in Λ/,/V-dimethyl formamide at room temperature; b) heating up the suspension of step a) to 40 to 60 °C; c) stirring the suspension of step b); d) isolating the Crystal modification 2 of idelalisib.
19. The process according to claim 18, further comprising the step of drying of the product of step d) at laboratory condition until the constant weight of the product is reached.
20. The process according to claim 17, comprising the steps of: a) suspending idelaiisib in /y,/V-dimethyl formamide at room temperature; b) stirring the suspension of the step a); c) isolating the Crystal modification 2 of idelaiisib.
21. The process according to claim 20, further comprising the step of drying of the product of step c) at laboratory condition until the constant weight of the product is reached.
22. The process according to any one of claims 20 to 21, wherein the suspension is heated to a temperature of at least 40 to 60 °C.
23. The process according to any one of claims 18 to 22, wherein the suspension is stirred for at least 48 hours.
24. The process according to any one of claims 18 to 23, wherein the suspension is stirred for at least 2 weeks.
25. A composition comprising the Crystal modification 2 of any one of claims 13 to 16, wherein the composition is substantially free of solid forms other than the Crystal modification 2 of 5-fluoro-3-phenyl-2-[(lS)-l-{9H-purin-6-ylamino)propyl]quinazolin-4- one.
26. Use of the Crystal modification 1 of idelaiisib as claimed in of any one of claims 1 to 5 for the preparation of a pharmaceutical composition.
27. Use of the Crystal modification 2 of idelaiisib as claimed in of any one of claims 13 to 16 for the preparation of a pharmaceutical composition.
28. A pharmaceutical composition comprising the Crystal modification 1 as claimed in any one of claims 1 to 5 and/or the Crystal modification 2 as claimed in any one of claims 13 to 16 of 5-fluoro-3-pheny[-2-[(lS)-l-{9H-purin-6-ylamino)propyl]quinazolin-4-one.
29. The pharmaceutical composition according to claim 28, further comprising one or more pharmaceutically acceptable carriers or excipients.
30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is a tablet.
31. The Crystal modification as claimed in any one of claims 1 to 5 and/or 13 to 16 of 5- fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-y!amino)propyl]quinazolin-4-one for use in the treatment of cancer.
32. The Crystal modification according to claim 31, wherein the cancer is a hematologic malignancy.
33. The Crystal modification according to claim 31, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplasia syndrome (MDS), myeloproliferative disease ( PD), chronic myeloid leukemia {C L), multiple myeloma (MM), non-Hodgkin's lymphoma (iNHL), refractory iNHL, non- Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).
34. The Crystal modification according to claim 31, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (iNHL), and refractory iNHL.
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