SOLID STATE FORMS OF ZANDELISIB AND SALTS THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Zandelisib and salts thereof, in embodiments processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Zandelisib, 4-[2-(difhioromethyl)benzimidazol-l -yl]-N-[2 -methyl- l-[2-(l- methylpiperidin-4-yl)phenyl]propan-2-yl]-6-morpholin-4-yl-l, 3,5-triazin-2-amine, has the following chemical structure:

[0003] Zandelisib is an investigational oral phosphatidylinositol 3-kinase delta (PI3K5) inhibitor in clinical development for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies. Zandelisib is also being investigated for treatment in combination with rituximab of patients with relapsed indolent non-Hodgkin’s lymphoma.

[0004] The compound is described in International Publication No. WO 2012/135160. International Publication No. WO 2021/207024 discloses processes for preparation of Zandelisib.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state ( ¹³ C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Zandelisib.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides a crystalline form of Zandelisib, crystalline polymorphs of Zandelisib HC1 and Zandelisib HBr, processes for preparation thereof, and pharmaceutical compositions thereof. The crystalline polymorphs of the disclosure can be used to prepare Zandelisib, other salts of Zandelisib and their solid state forms or other solid state forms of Zandelisib HC1 and Zandelisib HBr. [0009] The present disclosure also provides uses of the said solid state forms of Zandelisib, Zandelisib HC1 and Zandelisib HBr in the preparation of Zandelisib, Zandelisib HC1 and Zandelisib HBr or other salts of Zandelisib and solid state forms thereof.

[0010] The present disclosure provides the crystalline forms of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr for use in medicine, including for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies.

[0011] The present disclosure also encompasses the use of the crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising the crystalline polymorph of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr according to the present disclosure.

[0013] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Zandelisib HC1 and/or Zandelisib HBr with at least one pharmaceutically acceptable excipient.

[0014] The crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr may be used as medicaments, such as for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies.

[0015] The present disclosure also provides methods for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Zandelisib, Zandelisib HC1 or Zandelisib HBr of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies or otherwise in need of the treatment.

[0016] The present disclosure also provides uses of crystalline polymorphs of Zandelisib, Zandelisib HC1 and Zandelisib HBr of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib Form Zl.

[0018] Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form A.

[0019] Figure 2A shows the X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form A obtained by Procedure B of Example 2.

[0020] Figure 3 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form E.

[0021] Figure 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form B.

[0022] Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form C.

[0023] Figure 6 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HC1 salt Form D.

[0024] Figure 7 shows X-ray powder diffraction pattern (XRPD) of amorphous Zandelisib HC1 .

[0025] Figure 8 shows a characteristic X-ray powder diffraction pattern (XRPD) of Zandelisib HBr salt Form A.

[0026] Figure 9 shows X-ray powder diffraction pattern (XRPD) of amorphous Zandelisib obtained according to example 3.

[0027] Figure 10 shows X-ray powder diffraction pattern (XRPD) of amorphous Zandelisib obtained according to example 3 and stored at 25 °C for 7 days.

[0028] Figure 10A shows X-ray powder diffraction patterns (XRPD) of Zandelisib obtained according to example 3. The bottom pattern corresponds to initial amorphous sample. The upper XRPD patterns correspond to sample stored for 3, and 7 days. The top XRPD pattern corresponds to sample stored for 24 days.

[0029] Figure 11 shows ¹³ C solid state NMR spectrum of Form A Zandelisib HC1 salt (200-0 ppm). [0030] Figure 12 shows ¹³ C solid state NMR spectrum of Form A Zandelisib HC1 salt (200- 100 ppm).

[0031] Figure 13 shows ¹³ C solid state NMR spectrum of Form A Zandelisib HC1 salt (100-0 ppm).

DETAILED DESCRIPTION OF THE DISCLOSURE

[0032] The present disclosure provides crystalline polymorphs of Zandelisib, Zandelisib HC1 and Zandelisib HBr, processes for preparation thereof, and pharmaceutical compositions thereof. [0033] Solid state properties of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr and crystalline polymorphs thereof can be influenced by controlling the conditions under which Zandelisib, Zandelisib HC1 and/or Zandelisib HBr and crystalline polymorphs thereof are obtained in solid form.

[0034] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Zandelisib described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr. In some embodiments of the disclosure, the described crystalline polymorph of Zandelisib HC1 or Zandelisib HBr may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr, respectively.

[0035] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Zandelisib, Zandelisib HC1 and Zandelisib HBr of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density. Particularly, a crystalline polymorph of Zandelisib, Zandelisib HC1 or Zandelisib HBr, as described in any aspect or embodiment of the present disclosure may be stable, for example to conditions of high relative humidity, and/or may be thermally stable. Crystalline Forms A, C, E and D of Zandelisib HC1 as described in any aspect or embodiment of the present disclosure, may be especially stable to conditions of high relative humidity and/or may be thermally stable.

[0036] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Zandelisib HC1 or Zandelisib HBr referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Zandelisib HC1 or Zandelisib HBr characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0037] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Zandelisib, Zandelisib HC1 or Zandelisib HBr, relates to a crystalline form of which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA. [0038] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0039] As used herein, the term "isolated" in reference to crystalline polymorph of Zandelisib of the present disclosure corresponds to a crystalline polymorph of Zandelisib HC1 or Zandelisib HBr that is physically separated from the reaction mixture in which it is formed. [0040] As used herein, the XRPD measurements of figures 1-2, are taken using copper Kal radiation wavelength 1.54060 A. XRPD peaks reported herein are measured using CuK al radiation, l = 1.54060 A, typically at a temperature of 25 ± 3°C. As used herein, unless stated otherwise, the XRPD measurements of figures 3-10 are taken using copper Kal radiation wavelength 1.54187 A. XRPD peaks reported herein are measured using CuK al radiation, l = 1.54187 A, typically at a temperature of 25 ± 3°C. It is noted that whilst there is small difference in the wavelengths used for figure 1 and 2 and figures 3-10, the difference is negligible and does not affect the reported 2-theta values, noting that a standard error margin of ± 0.2 degrees 2-theta is applicable to the 2-theta values and diffractograms reported throughout the disclosure.

[0041] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0042] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added. [0043] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0044] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0045] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0046] The present disclosure includes a crystalline polymorph Zandelisib designated form Zl. The crystalline Form Z1 of Zandelisib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 10.0, 11.8, 14.4, 15.7 and 19.6 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0047] Crystalline Form Zl of Zandelisib may be further characterized by an X-ray powder diffraction pattern having peaks at 10.0, 11.8, 14.4, 15.7 and 19.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.2, 13.0, 21.6, 22.1 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0048] Crystalline Form Zl of Zandelisib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 10.0, 11.2, 11.8, 13.0, 14.4, 15.7, 19.6, 21.6, 22.1 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] In one embodiment of the present disclosure, crystalline Form Zl of Zandelisib is isolated. Particularly, crystalline Form Zl of Zandelisib according to any aspect or embodiment of the disclosure may be isolated.

[0050] In any embodiment crystalline Form Zl of Zandelisib may be polymorphically pure. [0051] Crystalline Form Zl of Zandelisib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 10.0, 11.8, 14.4, 15.7 and 19.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0052] In any embodiment of the present disclosure, crystalline Form Zl of Zandelisib may be anhydrous. [0053] The present disclosure includes a crystalline polymorph of Zandelisib HC1 salt designated Form A. The crystalline Form A of Zandelisib HC1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2 or Figure 2A; an X-ray powder diffraction pattern having peaks at 7.6, 8.5, 10.8, 13.8 and 16.3 degrees 2-theta ± 0.2 degrees 2-theta; a solid state ¹³ C NMR spectrum having characteristic peaks at 165.1, 161.5, 137.2, 133.0 and 128.7 ppm ± 0.2 ppm; A solid state ¹³ C NMR spectrum having the following chemical shift absolute differences from reference peak at 117.5 ppm ± 1 ppm: 47.5, 44.0, 19.7, 15.5 and 11.2 ppm ± 0.1 ppm; and combinations of these data.

[0054] Crystalline Form A of Zandelisib HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 7.6, 8.5, 10.8, 13.8 and 16.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.1, 20.2, 21.7, 22.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta. For example, according to any aspect or embodiment of the present disclosure, crystalline Form A of Zandelisib HC1 may be characterized by an X-ray powder diffraction pattern having peaks at 7.6, 8.5, 10.8, 13.8 and 16.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having an additional peak at 12.1 degrees 2- theta ± 0.2 degrees 2-theta.

[0055] Crystalline Form A of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.6, 8.5, 10.8, 12.1, 13.8, 16.3, 20.2, 21.7, 22.3 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta.

[0056] Crystalline Form A of Zandelisib HC1 as described in any aspect or embodiment of the disclosure herein may be additionally characterized by an absence of either one or both peaks at 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta. For example, crystalline Form A of Zandelisib HC1 may be characterized by an XRPD pattern having peaks at 7.6, 8.5, 10.8, 13.8 and 16.3 degrees 2-theta ± 0.2 degrees 2-theta and optionally 12.1 degrees 2-theta ± 0.2 degrees 2-theta and also having: an absence of a peak at 14.5 degrees 2-theta ± 0.2 degrees 2-theta or an absence of a peak at 16.7 degrees 2-theta ± 0.2 degrees 2-theta, or an absence of peaks at 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta.

[0057] In one embodiment of the present disclosure, crystalline Form A of Zandelisib HC1 is isolated. Particularly, crystalline Form A of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated. Particularly, crystalline Form A of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated.

[0058] In any embodiment crystalline Form A of Zandelisib HC1 may be polymorphically pure.

[0059] Crystalline Form A of Zandelisib HC1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.6, 8.5, 10.8, 13.8 and 16.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0060] In any embodiment of the present disclosure, crystalline Form A of Zandelisib HC1 may be a hydrate, preferably a dihydrate. In any embodiment, crystalline Form A may contain from about 3% to about 6% of water, as measured by TGA.

[0061] Crystalline Form A of Zandelisib HC1 according to any aspect or embodiment of the present disclosure may be advantageously stable, for example to conditions of high relative humidity [for example Form A may show no polymorphic changes when exposed to 100 %RH (e.g. at room temperature), e.g. for 3 days, or up to 7 days.

[0062] Form A of Zandelisib HC1 may be prepared by crystallizing Zandelisib HC1 in an a mixture of an alcohol and water. The alcohol is preferably a Ci to Cx alcohol, more preferably a Ci-Ce alcohol, most preferably a C2-4 alcohol, and particularly ethanol. The process may comprise obtaining a solution of Zandelisib HC1 in the alcohol, or mixture of the alcohol and water (preferably wherein the alcohol is ethanol) preferably at elevated temperature, and crystallising preferably by cooling. The solution of Zandelisib HC1 in the alcohol or mixture of alcohol and water may be heated to a temperature of about 25°C to about 75°C, about 40°C to about 70°C, about 50°C to about 65°C, or about 60°C. The solution may be stirred at this temperature for a period of about 5 minutes to about 100 minutes, about 5 minutes to about 50 minutes, about 10 minutes to about 20 minutes, or about 15 minutes. The mixture may be cooled to a temperature of: about room temperature. The mixture may be stirred at the cooled temperature for about 30 minutes to about 6 hours, about 1 hour to about 4 hours, about 1.5 hours to about 2.5 hours, or about 2 hours. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time. The solution of Zandelisib in the alcohol (preferably ethanol) may be obtained by combining a mixture of Zandelisib in the alcohol with hydrochloric acid, preferably at an elevated temperature as described above. The process may further comprise combining the Form A of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0063] Form A of Zandelisib HC1 as described in aspect or embodiment of the present disclosure, may be prepared by slurrying Zandelisib HC1 in water. The starting Zandelisib HC1 may be any other form of Zandelisib HC1, but is preferably Form E as described in any aspect or embodiment of the present disclosure. Preferably, the slurrying comprises stirring Zandelisib HC1 in water. In any aspect or embodiment of the process, the stirring may be carried out at a temperature of about 10°C to about 40°C, but is preferably at room temperature. The stirring may be carried out for any suitable time to prepare Form A of Zandelisib HC1. Preferably, the stirring may be for a period of: about 1 hour to about 7 days, about 2 hours to about 5 days, or about 2.5 hours to about 4 days. The reaction mixture of the Zandelisib HC1 in water may be formed by combining Zandelisib HC1, preferably Form E, with the water. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The process may further comprise combining the Form A of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition. [0064] The present disclosure includes a crystalline polymorph Zandelisib HC1 designated Form E. The crystalline Form E of Zandelisib HC1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 7.3, 8.9, 13.5, 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. Crystalline Form E of Zandelisib HC1 may alternatively be characterized by an X-ray powder diffraction pattern having peaks at 7.3, 8.9, 13.5, 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta; and absence of a peak at 12.1 degrees 2-theta ± 0.2 degrees 2-theta

[0065] Crystalline Form E of Zandelisib HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 7.3, 8.9, 13.5, 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.5, 11.1, 11.5, 21.7 and 22.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form E of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.3, 8.9, 13.5, 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 5.5, 11.1, 11.5, 21.7 and 22.4 degrees 2-theta ± 0.2 degrees 2-theta and an absence of a peak at 12.1 degrees 2-theta ± 0.2 degrees 2- theta.

[0066] Crystalline form E of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.5, 7.3, 8.9, 11.1, 11.5, 13.5, 14.5, 16.7, 21.7 and 22.4 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form E of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.5, 7.3, 8.9, 11.1, 11.5, 13.5, 14.5, 16.7, 21.7 and 22.4 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of a peak at 12.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0067] Crystalline Form E of Zandelisib HC1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.3, 8.9, 13.5, 14.5 and 16.7 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 3, and combinations thereof. In one embodiment of the present disclosure, crystalline Form E of Zandelisib HC1 is isolated. Particularly, crystalline Form E of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated.

[0068] In any embodiment crystalline Form E of Zandelisib HC1 may be polymorphically pure.

[0069] In any embodiment of the present disclosure, crystalline Form E of Zandelisib HC1 may be a hydrate. In any embodiment, crystalline Form E may contain from about 3% to about 4% of water as measured by TGA.

[0070] Crystalline Form E of Zandelisib HC1 according to any aspect or embodiment of the present disclosure may be advantageously stable, for example to conditions of high relative humidity [for example Form E may show no polymorphic changes when exposed to 40-50 %RH (e.g. at 5°C) for prolonged periods (e.g. 29 days)].

[0071] Form E of Zandelisib HC1 may be prepared by crystallising Zandelisib HC1 in an ether, or a mixture of an ether and water. The ether is preferably a C4 to Cx ether, more preferably a C ₄ -C ₆ ether, most preferably a C _4-6 cyclic ether, preferably wherein the ether is water-miscible, and more particularly wherein the ether is tetrahydrofuran. The process may comprise obtaining a solution of Zandelisib HC1 in the ether, or mixture of the ether and water (preferably wherein the ether is tetrahydrofuran) preferably at elevated temperature, and crystallising preferably by cooling. The solution of Zandelisib HC1 in the ether or mixture of ether and water may be heated to a temperature of about 25°C to about 75°C, about 40°C to about 70°C, about 50°C to about 65°C, or about 60°C. The solution may be stirred at this temperature for a period of about 5 minutes to about 100 minutes, about 5 minutes to about 50 minutes, about 10 minutes to about 20 minutes, or about 15 minutes. The mixture may be cooled to a temperature of: about -10°C to about 20°C, about -5°C to about 15°C, about -2°C to about 10°C, or about 0°C to about 5°C. The cooling may be conducted over a period of about 10 minutes to about 200 minutes, about 20 minutes to about 150 minute, about 40 minutes to about 120 minutes, about 60 minutes to about to about 100 minutes, or about 90 minutes. The mixture may be stirred at the cooled temperature for about 30 minutes to about 6 hours, about 1 hour to about 4 hours, about 1.5 hours to about 2.5 hours, or about 2 hours. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The solution of Zandelisib in the ether (preferably tetrahydrofuran) may be obtained by combining a mixture of Zandelisib in the ether, with hydrochloric acid (particularly aqueous hydrochloric acid), preferably at an elevated temperature as described above. The process may further comprise combining the Form E of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0072] Form E of Zandelisib HC1 may be prepared by crystallising Zandelisib HC1 in a mixture of an alcohol and water. The alcohol is preferably a Ci to Cx alcohol, more preferably a Ci-Ce alcohol, most preferably a C2-4 alcohol, and particularly ethanol. The process may comprise obtaining a solution of Zandelisib HC1 in the alcohol, or mixture of the alcohol and water (preferably wherein the alcohol is ethanol) preferably at elevated temperature, and crystallising preferably by cooling. The solution of Zandelisib HC1 in the alcohol or mixture of alcohol and water may be heated to a temperature of about 25°C to about 75°C, about 40°C to about 70°C, about 50°C to about 65°C, or about 60°C. The solution may be stirred at this temperature for a period of about 5 minutes to about 100 minutes, about 5 minutes to about 50 minutes, about 10 minutes to about 20 minutes, or about 15 minutes. The mixture may be cooled to a temperature of: about -10°C to about 15°C, about -5°C to about 10°C, about -2°C to about 10°C, or about 0°C to about 5°C. The cooling may be conducted over a period of about 10 minutes to about 200 minutes, about 20 minutes to about 150 minute, about 40 minutes to about 120 minutes, about 60 minutes to about to about 100 minutes, or about 90 minutes. The mixture may be stirred at the cooled temperature or at a temperature of up to about 15°C, preferably up to about 10°C, for about 30 minutes to about 6 hours, about 1 hour to about 4 hours, about 1.5 hours to about 2.5 hours, or about 2 hours. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The solution of Zandelisib in the alcohol (preferably ethanol) may be obtained by combining a mixture of Zandelisib in the alcohol with hydrochloric acid (particularly aqueous hydrochloric acid), preferably at an elevated temperature as described above. The process may further comprise combining the Form E of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0073] Form E of Zandelisib HC1 as described in aspect or embodiment of the present disclosure, may be prepared by slurrying Zandelisib HC1 in water. The starting Zandelisib HC1 may be any other form of Zandelisib HC1, but is preferably Form D as described in any aspect or embodiment of the present disclosure. Preferably, the slurrying comprises stirring Zandelisib HC1 in water. In any aspect or embodiment of the process, the stirring may be carried out at a temperature of about 10°C to about 40°C, but is preferably at room temperature. The stirring may be carried out for any suitable time to prepare Form E of Zandelisib HC1. Preferably, the stirring may be for a period of: about 1 hour to about 7 days, about 2 hours to about 5 days, or about 2.5 hours to about 4 days. The reaction mixture of the Zandelisib HC1 in water may be formed by combining Zandelisib HC1, preferably Form D, with the water. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The process may further comprise combining the Form E of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition. [0074] The present disclosure includes a crystalline polymorph Zandelisib HC1 designated Form B. The crystalline Form B of Zandelisib HC1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 6.6, 9.8, 10.3, 10.9 and 11.8 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0075] Crystalline Form B of Zandelisib HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 6.6, 9.8, 10.3, 10.9 and 11.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from

13.6, 15.0, 18.3, 20.6 and 25.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0076] Crystalline Form B of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 6.6, 9.8, 10.3, 10.9, 11.8, 13.6, 15.0, 18.3, 20.6 and 25.5 degrees 2-theta ± 0.2 degrees 2-theta

[0077] Crystalline Form B of Zandelisib HC1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at

6.6, 9.8, 10.3, 10.9 and 11.8 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0078] In one embodiment of the present disclosure, crystalline Form B of Zandelisib HC1 is isolated. Particularly, crystalline Form B of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated.

[0079] In any embodiment crystalline Form B of Zandelisib HC1 may be polymorphically pure.

[0080] In any embodiment of the present disclosure, crystalline Form B of Zandelisib HC1 may be a hydrate. In any embodiment, crystalline Form B may contain from about 1% to about 4% of water, preferably from about 1.9% to about 3.2% of water as measured by TGA.

[0081] The present disclosure includes a crystalline polymorph Zandelisib HC1 designated Form C. The crystalline Form C of Zandelisib HC1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0082] Crystalline Form C of Zandelisib HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 16.3, 18.2, 19.5, 20.7 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta. [0083] Crystalline Form C of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.6, 7.6, 10.7, 12.6, 16.3, 17.8, 18.2, 19.5, 20.7 and

21.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0084] Crystalline Form C of Zandelisib HC1 according to any aspect or embodiment of the present disclosure may be further characterized by an XRPD pattern which has: an absence of a peak at either: 8.5 degrees 2-theta ± 0.2 degrees 2-theta; or 13.8 degrees 2-theta ± 0.2 degrees 2- theta (more particularly an absence of a peak at 8.5 degrees 2-theta ± 0.2 degrees 2-theta); or an absence of peaks at 8.5 and 13.8 degrees 2-theta ± 0.2 degrees 2-theta.

[0085] Crystalline Form C of Zandelisib HC1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 5, and combinations thereof. As further, non-limiting, examples crystalline Form C of Zandelisib HC1 may be characterized by an XRPD pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at: 8.5 or 13.8 degrees 2-theta ± 0.2 degrees 2-theta (more particularly an absence of a peak at 8.5 degrees 2- theta ± 0.2 degrees 2-theta); or an XRPD pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and an absence of peaks at 8.5 and 13.8 degrees 2-theta ± 0.2 degrees 2-theta; or an XRPD pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2- theta ± 0.2 degrees 2-theta, and having any one, two, three, four or five additional peaks selected from 16.3, 18.2, 19.5, 20.7 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta and an absence of peaks at 8.5 or 13.8 degrees 2-theta ± 0.2 degrees 2-theta (more particularly an absence of a peak at 8.5 degrees 2-theta ± 0.2 degrees 2-theta); or an XRPD pattern having peaks at 5.6, 7.6, 10.7, 12.6 and 17.8 degrees 2-theta ± 0.2 degrees 2-theta, and having any one, two, three, four or five additional peaks selected from 16.3, 18.2, 19.5, 20.7 and 21.8 degrees 2-theta ± 0.2 degrees 2- theta and an absence of peaks at 8.5 and 13.8 degrees 2-theta ± 0.2 degrees 2-theta; or an X-ray powder diffraction pattern having peaks at 5.6, 7.6, 10.7, 12.6, 16.3, 17.8, 18.2, 19.5, 20.7 and

21.8 degrees 2-theta ± 0.2 degrees 2-theta and an absence of peaks at 8.5 or 13.8 degrees 2-theta ± 0.2 degrees 2-theta (more particularly an absence of a peak at 8.5 degrees 2-theta ± 0.2 degrees 2-theta); or an X-ray powder diffraction pattern having peaks at 5.6, 7.6, 10.7, 12.6, 16.3, 17.8, 18.2, 19.5, 20.7 and 21.8 degrees 2-theta ± 0.2 degrees 2-theta and an absence of peaks at 8.5 and

13.8 degrees 2-theta ± 0.2 degrees 2-theta. [0086] In one embodiment of the present disclosure, crystalline Form C of Zandelisib HC1 is isolated. Particularly, crystalline Form C of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated.

[0087] In any embodiment crystalline Form C of Zandelisib HC1 may be polymorphically pure.

[0088] In any embodiment of the present disclosure, crystalline Form C of Zandelisib HC1 may be anhydrous.

[0089] Crystalline Form C of Zandelisib HC1 according to any aspect or embodiment of the present disclosure may be advantageously stable, for example to conditions of high relative humidity [for example Form C may show no polymorphic changes when exposed to 60% relative humidity (e.g. at 25°C) for e.g. at least 7 days]

[0090] The present disclosure further provides processes for preparing Form C of Zandelisib HC1 as described in any aspect or embodiment of the present disclosure. Form C of Zandelisib HC1 may be prepared by slurrying Zandelisib HC1 in an ester solvent, preferably a C4 to Cx ester, more preferably a C4-C6 ester, and most preferably ethylacetate. The starting Zandelisib HC1 may be any other form of Zandelisib HC1, but is preferably Form E as described in any aspect or embodiment of the present disclosure. Preferably, the slurrying comprises stirring a suspension of the Zandelisib HC1 in ethylacetate at elevated temperature. In any aspect or embodiment of the process, the stirring may be carried out at a temperature of about 25°C to about 75°C, about 40°C to about 70°C, about 50°C to about 65°C, or about 60°C. The stirring may be carried out for any suitable time to prepare Form C of Zandelisib HC1. Preferably, the stirring may be for a period of: about 1 to about 20 hours, about 2 to about 10 hours, about 2 to about 5 hours, about 3 to about 4 hours, or about 3.5 hours. The suspension of the Zandelisib HC1 in the ester (preferably ethylacetate) may be formed by combining Zandelisib HC1, preferably Form E, with the ester. The mixture may be heated to the elevated temperature over a suitable period of time, such as: about 10 to about 120 minutes, about 20 to about 100 minutes, about 20 to about 40 minutes, or about 30 minutes. The stirring may then be conducted at the elevated temperature and for the suitable time period as described above. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The process may further comprise combining the Form C of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0091] Form C of Zandelisib HC1 as described in any aspect or embodiment of the present disclosure may also be obtained by a process comprising heating Form D of Zandelisib HC1 as described in any aspect or embodiment described herein, preferably wherein the heating is conducted in an inert atmosphere. The heating may be to a temperature of: about 100°C to about 230°C, about 150°C to about 220°C, about 180°C to about 215°C, about 190°C to about 210°C, or about 200°C. The heating can be carried out at a rate of about 5°C to about 20°C per minute, about 8°C to about 15°C per minute, or about 10°C per minute. The process may further comprise combining the Form C of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0092] The present disclosure includes a crystalline polymorph Zandelisib HC1 designated Form D. The crystalline Form D of Zandelisib HC1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 4.5, 6.9, 8.5, 9.1 and 17.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.

[0093] Crystalline Form D of Zandelisib HC1 may be further characterized by an X-ray powder diffraction pattern having peaks at 4.5, 6.9, 8.5, 9.1 and 17.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 14.8, 15.2, 18.8, 19.2 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0094] Crystalline Form D of Zandelisib HC1 may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.5, 6.9, 8.5, 9.1, 14.8, 15.2, 17.0, 18.8, 19.2 and 24.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0095] Crystalline Form D of Zandelisib HC1 may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 4.5, 6.9, 8.5, 9.1 and 17.0 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 6, and combinations thereof.

[0096] In one embodiment of the present disclosure, crystalline Form D of Zandelisib HC1 is isolated. Particularly, crystalline Form D of Zandelisib HC1 according to any aspect or embodiment of the disclosure may be isolated. [0097] In any embodiment crystalline Form D of Zandelisib HC1 may be polymorphically pure.

[0098] In any embodiment of the present disclosure, crystalline Form D of Zandelisib HC1 may be an isopropanol solvate. Crystalline Form D may contain from about 6% to about 10% of isopropanol, preferably from about 7.6% to about 8.2% of isopropanol as measured by TGA. [0099] Crystalline Form D of Zandelisib HC1 according to any aspect or embodiment of the present disclosure may be advantageously stable, for example to conditions of high relative humidity.

[00100] Form D of Zandelisib HC1 as described in aspect or embodiment of the present disclosure, may be prepared by slurrying Zandelisib HC1 in isopropanol. The starting Zandelisib HC1 may be any other form of Zandelisib HC1, but is preferably Form E as described in any aspect or embodiment of the present disclosure. Preferably, the slurrying comprises stirring a suspension of the Zandelisib HC1 in isopropanol. In any aspect or embodiment of the process, the stirring may be carried out at a temperature of about 0°C to about 85°C, or about 0°C to about 70°C. The stirring may be carried out for any suitable time to prepare Form D of Zandelisib HC1. Preferably, the stirring may be for a period of: about 1 hour to about 7 days, about 2 hours to about 5 days, or about 2.5 hours to about 4 days. The suspension of the Zandelisib HC1 isopropanol may be formed by combining Zandelisib HC1, preferably Form E, with the isopropanol. The mixture may be optionally heated. The stirring may then be conducted at the elevated temperature and for the suitable time period as described above. Prior to isolation, the mixture may be cooled. The product may be isolated by any suitable procedure, such as decantation, centrifugation or filtration, preferably by filtration. The resulting solid may be dried, preferably under vacuum, and preferably at room temperature for a suitable period of time, preferably about 10 to about 60 minutes, or about 15 to about 30 minutes. The process may further comprise combining the Form D of Zandelisib HC1 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

[00101] The present disclosure includes a crystalline polymorph Zandelisib HBr designated Form A. The crystalline Form A of Zandelisib HBr may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at 7.1, 8.9, 13.3, 14.4 and 19.8 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. [00102] Crystalline Form A of Zandelisib HBr may be further characterized by an X-ray powder diffraction pattern having peaks at 7.1, 8.9, 13.3, 14.4 and 19.8 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 8.3, 11.0, 21.1, 21.5 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00103] Crystalline Form A of Zandelisib HBr may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.1, 8.3, 8.9, 11.0, 13.3, 14.4, 19.8, 21.1, 21.5 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta.

[00104] Crystalline Form A of Zandelisib HBr may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.1, 8.9, 13.3, 14.4 and 19.8 degrees 2-theta ± 0.2 degrees 2-theta and an XRPD pattern as depicted in Figure 8, and combinations thereof.

[00105] In one embodiment of the present disclosure, crystalline Form A of Zandelisib HBr is isolated. Particularly, crystalline Form A of Zandelisib HBr according to any aspect or embodiment of the disclosure may be isolated.

[00106] In any embodiment crystalline Form A of Zandelisib HBr may be polymorphically pure.

[00107] In any embodiment of the present disclosure, crystalline Form A of Zandelisib HBr may be a hydrate, preferably a monohydrate. Crystalline Form A of Zandelisib HC1 may contain from about 2% to about 4% of water, preferably from about 3% of water as measured by TGA. [00108] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Zandelisib or other salts thereof.

[00109] The present disclosure encompasses a process for preparing other solid state forms of Zandelisib, Zandelisib salts and solid state forms thereof. The process includes preparing any one of the solid state forms of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr by the processes of the present disclosure, and converting that form to a different form of Zandelisib or salts thereof. The conversion can be done, for example, by a process comprising basifying the above described forms of Zandelisib HC1 salt and reacting the obtained Zandelisib base with an appropriate acid, to obtain the corresponding salt. Alternatively, the conversion can be done by salt switching, i.e., reacting the form of the Zandelisib salt of the present disclosure with an acid having a pKa which is lower than that of the acid of the original salt. [00110] Any one of the crystalline forms of Zandelisib HC1 or Zandelisib HBr described above may be used for purification of Zandelisib.

[00111] In a further aspect, the present disclosure provides a process for purification of Zandelisib or salt of Zandelisib comprising: a) preparing an HC1 salt of Zandelisib; and b) converting Zandelisib HC1 salt to Zandelisib or another salt thereof

[00112] Particularly, the present invention provides a process for the preparation of Zandelisib or a salt thereof, preferably substantially pure Zandelisib or pure salt thereof, wherein the process comprises: a) contacting Zandelisib with an acid, preferably HC1 or HBr to produce the corresponding acid addition salt of Zandelisib, preferably Zandelisib HC1 or Zandelisib HBr respectively; and b) converting the acid addition salt of Zandelisib to Zandelisib or another salt thereof, preferably to Zandelisib.

[00113] In embodiments, Zandelisib HC1 formed in step a) is crystalline, preferably Zandelisib HC1 Form A, B, C, D or E.

[00114] The present disclosure provides the above described crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr for use in the preparation of pharmaceutical compositions comprising Zandelisib HC1 and/or Zandelisib HBr and/or crystalline polymorphs thereof.

[00115] The present disclosure also encompasses the use of crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Zandelisib HC1 and/or Zandelisib HBr and/or crystalline polymorphs thereof.

[00116] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr of the present disclosure with at least one pharmaceutically acceptable excipient.

[00117] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[00118] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00119] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch. [00120] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[00121] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[00122] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00123] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00124] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00125] In liquid pharmaceutical compositions of the present invention, Zandelisib,

Zandelisib HC1 and/or Zandelisib HBr and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00126] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00127] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof. [00128] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[00129] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00130] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00131] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00132] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00133] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.

[00134] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00135] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant. [00136] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00137] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00138] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00139] A pharmaceutical formulation of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr or the crystalline forms thereof can be administered. Zandelisib, Zandelisib HC1 and/or Zandelisib HBr or the crystalline forms thereof may be formulated for administration to a mammal, in embodiments to a human, by injection. Zandelisib, Zandelisib HC1 and/or Zandelisib HBr or the crystalline forms thereof can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et ak, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00140] The crystalline polymorphs of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr or the crystalline forms thereof and the pharmaceutical compositions and/or formulations of Zandelisib, Zandelisib HC1 and/or Zandelisib HBr or the crystalline forms thereof of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies. [00141] The present disclosure also provides methods of treating of patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and other B-cell Malignancies by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Zandelisib HC1 and/or Zandelisib HBr of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00142] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.

Powder X-ray Diffraction ("XRPD") method [Figures 1-21

[00143] XRPD analysis was performed on Bruker powder X-Ray diffractometer model D8 ADVANCE equipped with a solid state detector. Copper radiation of 1.54060 A was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode; step size: 0.05°.

The positions of the peaks were corrected respective to the position of the silicon theoretical peak at 28.45 degrees two theta.

Powder X-ray Diffraction ("XRPD") method (Figures 2A, 3-10)

[00144] Powder X-ray Diffraction was performed on an X-Ray powder diffractometer PanAlytical X’pert Pro; CuKa radiation (l = 1.54187 A); X'Celerator detector with active length 2.122 degrees 2-theta; laboratory temperature 25 ± 3 °C; zero background sample holders. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed using a cover glass.

Measurement parameters:

Scan range: 3 - 40 degrees 2-theta Scan mode: continuous Step size: 0.0167 degrees

Step size: 42 s Sample spin: 60 rpm Sample holder: zero background silicon plate The positions of the peaks were corrected respective to the position of the silicon theoretical peak at 28.45 degrees two theta.

¹³ C Solid State NMR method:

[00145] 13C CP/MAS NMR spectra were measured at 125 MHz using Bruker Avance III 500

WB/US NMR spectrometer (Karlsruhe, Germany, 2003) at magic angle spinning (MAS) frequency ® _G /2p = 18 kHz. In all cases finely powdered samples were placed into 4-mm Zr02 rotors and the standard “cpmas” pulse program was used. During acquisition of the data the high- power dipolar decoupling “TPPM” (two-pulse phase-modulated) was applied. The number of scans was 4096, repetition delay was 6.0 s. Taking into account frictional heating of the samples during fast rotation all NMR experiments were performed at 293 K (precise temperature calibration was performed).

[00146] The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation of samples. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Avl/2 was less than 3.5 Hz at 250 ms of acquisition time).

TGA analysis method

Equipment: TA Discovery;

Crucibles: Aluminum, 100 pi;

Heating range: 20 - 200 °C; Heating rate: 10 °C/min; Purging gas: Nitrogen; Purging gas flow: 25 ml/min.

EXAMPLES

Preparation of starting materials

[00147] Zandelisib can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO 2012/135160. Example 1: Preparation of Zandelisib crystal Form Z1

Procedure A

[00148] Isopropyl alcohol (1.2 ml, 10V) was added to Zandelisib (120 mg, 0.2 mmol) to obtain a slurry. The slurry was stirred and heated to 70 °C. Isopropyl alcohol (21.6 ml, 180V) was added to the stirred slurry to obtain clear solution. The solution was mechanically filtrated and allowed to spontaneously cool to room temperature while stirring. The solution was cooled to 4 °C with stirring and after 20 hours precipitation was observed. The solid was isolated by centrifuge. The obtained wet solid was dried in a vacuum oven at 45 °C over a period of 16 hours to afford white solid, which was characterized by X-ray powder diffraction as Zandelisib crystal Form Z1 and the XRPD pattern is presented in Figure 1.

Procedure B

[00149] Dichloromethane (8 ml, 8V) was added to Zandelisib (1 gram, 1.73 mmol) to obtain a slurry. The slurry was stirred at room temperature for 15 minutes to obtain clear solution which was mechanically filtered under filter disk. To the obtained clear filtrate, Isopropyl alcohol as anti-solvent (8 ml, 8V) was added. The solution was stirred at room temperature for 72 hours for precipitation .The solid was isolated by centrifuge and was dried in a vacuum oven at 45 °C over a period of 16 hours to afford white solid, which was analyzed by X-ray powder diffraction and characterized as Zandelisib crystal Form Zl.

Procedure C

[00150] Ethanol (6.8 ml, 170V) was added to Zandelisib (40 mg, 0.07 mmol) to obtain slurry. The slurry was stirred and heated to 75 °C for 30 minutes to obtain a clear solution. Next, the clear solution was cooled to 0°C for 16 hours for precipitation. The precipitate was isolated using centrifuge. The obtained solid was analyzed by X-ray powder diffraction and identified as Zandelisib Form Zl.

Example 2: Preparation of Zandelisib HC1 salt crystalline Form A Procedure A

[00151] Ethanol (15 ml, 15 V) and water (5 ml, 5 V) were added to Zandelisib (1 gram, 1.73 mmol) to obtain a slurry. The slurry was stirred and heated to 60°C. Then, 37% HC1 aqueous solution (1.1 eq, 0.18 ml) was added to the stirred slurry to obtain a clear solution. The solution was stirred at 60°C for 4 hours and then allowed to spontaneously cool to room temperature while stirring. The solution was stirred at room temperature for 18 hours for precipitation. The solid was isolated by centrifuge. The obtained wet solid was dried in a vacuum oven at 45 °C over a period of 16 hours to afford white solid, which was characterized by X-ray powder diffraction as Zandelisib HC1 salt crystal Form A and the XRPD pattern is presented in Figure 2.

Procedure B

[00152] Zandelisib HC1 Form E (100 mg) was suspended in water. Sample partially dissolved. The sample was slurried in water at RT for 3 days. The suspension was filtered and dried under vacuum for 15 minutes. The obtained sample was analyzed by XRPD and identified as Zandelisib HC1 Form A (Figure 2A).

Procedure C

[00153] Ethanol (31.3 ml, 15 V) and water (5 ml, 10.4V) were added to Zandelisib (2.085 gram, 3.63 mmol) to obtain a slurry. The slurry was stirred and heated to 60°C. Then, 37% HC1 aqueous solution (l.leq, 0.38 ml) was added to the stirred slurry to obtain a clear solution. The solution was stirred at 60°C for 4 hours and then allowed to spontaneously cool to room temperature while stirring. The solution was stirred at room temperature for 72 hours for precipitation. The solid was isolated by centrifuge and analyzed by XRPD and confirmed to be Form A.

Example 3: Preparation of amorphous Zandelisib

[00154] Zandelisib (300 mg) was immediately dissolved in tetrahydrofuran (16 mL) at 25°C. The solution was filtered and the filtrate was evaporated (for about 5 minutes) on the rotary vacuum evaporator. The obtained solid was analyzed by X-ray powder diffraction as and the XRPD pattern is presented in Figure 9.

[00155] The obtained amorphous material was stored open at room temperature, relative humidity (“RH”) about 40% for 24 days and was analyzed by X-ray powder diffraction after 3, 7 and 24 days. The XRPD patterns in Figures 10 and 10A show that under these conditions the amorphous Zandelisib was partially converted to a crystalline form already after 3 days.

Example 4: Preparation of Form E of Zandelisib HC1 Procedure A

[00156] Zandelisib (100 mg) was suspended in tetrahydrofuran (1 mL). The suspension was heated to 60 °C during a period of about 30 minutes. The sample did not dissolve. The hydrochloric acid (1.1 eq, 16.8 mΐ) was added at 60 °C and sample dissolved. The clear solution was stirred at 60 °C for 15 minutes and cooled down to 0°C over a period of about 90 minutes. The sample crystallized at the temperature lower than 10 °C. Then, the suspension was stirred for about 2 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The obtained solid material was analyzed by X-ray powder diffraction and identified as Form E.

Procedure B

[00157] Zandelisib (100 mg) was suspended in ethanol (1.5 mL) and water (0.5 mL). The suspension was heated to 60 °C over a period of about 30 minutes. The sample did not dissolve. The 35 % hydrochloric acid (1.1 eq, 16.8 mΐ) was added at 60 °C and sample dissolved. The clear solution was stirred at 60 °C for 15 minutes and cooled down to 0°C over a period of about 90 minutes. The sample crystallized at the temperature lower than 10 °C. Then, the suspension was stirred for about 2 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The obtained solid material was analyzed by X-ray powder diffraction and identified as Zandelisib HC1 Form E.

Procedure C

[00158] Zandelisib HC1 Form D (100 mg) was suspended in water. Sample partially dissolved. The sample was slurried in water at RT for 3 days. The suspension was filtered and dried under vacuum for 15 minutes. The obtained sample was analyzed by XRPD and identified as Zandelisib HC1 Form E.

Example 5: Preparation of Form B of Zandelisib HC1 Procedure A

[00159] Zandelisib (500 mg) was suspended in diisopropyl ether (3 mL) and 1.9 M hydrochloric acid solution in diisopropyl ether (1.1 eq HC1, 0.526 mL). The suspension was stirred at 25 °C for 24 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The obtained solid matter was analyzed by X-ray powder diffraction and the XRPD pattern is presented in Figure 4.

Procedure B

[00160] Zandelisib (1000 mg) was suspended in diisopropyl ether (3 mL) and 1.9 M hydrochloric acid solution in diisopropyl ether (1.1 eq HC1, 1.052 mL). The suspension was stirred at 25 °C for 24 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The solid matter was analyzed by X-ray powder diffraction and identified as Form B of Zandelisib HC1. Procedure C

[00161] Zandelisib Form Z1 (500 mg) was suspended in diisopropyl ether (3 mL) and 1.9 M solution of HC1 in diisopropyl ether (1.1 eq HC1, 0.526 mL). The suspension was stirred at 25 °C for 24 hours. The solid was filtered and dried under the vacuum for 15 minutes.

Example 6: Preparation of Form C of Zandelisib HC1 Procedure A

[00162] Zandelisib hydrochloride Form E (300 mg, obtained according to example 4) was suspended in ethylacetate (6 mL). The suspension was heated to 60 °C during a period of about 30 minutes. The suspension was stirred at 60 °C for 3.5 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The solid matter was analyzed by X-ray powder diffraction as and the XRPD pattern is presented in Figure 5.

Procedure B

[00163] Zandelisib hydrochloride Form E (1.2 grams, obtained according to example 4) was suspended in ethylacetate (24 mL). The suspension was heated to 60 °C during a period of about 30 minutes. The suspension was stirred at 60 °C for 3.5 hours. Then the sample was filtered and dried under the vacuum for 30 minutes. The solid matter was analyzed by X-ray powder diffraction and identified as Form C of Zandelisib HC1.

Procedure C

[00164] Zandelisib hydrochloride Form C was obtained by heating (heating rate 10 “Cmin ¹ ) of the Form D (16 mg) to 200 °C, during TGA heating.

Example 7: Preparation of Form D of Zandelisib HC1 Procedure A

[00165] Zandelisib hydrochloride Form E (150 mg, obtained according to example 4) was suspended in isopropanol (2 mL). The suspension was cooled down to 0 °C and stirred for 4 hours. Then the sample was filtered and dried under the vacuum for 15 minutes. The solid matter was analyzed by X-ray powder diffraction as and the XRPD pattern is presented in Figure 6.

Procedure B

[00166] Zandelisib hydrochloride Form E (100 mg, obtained according to example 4) was suspended in isopropanol (2 mL). The suspension was stirred at 40 °C for 4 days. Then the sample was filtered and dried under the vacuum for 15 minutes. The solid matter was analyzed by X-ray powder diffraction and identified as Form D of Zandelisib HC1. Procedure C

[00167] Zandelisib hydrochloride Form E (1.1 grams, obtained according to example 4) was suspended in isopropanol (30 mL). The suspension was heated to 70 °C during a period of about 10 minutes. The suspension was stirred at 70 °C for about 2.5 hours. Then, the suspension was cooled down to 25 °C within a period of 15 minutes. The sample was filtered and dried under the vacuum for 15 minutes. The solid matter was analyzed by X-ray powder diffraction and identified as Form D of Zandelisib HC1.

Example 8: Preparation of amorphous Zandelisib HC1 Procedure A

[00168] Zandelisib Hydrochloride Form E (100 mg, obtained according to example 4) was immediately dissolved in methanol (10 mL) at 25°C. Solution was filtered. The amorphous sample was prepared by fast evaporation (about 5 minutes) of the solvent on the rotary vacuum evaporator. The solid material was analyzed by XRPD and the pattern obtained is presented in Figure 7.

Procedure B

[00169] Zandelisib Hydrochloride Form E (300 mg, obtained according to example 4) was immediately dissolved in tetrahydrofuran (12 mL) at 25°C. Solution was filtered. The amorphous sample was prepared by fast evaporation (about 5 minutes) of the solvent on the rotary vacuum evaporator.

Example 9: Preparation of Form A of Zandelisib HBr

[00170] Zandelisib (0.5 grams) was suspended in ethanol (7.5 mL) and water (2.5 mL). The suspension was heated to 60 °C during the period of about 30 minutes. The 48 % hydrobromic acid (1.1 eq, 108 uL) was added at 60 °C The Zandelisib dissolved. The clear solution was stirred at 60 °C for 30 minutes. The solution was cooled down to 0 °C within the period of about 90 minutes. The sample crystallized at 5 °C. The suspension was stirred at 0 °C for 2 hours.

Then, the sample was filtrated and dried under vacuum for 15 minutes. The solid matter was analyzed by XRPD and the pattern obtained is presented in Figure 8.