CZ2015347A3 - Solid forms of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4-one and their preparation - Google Patents

Abstract

The 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 meet pharmaceutical requirements. Preparation and characterization of crystal form 1 and crystal form 2.

Description

Prior art

The compound 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one, which is known as idelalisib (CAS No .: 870281-82-6 ) has phosphoinositide 3-kinase (PI3K) inhibitory activity, which is effectively used to treat chronic lymphocytic leukemia (CLL).

Phosphoinositide 3-kinase (PI3K) enzymes are a group of enzymes that are involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival, and intracellular transmigration that are associated with cancer.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and attacks B-lymphocytes that form in the bone marrow, develop in the lymph nodes, and normally fight infection by producing antibodies.

Idelalisib blocks ΡΙΙΟδ, a 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, leading to inhibition of phosphorylation of the key second lipid messenger phosphatidylinositol and inhibition of Akt (protein kinase B) phosphorylation. .

WO2005113556 describes selective inhibitors of the enzymes phosphoinositide 3-kinases (PI3K) with a valuable pharmacological effect in the treatment of related diseases. 5-Fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one is one example of the disclosed compounds and the preparation of a base is given.

Various crystalline forms of idelalisib are described in WO2013134288 and WO2015014315. Further described is a process for preparing anhydrous crystalline forms of idelalisib, designated Form I, Form II, solvated forms designated Form III, Form IV, Form V, Form VI and Form VII, as well as crystalline Forms II, IV and VI, polymorph II and hydrated crystalline forms designated as Form IX, resp. Vlil.

Many pharmaceutical solid compounds can exist in different crystalline forms, which are considered to be polymorphs and hydrates / solvates having different crystal units and thus different physicochemical properties such as melting point, solubility, dissolution rate and also bioavailability. Several solid state analytical methods can be used to distinguish the individual solid phases of a compound, such as X-ray powder diffraction, solid state NMR, and Raman spectroscopy, as well as thermoanalytical methods.

The discovery of new solid phases (polymorphs, solvates and hydrates) of a pharmaceutically active compound offers the opportunity to choose a suitable modification with the desired physicochemical properties and processability and to improve the characteristics of the pharmaceutical product. For this reason, there is a clear need for new solid forms (polymorphs, solvates, hydrates) of idelalisib.

The essence of the invention

The present invention provides 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 meet pharmaceutical requirements.

In some embodiments of the invention, these solid forms are characterized by various solid state analytical data, such as X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The present invention provides a crystal modification of 15-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] -quinazolin-4-one of formula I, having an X-ray powder diffraction pattern containing characteristic peaks at about 10 4; 11.9 and 15.7 ± 0.2 ° 2-theta, measured by CuKα radiation. In some embodiments, 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 CuKα radiation. In some embodiments, the crystal modification 1 is characterized by a differential scanning calorimetry curve exhibiting a melting process with T _onS et, i = 67 ° C corresponding to water loss; T _onS et, 2 = 141.3 ° C; T _reC rystaiiization = 205 C and Tonset 3 = 245.5 ° C. In some embodiments, the crystal modification 1 is characterized by a thermal gravimetric curve exhibiting a weight loss of 4.3% in the range of 20 ° C to 150 ° C. In one variant, the crystal modification 1 is essentially a hydrate.

It should be emphasized that the relative intensities may vary depending on various factors, such as sample preparation and placement, and on the equipment and analytical procedure and settings used to measure the spectrum.

The invention further relates to a process for the preparation of crystal modification 1, which comprises dissolving idelalisib in a suitable organic solvent, preferably a polar aprotic solvent, more preferably tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethyl sulfoxide or a mixture thereof, especially acetonitrile. system to a temperature close to the boiling point of the solvent.

In some embodiments, the method of preparing crystal modification 1 comprises the steps of: a) dissolving idelalisib in acetonitrile at a temperature close to the boiling point of the appropriate solvent; b) cooling the solution from step a) to 0-5 ° C to form a suspension; c) maintaining the suspension from step b) for about 4 hours at 0-5 ° C and d) isolating idelalisib free base in crystal modification 1. In some embodiments, the method of preparing crystal modification 1 further comprises the step of drying the product of step d) under laboratory conditions until a constant product weight is reached.

In yet another embodiment, the method of preparing crystal modification 1 further comprises cooling the heated solution to a temperature of at least about 0 ° C. In yet another embodiment, the method of preparing crystal modification 1 further comprises keeping the heated solution cooled for about 4 hours. In some embodiments, the invention further comprises a process for preparing crystal modification 1, comprising dissolving idelalisib in a suitable organic solvent, preferably a polar aprotic solvent, more preferably tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethyl sulfoxide or mixtures thereof, especially acetonitrile. , heating the system to a temperature close to the boiling point of the solvent.

The invention further provides a crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (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 CuKα radiation. In some embodiments, the crystal modification 2 is characterized by a differential scanning calorimetry curve exhibiting a melting process with T _on set values, i = 109 ° C corresponding to solvent loss, and T _O n _Se t, 2 = 249.4 ° C. In some embodiments, the crystal modification 2 is characterized by a thermal gravimetric curve exhibiting a weight loss of 14.3% in the range of 20 ° C to 180 ° C. In one variant, the crystal modification 2 is essentially a solvate.

It should be emphasized that the relative intensities may vary depending on various factors, such as sample preparation and placement, and on the equipment and analytical procedure and settings used to measure the spectrum.

The invention further relates to a process for the preparation of crystal modification 2, in which idelalisib is suspended in N, N-dimethyl formamide at room temperature. In some embodiments, the method of preparing crystal modification 2 comprises the steps of: a) suspending idelalisib in N, N-dimethyl formamide at room temperature; b) heating the suspension from step a) to 40 to 60 ° C; c) stirring the suspension from step b); d) isolating crystal modification 2 of idelalisib. In some embodiments, the method of preparing crystal modification 2 further comprises the step of drying the product of step d) under laboratory conditions until a constant weight of product is reached.

In another embodiment, the process for preparing crystal modification 2 comprises the steps of: a) suspending idelalisib in N, N-dimethyl formamide at room temperature; b) stirring the suspension from step a); c) isolating crystal modification 2 of idelalisib. In some embodiments, the method of preparing crystal modification 2 further comprises the step of drying the product of step c) under laboratory conditions until a constant weight of product is reached.

In yet another embodiment, the method of preparing crystal modification 2 further comprises heating the slurry to a temperature of at least about 40 to 60 ° C, preferably 50 ° C. In another embodiment, the method of preparing crystal modification 2 further comprises stirring the suspension for at least 48 hours. In another embodiment, the method of preparing crystal modification 2 further comprises stirring the suspension for at least 2 weeks.

The invention further relates to the use of a crystal modification of 1 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one of formula I for the preparation of a pharmaceutical composition.

In another embodiment, the invention further relates to the use of a crystal modification of 2 5-fluoro-3-phenyl-2 [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one of formula I for the preparation of a pharmaceutical composition.

In yet another embodiment, the invention further relates to pharmaceutical formulations comprising one or more solid forms of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one (any one or more solid modifications of crystalline form 1, crystalline form 2 and the amorphous phase) and a pharmaceutically acceptable carrier, for use in the treatment of cancer.

The invention also relates to the above-mentioned crystal modification 15-fluoro-3-phenyl-2 - [(1S) 1- (9H-purin-6-ylamino) propyl] quinazolin-4-one and / or the above-mentioned crystal modification 25 -fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one for use in the treatment of cancer by administering a composition comprising crystal modification 1 and / or described herein. crystal modification 2 and pharmaceutically acceptable excipients to the patient.

In some embodiments, the cancer is a hematological malignancy. In other embodiments, the hematological malignancy is leukemia, wherein the leukemia is non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). In particular embodiments, the hematological malignancy is leukemia or lymphoma. In specific embodiments, the cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small cell lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia. , multiple myeloma (MM), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM), T-lymphoblastic lymphoma, B-lymphoblastic lymphoma and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the cancer is acute Lymphoblastic leukemia (T-ALL) or acute B-lymphoblastic leukemia (B-ALL). Non-Hodgkin's lymphoma includes indolent B-cell diseases such as follicular lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, and marginal zone lymphoma, as well as aggressive lymphomas such as Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL). mantle cells (MCL). In one embodiment, the cancer is indolent non-Hodgkin's lymphoma (iNHL).

It has now surprisingly been found that the compound of formula I can be prepared in 2 different crystal modifications as well as in the amorphous phase. These 3 solid modifications, referred to herein as crystal modification 1, crystal modification 2, and amorphous phases, have different physicochemical properties. Each solid phase was identified by characteristic X-ray powder diffractograms and Raman spectra, and their differential scanning calorimetry and thermal gravimetric analysis curves also differ.

Overview of figures in the drawings

The figures show the following spectra of the individual solid forms prepared according to the invention:

Figure 1 is an XRPD pattern of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 2 is a Raman spectrum of crystal modification of 1 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 3 is a DSC curve of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 4 is a TGA curve of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 5 is an XRPD pattern of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 6 is a Raman spectrum of crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 7 is a DSC curve of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 8 is a TGA curve of crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 9 is an XRPD pattern of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 10 is a Raman spectrum of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 11 is a DSC curve of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one;

Figure 12 is a TGA curve of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one.

Detailed description of the invention

The following description is provided to enable any person of ordinary skill in the art to prepare and use the individual embodiments. The description of specific devices, techniques and applications is given by way of example only. One of ordinary skill in the art will readily appreciate various modifications of the examples provided herein, and the general principles described herein may be applied to other examples and applications without departing from the nature and scope of the embodiments. Therefore, the individual embodiments are not intended to be limited to the examples set forth and illustrated herein, but their scope is to be understood in accordance with the claims.

The invention provides novel solid forms of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one (idelalisib) of formula I

H

O) with advantageous properties for pharmaceutical use in terms of physicochemical properties, which can be reproducibly obtained on an industrial scale.

Changes in the crystal structure of idelalisib may affect the dissolution rate (which may affect bioavailability, etc.), processability (e.g., ease of handling, ability to consistently prepare doses of known strength) and stability (e.g., thermal stability, storability, etc.) of a pharmaceutical drug product, especially when formulated in a solid dosage form (e.g., in the form of a tablet). Therapeutic use and production of idelalisib involves the development of a new solid form of idelalisib that is better bioavailable and more stable.

The term "modification of idelalisib," as used herein, is synonymous with the terms "solid state form, solid phase modification of idelalisib, and includes crystal modifications, amorphous phases, hydrates, and solvates of idelalisib."

The term "crystal modification of idelalisib," as used herein, is synonymous with the commonly used terms "polymorphic form" or "crystalline form of idelalisib."

The term "amorphous phase of idelalisib," as used herein, is synonymous with the commonly used term "amorphous idelalisib."

The use of an expression probably includes and describes the value or parameter itself. For example, about x includes and describes x as such. In some cases, when the term is probably used in connection with a measurement or when used to modify a value, unit, constant, or range of values, it refers to deviations in the range of +/- 5 percent.

The term substantially or substantially free / pure in relation 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. percent or about less than 1 percent by weight of impurities. In other embodiments, substantially or substantially free / pure refers to an impurity-free substance. Impurities can include, for example, by-products or unreacted substances from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.

Surprisingly, it has been found that the above solid forms of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be prepared and have not been described in the literature. and no analytical data for the solid form (X-ray powder diffractograms, single crystal X-ray diffraction data, etc.) were used to characterize the crystalline phases.

The crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one according to the invention has the characteristic XRPD pattern shown in Figure 1. The XRPD pattern was measured on X - ray powder diffractometer (X'PERT PRO MPD

PANalytical). Crystal modification of 5-fluoro-3-phenyl-2 - [(IS) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one shows the following diffraction peaks in the XRPD record, see Table 1 below:

Pos. [° 2Th.] Distance d [Á] Rel. Int. [%] 2.87 30,778 th most common 9.2 6.45 13,704 th most common 16.3 8.18 10,803 th most common 35.0 8.66 10,203 th most common 31.4 9.13 9,679 th most common 32.7 10.43 8,478 th most common 100.0 11.93 7,410 th most common 43.0 14.71 6,019 th most common 34.5 15.69 5,643 th most common 41.3 16.36 5,414 th most common 21.0 17.51 5,061 th most common 10.2 18.84 4,706 th most common 16.2 20.40 4,350 th most common 6.6 22.02 4,034 th most common 11.9 23.71 3,749 th most common 15.4 24.92 3,570 th most common 3.6 28.61 3,117 th most common 3.9

Table 1

Crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be characterized by Raman spectroscopy. Figure 2 is a Raman spectrum (Bruker RFS 100 / S) containing characteristic peaks at wavelengths 3067, 2933, 1690, 1612, 1568, 1324, 1002, 760, 268 and 235 cm- ¹ .

The crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be further described by thermoanalytical methods (differential scanning calorimetry, DSC; thermal gravimetric analysis, TGA). Figure 3 shows a DSC curve (Perkin Elmer Pyris 1 DSC) and Figure 4 a TGA curve (Perkin Elmer TGA 6), measured between 20 ° C and 300 ° C, respectively. 20 ° C to 300 ° C. Crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one is a hydrate and exhibits a weight loss of 4.3% in the range of 20 ° C to 150 ° C. DSC measurement provides a melting process with T _onS et, i = 67 ° C (corresponding to water loss); T _onS et, 2 = 141.3 ° C; T _reC rystaiiization = 205 ° C and T _onS et, 3 = 245.5 ° C.

In one aspect, the invention provides a process for preparing crystal modification 1. In this process, idelalisib is dissolved in a suitable organic solvent by heating the system to a temperature close to the boiling point of the solvent. The solution is then cooled by placing on ice. After filtration and drying under laboratory conditions, the product was analyzed by the methods described above and characterized as crystal modification 1 of idelalisib.

A suitable organic solvent is acetonitrile.

Thus, the process for preparing crystal modification 1 of idelalisib comprises the following steps:

a / dissolving idelalisib in acetonitrile at a temperature close to the boiling point of the respective solvent;

b) cooling the suspension from step a / to a temperature of 0-5 ° C;

c) maintaining the suspension from step b) for 4 hours at 0-5 ° C;

d) isolation of idelalisib free base in crystal modification 1;

e) optionally drying the product from step d) under laboratory conditions until a constant weight of product is reached.

The crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one according to the invention has the characteristic XRPD pattern shown in Figure 5. The XRPD pattern was measured on X-ray powder diffractometer (X'PERT PRO MPD PANalytical). Crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one shows the following diffraction peaks in the XRPD pattern, see Table 2 below:

Pos. [° 2Th.] Distance d [AND] Rel. Int. [%] 8.15 10,840 th most common 13.4 10.85 8,151 th most common 26.2 11.26 7,849 th most common 34.5 11.80 7,492 th most common 55.8 12.27 7,206 th most common 18.5 14.22 6,223 th most common 9.7 14.57 6,077 th most common 5.4 14.94 5,926 th most common 3.1 16.44 5,388 th most common 6.8 16.76 5,285 th most common 5.6 17.62 5,030 th most common 25.2

18.30 4,843 th most common 100.0 18.86 4,703 th most common 18.1 19.14 4,632 th most common 7.3 19.70 4,503 th most common 18.8 20.04 4,427 th most common 45.7 20.49 4,331 th most common 9.6 21.45 4,139 th most common 27.1 22.72 3,911 th most common 12.4 23.74 3,745 th most common 30.3 24.59 3,618 th most common 5.2 25.47 3,495 th most common 23.2 26.11 3,411 th most common 8.0 27.54 3,236 th most common 7.4 27.73 3,214 th most common 8.1 28.51 3,128 th most common 15.2 28.79 3,098 th most common 17.4 29.03 3,073 th most common 8.6 29.32 3,044 th most common 8.5 29.93 2,983 th most common 10.1 34.16 2,623 th most common 4.1 37.19 2,416 th most common 4.1 38.09 2,360 th most common 6.1

Table 2

The crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be characterized by Raman spectroscopy. Figure 6 is a Raman spectrum (Bruker RFS 100 / S) containing characteristic peaks at wavelengths 3069, 2956, 2930, 2875, 1684, 1612, 1328, 1290, 1004 and 616 cm- ¹ .

The crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be further described by thermoanalytical methods. Figure 7 shows a Perkin Elmer Pyris 1 DSC (DSC) curve and Figure 8 a TA Instruments DSC Discovery (TGA) curve, measured between 20 ° C and 300 ° C, respectively. 20 ° C to 300 ° C. Crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one is a solvate that shows a 14.3% weight loss in the range of 20 ° C up to 180 ° C. DSC measurements provide a melting process with T _onset , i = 109 ° C (corresponding to solvent loss) and T _onset , 2 = 249.4 ° C.

Crystal modification 2 of idelalisib can be prepared by a process comprising the following steps:

a) suspending idelalisib in N, N-dimethyl formamide at room temperature;

b) heating the suspension from step a / to 50 ° C with continuous stirring;

c) stirring the suspension from step b) for 2 weeks;

d / isolating crystal modification 2 of idelalisib;

e) optionally drying the product from step d) under laboratory conditions until a constant weight of product is reached.

Another method of preparing crystal modification 2 of idelalisib involves the following steps:

a) suspending idelalisib in N, N-dimethyl formamide at room temperature;

b) stirring the suspension from step a / for 48 hours;

c / isolating crystal modification 2 of idelalisib;

d) optionally drying the product from step c) under laboratory conditions until a constant weight of product is reached.

The amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one of the invention has the characteristic XRPD pattern shown in Figure 9. The XRPD pattern was measured on an X-ray powder diffractometer (X'PERT PRO MPD PANalytical).

The amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be characterized by Raman spectroscopy. Figure 10 shows the Raman spectrum (Bruker RFS 100 / S) containing characteristic peaks at wavelengths 3066, 2938, 2874, 1695, 1454, 1326, 1003, 618 and 269 cm -1.

The amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one can be further described by thermoanalytical methods. Figure 11 shows a DSC curve (TA Instruments DSC Discovery) and Figure 12 a TGA curve (Perkin Elmer TGA 6), measured between 0 ° C and 300 ° C, respectively. 20 ° C to 300 ° C. The amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one shows a 3.5% weight loss of 20 ° C to 200 ° C. melting process with values T _g i _ass = 132.6 ° C; T _reC rystaiiization = 196.0 ° C and Tonset, 1 = 234.4 ° C.

Amorphous idelalisib can be prepared by a process that includes the following steps:

and / 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 a volume ratio of 1: 1 and water-ethanol in a volume ratio of 25:75 at room temperature;

b) isolating the amorphous idelalisib by evaporating the solvent in a vacuum oven at 60 ° C using a vacuum pressure of 500 mbar.

Another method of preparing amorphous idelalisib involves the following steps:

and / 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 a volume ratio of 1: 1 and water-ethanol in a volume ratio of 25:75 at room temperature;

b) isolating amorphous idelalisib by evaporating the solvent in a vacuum oven under laboratory conditions.

Yet another method of preparing amorphous idelalisib comprises the following steps:

and / dissolving idelalisib in a solvent selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran and xylenes or a mixture thereof at a temperature close to the boiling point of the respective solvent or at room temperature;

b) cooling the solution from step a / to room temperature;

c / isolation of amorphous idelalisib;

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

The term "room temperature" is defined for the purposes of this document as a temperature between 15 ° C and 29 ° C; 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 20-60% relative humidity.

The term "heating to boiling" or "heating to boiling point" or "heating to a temperature close to the boiling point of the solvent" means heating to a temperature which is between 5 ° C and 5 ° C lower than the boiling point of the respective solvent, including limits.

Analysis-XRPD (X-ray powder diffractometry)

Diffractograms were obtained on a laboratory X PERT PRO MPD PANalytical diffractometer, using CuKa radiation (λ = 1.542 Å).

Generator settings:

- excitation voltage 45 kV

- anodic current 40 mA.

Scanning description:

- sensing type-gonio measuring range 2 - 40 ° 2Θ step size 0.01 ° 20

- step duration: 0.5 s.

Samples were measured as received on a Si plate (zero background plate).

Incident beam optics: programmable divergence diaphragms (irradiated length 10 mm). 10 mm mask. 1/4 ° against scattering fixed aperture, 0.02 rad Soller aperture.

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

Analysis - Roman spectroscopy

FTIR spectra were measured using a FT-Raman Bruker RFS 100 / S spectrometer.

General settings:

Excitation radiation source: Nd-YAG laser (1064 nm)

Spectrum region used: 4000-200 cm

Used laser power: 250 mW

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

Resolution: 4 cm

Number of accumulations: 128

Scattering geometry: 180 ° (backscattering)

Aperture: 3.5 mm

Analysis - DSC (differential scanning calorimetry)

Crystal modifications:

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

The samples were weighed in aluminum candle pans (20 μΙ_) and measured in a stream of nitrogen. The investigation was performed in the temperature range of 20 ° C to 300 ° C at a heating rate of 10 ° C / min. The temperatures reported in connection with DSC analyzes are the maximum peak temperatures (T _pea k) and the initial peak temperatures (T _on set) for the crystalline form and the glass transition temperature (Tg) for the amorphous form. Enthalpy is given in J / g.

The weight of the sample was about 2.5-3 mg.

Amorphous phase:

DSC measurements were performed on a TA Instruments DSC Discovery instrument.

Samples were weighed in aluminum dishes with lids (40 μι) and measured in a stream of nitrogen. The investigation was performed in the temperature range 0 ° C to 300 ° C at a heating rate of 5 ° C / min (amplitude = 0.8 ° C and period = 60 s). The temperatures reported in connection with DSC analyzes are the maximum peak temperatures (T _pea k) and the initial peak temperatures (T _on set) for the crystalline form and the glass transition temperature (Tg) for the amorphous form. Enthalpy is given in J / g.

The weight of the sample was about 3.5-5 mg.

Analysis - TGA (thermogravimetric analysis)

TGA measurements were performed on a Perkin Elmer TGA 6 instrument.

The samples were weighed in ceramic dishes and measured in a stream of nitrogen. TGA examination was performed in the temperature range of 20 ° C to 300 ° C at a heating rate of 10 ° C / min.

The weight of the sample was about 6-22 mg.

Exemplary embodiments

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

Example 1

Preparation of crystal modification of 1 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one

300 mg (0.722 mmol) of idelalisib was dissolved in 10 ml of acetonitrile at reflux temperature. The hot solution was filtered to remove any insoluble particles.

The clear solution was placed in a refrigerator (5 ° C) for rapid cooling. The suspension was left in the refrigerator for 4 hours.

The solid obtained was filtered off, washed with a few drops of pre-cooled acetonitrile and then dried by vacuum suction under laboratory conditions.

Product: 172 mg (0.414 mmol) of white crystals

Yield: 57%

HPLC: 99.67%

Chiral HPLC: 100%

An XRPD record was obtained (Figure 1) and showed that the compound was in a crystalline state, which was designated as crystal modification 1.

Example 2

Preparation of crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (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 to 50 ° C and kept at this temperature with stirring for 2 weeks.

The solid obtained was filtered off and then dried by vacuum suction under laboratory conditions.

Product: 150 mg (0.361 mmol) of white crystals

Yield: 100%

HPLC: 99.60%

ChiralHPLC: 99.56%

An XRPD record was obtained (Figure 2) and showed that the compound was in a crystalline state, which was designated as crystal modification 2.

Example 3

Preparation of crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one

300 mg (0.722 mmol) of idelalisib was suspended in 0.2 ml of dimethylformamide at room temperature.

The suspension was kept at room temperature with stirring for 48 hours.

The solid obtained was filtered off, washed with a few drops of pre-cooled dimethylformamide and then dried by vacuum suction under laboratory conditions.

Product: 238 mg (0.573 mmol) of white crystals

Yield: 79%

An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as crystal modification 2.

Example 4

Preparation of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one

300 mg (0.722 mmol) of idelalisib was dissolved in 6.75 ml of dichloromethane at room temperature.

The solvent was completely evaporated using a rotadest, a constant stirring speed and a water bath at 40 ° C and a vacuum of 50 mbar.

Product: 267 mg (0.643 mmol) of off-white crystals

Yield: 89%

HPLC: 99.21%

ChiralHPLC: 99.59%

An XRPD record was obtained (Figure 3) and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

Example 5

Preparation of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one

300 mg (0.722 mmol) of idelalisib was dissolved in 8.25 ml of tetrahydrofuran at room temperature.

The solvent was completely evaporated using a rotadest, a constant stirring speed and a water bath at 40 ° C and a vacuum of 50 mbar.

Product: 259 mg (0.623 mmol) of off-white crystals

Yield: 86%

HPLC: 99.25%

ChiralHPLC: 99.59%

An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

Example 6

Preparation of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one mg (0.144 mmol) of idelalisib was dissolved in chloroform by heating the solvent quartz.

The solution was stirred at this temperature for 10-15 minutes, then cooled again to room temperature and allowed to stir overnight. The solid was filtered off and dried under laboratory conditions. An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

The same result was similarly obtained using any of the solvents listed in Table 3.

Example 7

Preparation of the amorphous phase of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one mg (0.144 mmol) of idelalisib was dissolved in dichloromethane by heating the solvent quartz.

The solution was stirred at this temperature for 10-15 minutes, then poured onto ice to cool. The obtained solid was stored in a refrigerator overnight, then filtered and dried under laboratory conditions.

An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

The same result was similarly obtained using xylenes.

Example 8

Preparation of the amorphous phase 5-Fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one mg (0.072 mmol) of idelalisib was dissolved in chloroform at room temperature.

The solvent was completely evaporated in a vacuum oven at 60 ° C using a vacuum pressure of 500 mbar.

An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

The same result was similarly obtained using any of the solvents listed in Table 4.

Example 9

Preparation of the amorphous phase 5-Fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one mg (0.072 mmol) of idelalisib was dissolved in chloroform at room temperature.

The solvent was completely evaporated under laboratory conditions.

An XRPD record was obtained and showed that the compound was in a crystalline state, which was designated as amorphous idelalisib.

The same result was similarly obtained using any of the solvents listed in Table 4.

Solvent acetone ethanol - water [75-25% vol.] acetonitrile 2-propanol butyl acetate methanol ethyl acetate 2-butanone dioxane 4-methyl-2-pentanone dioxane - water [50-50% vol.]

Table 5

Claims (34)

PATENT CLAIMS 1. Crystal modification of 1 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazoline- 4-one of formula I (O, showing an X-ray powder diffraction pattern containing characteristic peaks at about 10.4; 11.9 and 15.7 ± 0.2 ° 2-theta, measured using CuKα radiation. The crystal modification 1 of claim 1, wherein the X-ray powder diffractogram further comprises characteristic peaks at about 8.2; 9.1; 14.7; 18.8 and 23.7 ± 0.2 ° 2-theta, measured using CuKα radiation. Crystal modification 1 according to claim 1 or 2, characterized by a differential scanning calorimetry curve showing a melting process sT _onS et, i ⁼ 67 ° C corresponding to the loss of water; TOnset, 2 ⁼ 141.3 C; Trecrystallization ~ 205 C 3 TonSet, 3 245.5 C. Crystal modification 1 according to any one of claims 1 to 3, characterized by a thermal gravimetric curve showing a weight loss of 4.3% in the range from 20 ° C to 150 C The crystal modification 1 according to any one of claims 1 to 4, wherein the crystal modification is substantially a hydrate. Composition comprising crystal modification 1 according to any one of claims 1 to 5, characterized in that the composition is substantially free of solid forms other than crystal modification 1 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazoline- 4-onu. Process for the preparation of crystal modification 1 according to any one of claims 1 to 5, characterized in that idelalisib is dissolved in a suitable organic solvent, preferably a polar aprotic solvent, by heating the system to a temperature close to the boiling point of the solvent. Process according to Claim 1, characterized in that the polar aprotic solvent is tetrahydrofuran, dichloromethane, ethyl acetate, acetone, acetonitrile or dimethyl sulfoxide or mixtures thereof, preferably acetonitrile. The method of claim 8, further comprising the steps of: (a) dissolving idelalisib in acetonitrile at a temperature close to the boiling point of the appropriate solvent; b) cooling the solution from step a) to 0-5 ° C to form a suspension; c) maintaining the suspension from step b) at a temperature of 0-5 ° C for about 4 hours; d) isolation of idelalisib free base in crystal modification 1. The method of claim 9, further comprising the step of drying the product of step d) under laboratory conditions until a constant weight of product is reached. Process according to any one of claims 7 to 10, characterized in that the heated solution is cooled to a temperature of 5 ° C or lower. Process according to any one of claims 7 to 11, characterized in that the heated solution is kept cooled for about 4 hours. 13. Crystal modification of 2 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazoline- 4-one of formula I HI exhibiting an X-ray powder diffraction pattern containing characteristic peaks at about 10.8; 11.8; 18.3; 20.0; 23.7 and 25.5 ± 0.2 ° 2-theta, measured using CuKα radiation. The crystal modification 2 according to claim 13, characterized by a differential scanning calorimetry curve showing a melting process sT _O n _S et, i = 109 ° C corresponding to the loss of solvent and T _onS et, 2 = 249.4 ° C. Crystal modification 2 according to claim 13 or 14, characterized by a thermal gravimetric curve showing a weight loss of 14.3% in the range from 20 ° C to 180 ° C. The crystal modification 2 according to any one of claims 13 to 15, wherein the crystal modification is substantially a solvate. Process for the preparation of crystal modification 2 according to claims 13 to 16, characterized in that idelalisib is suspended in N, N-dimethylformamide at room temperature. The method of claim 17, comprising the steps of: a) suspending idelalisib in N, N-dimethylformamide at room temperature; b) heating the suspension from step a) to 40 to 60 ° C; c) stirring the suspension from step b); d) isolating crystal modification 2 of idelalisib. The method of claim 18, further comprising the step of drying the product of step d) under laboratory conditions until a constant weight of product is reached. The method of claim 17, comprising the steps of: a) suspending idelalisib in N, N-dimethylformamide at room temperature; b) stirring the suspension from step a); c) isolating crystal modification 2 of idelalisib. The method of claim 20, further comprising the step of drying the product of step c) under laboratory conditions until a constant weight of product is reached. Process according to Claim 20 or 21, characterized in that the suspension is heated to a temperature of at least 40 to 60 ° C. Process according to any one of claims 18 to 22, characterized in that the suspension is stirred for at least 48 hours. Process according to any one of claims 18 to 23, characterized in that the suspension is stirred for at least 2 weeks. Composition, characterized in that it comprises crystal modification 2 according to any one of claims 13 to 16, characterized in that the composition is substantially free of solid form other than crystal modification 2 5-fluoro-3-phenyl-2 - [( 1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one. Use of crystal modification 1 of idelalisib according to any one of claims 1 to 5 for the preparation of a pharmaceutical composition. Use of crystal modification 2 of idelalisib according to any one of claims 13 to 16 for the preparation of a pharmaceutical composition. A pharmaceutical composition comprising 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one in crystal modification 1 according to any one of claims 1 to 5 and / or crystal modification 2 according to any one of claims 13 to 16. The pharmaceutical composition of 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. A crystal modification of 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4-one according to any one of claims 1 to 5 and / or 13 to 16 for use in the treatment of cancer. The crystal modification of claim 31, wherein the cancer is a hematological malignancy. The crystal modification of 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 cell lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulin , T-lymphoblastic lymphoma, B-lymphoblastic lymphoma and diffuse large B-cell lymphoma (DLBCL). The crystal modification of claim 31, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (iNHL), and refractory iNH.