Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application Nos. 62/081, 1 19, filed November 18, 2014; 62/096, 127, filed December 23, 2014; and 62/138,061, filed March 25, 2015; the entireties of which are incorporated by reference herein.

Field of the Disclosure

[0002] The present disclosure relates to solid state forms of Ceritinib and of Ceritinib salts, in particular of Ceritinib dihydrochloride, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

Background of the Disclosure

[0003] Ceritinib has the chemical name 5-Chloro-N2-(2-isopropoxy-5-methyl-4- (piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyri midine-2,4-diamine. Ceritinib has the following chemical structure:

[0004] Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor being developed by Novartis for the treatment of tumors characterized by genetic abnormalities in ALK and is marketed as ZYKADIA by Novartis for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib.

[0005] Ceritinib is known from US 8,039,479 (US'479). Ceritinib dihydrochloride and crystalline forms of Ceritinib (A and B) as well as the preparation of the crystalline forms from Ceritinib di-HCl are described in WO2012/082972.

[0006] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Ceritinib, 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 powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman 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.

[0007] 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, improving the dissolution profile, 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 provide 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 use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0008] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide 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 salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Ceritinib and salts thereof. Summary of the Disclosure

[0009] The present disclosure relates to solid state forms of Ceritinib and of Ceritinib salts including Ceritinib dihydrochloride, to processes for preparation thereof, and to pharmaceutical compositions comprising these solid state forms.

[0010] The present disclosure also relates to the use of any one of the solid state forms of Ceritinib or Ceritinib salts of the present disclosure, for preparing other solid state forms of Ceritinib, or other Ceritinib salts and solid state forms thereof.

[0011] In another aspect, the present disclosure encompasses any one of the above described solid state forms of Ceritinib and Ceritinib salts and/or combinations thereof for use in the preparation of pharmaceutical compositions and/or formulations for use in medicine, preferably for the treatment of cancer, in particular, the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib.

[0012] The present disclosure also encompasses the use of any one of the above described solid state forms of Ceritinib and Ceritinib salts and/or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.

[0013] The present disclosure further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Ceritinib or Ceritinib salts according to the present disclosure.

[0014] In yet another embodiment, the present disclosure encompasses

pharmaceutical formulations comprising any one of the above described solid state forms of Ceritinib or Ceritinib salts and /or combinations thereof, or of pharmaceutical compositions comprising the solid state forms of Ceritinib or Ceritinib salts, and at least one

pharmaceutically acceptable excipient.

[0015] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Ceritinib or Ceritinib salt comprising combining any one of the above solid state forms of Ceritinib or Ceritinib salt and /or combinations thereof, or pharmaceutical compositions comprising them, and at least one pharmaceutically acceptable excipient.

[0016] Any of the solid state forms as defined herein and/or combinations thereof as well as the pharmaceutical compositions or formulations of the solid state forms of Ceritinib or Ceritinib salts can be used as medicaments, particularly for the treatment of cancer, preferably for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib.

[0017] The present disclosure also provides a method of treating cancer; for example, the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib, comprising administering a therapeutically effective amount of any one of the solid state forms of Ceritinib or Ceritinib salt of the present disclosure and /or combinations thereof, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cancer, or otherwise in need of the treatment.

[0018] The present disclosure also provides the use of any one of the solid state forms of Ceritinib or Ceritinib salt of the present disclosure and /or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating cancer, in particular, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib.

Brief Description of the Figures

[0019] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Ceritinib Form Beta.

[0020] Figure 2 shows a DSC thermogram of Ceritinib Form Beta.

[0021] Figure 2a shows a DSC thermogram of Ceritinib Form Beta, highly crystalline.

[0022] Figure 3 shows an FT-IR spectrum of Ceritinib Form Beta.

[0023] Figure 4 shows an XRPD pattern of amorphous Ceritinib.

[0024] Figure 5 shows an XRPD pattern of Ceritinib Form Gamma.

[0025] Figure 6 shows an XRPD pattern of solid dispersion of Ceritinib with hydroxypropylcellulose 1 :2 by weight.

[0026] Figure 7 shows an XRPD pattern of solid dispersion of Ceritinib with hydroxypropylcellulose 1 :2 by weight.

[0027] Figure 8 shows an XRPD pattern of solid dispersion of Ceritinib with hydroxypropylcellulose 1 : 1 by weight.

[0028] Figure 9 shows an XRPD pattern of Ceritinib dihydrochloride Form I.

[0029] Figure 10 shows an XRPD pattern of Ceritinib dihydrochloride Form II.

[0030] Figure 1 1 shows an XRPD pattern of Ceritinib dihydrochloride Form III.

[0031] Figure 12 shows an XRPD pattern of Ceritinib dihydrochloride Form IV. [0032] Figure 13 shows an XRPD pattern of Ceritinib sodium Form I.

[0033] Figure 14 shows an XRPD pattern of Ceritinib sodium Form II.

[0034] Figure 15 shows an XRPD pattern of Ceritinib dihydrochloride Form V.

[0035] Figure 16 shows an XRPD pattern of Ceritinib hydrochloride Form I.

[0036] Figure 17 shows an FT-IR spectrum of Ceritinib dihydrochloride Form III.

[0037] Figure 18 shows solid state ¹³ C NMR spectrum of Ceritinib Form Beta.

[0038] Figure 19 shows an FT-Raman spectrum of Ceritinib Form Beta

[0039] Figure 20 shows a SEM image of Ceritinib dihydrochloride Form III, at 50x magnification.

[0040] Figure 21 shows a SEM image of Ceritinib dihydrochloride prepared according to example 7 of US'479, at 5000x magnification.

Detailed Description of the Disclosure

[0041] The present disclosure relates to solid state forms of Ceritinib and Ceritinib salts, such as Ceritinib dihydrochloride, to processes for preparation thereof and to pharmaceutical compositions comprising at least one of, or a combination of, these solid state forms. The disclosure also relates to the conversion of Ceritinib or the Ceritinib salts of the present disclosure and its solid state forms to other solid state forms of Ceritinib, other Ceritinib salts and solid state forms thereof.

[0042] The Ceritinib and Ceritinib salts and solid state forms thereof according to the present disclosure may have advantageous properties selected from at least one of:

chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, 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, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density.

[0043] A crystal form may be referred to herein as being characterized by graphical data "as 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 can not 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 factors such as 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 Ceritinib or Ceritinib salt, e.g., of Ceritinib dihydrochloride referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of the Ceritinib or the Ceritinib salt, e.g., the Ceritinib dihydrochloride, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0044] 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 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less of any other forms of the subject compound as measured, for example, by XRPD. Thus, solid state of Ceritinib or Ceritinib salt described herein as substantially free of any other solid state forms would be understood to contain greater than 80% (w/w), greater than 90% (w/w), greater than 95% (w/w), greater than 98% (w/w), or greater than 99% (w/w) of the subject solid state form of Ceritinib or Ceritinib salt.

Accordingly, in some embodiments of the disclosure, the described solid state forms of Ceritinib or Ceritinib salt may contain from 1% to 20% (w/w), from 5% to 20% (w/w), or from 5% to 10% (w/w) of one or more other solid state forms of the same Ceritinib or Ceritinib salt.

[0045] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuK _α radiation, λ = 1.5418A.

[0046] As used herein, the term "isolated" in reference to solid state forms of

Ceritinib or Ceritinib salts of the present disclosure corresponds to solid state form of Ceritinib or Ceritinib salt that is physically separated from the reaction mixture in which it is formed.

[0047] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "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. [0048] 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, typically about 16 hours.

[0049] As used herein, the expression "wet crystalline form" refers to a polymorph that was not dried using any conventional techniques to remove residual solvent. Examples for such conventional techniques can be, but not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, and the like.

[0050] As used herein, the expression "dry crystalline form" refers to a polymorph that was dried using any conventional techniques to remove residual solvent. Examples of such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, and the like.

[0051] As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline Ceritinib or Ceritinib salt relates to crystalline Ceritinib or Ceritinib salt which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an "anhydrous" form does not contain more than 1% (w/w) of either water or organic solvents as measured for example by TGA.

[0052] 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.

[0053] The amount of solvent employed in a chemical process, e.g., a reaction or a 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 MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0054] As used herein the term non-hygroscopic in relation to crystalline Ceritinib or Ceritinib salt refers to less than 0.2% (w/w) absorption of water at 25°C and 80% RH, by the crystalline Ceritinib as determined for example by TGA. Water can be for example atmospheric water.

[0055] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 50 mbar.

[0056] As used herein, and unless indicated otherwise, the term "thermo-dynamical stability" in relation to solid state forms of Ceritinib refers to resistance of the solid state form to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than 20%, 10%, 5%, 1%, or 0.5% (w/w) conversion of crystalline Ceritinib to any other solid state form of Ceritinib as measured by XRPD. In some embodiments, the conversion is l%-20%, 1%-10% or l%-5% (w/w).

[0057] As used herein Form A of Ceritinib exhibits X-ray powder diffraction peaks having maxima at diffraction angles (2.theta.degrees) at 7.2. degree, 8.1. degree, 10.8. degree, 12.0. degree, 12.4. degree, 13.4. degree, 14.4.degree, 14.8. degree, 15.7. degree, 16.9. degree, 17.7. degree, 18.5. degree, 19.0. degree, 19.5. degree, 20.0.degree, 20.3. degree, 21.1. degree, 21.6. degree, 22.4. degree, 22.6. degree, 23.0.degree, 24.1. degree, 24.5. degree, 25.5. degree, 26.0. degree, 26.2. degree, 27.0. degree, 27.3. degree, 28.3. degree, 29.0.degree, 29.1. degree,

30.6. degree, 31.3. degree, 32.8. degree, 33.5. degree, 34.2. degree, and 36.4.degree.

[0058] As used herein Form B of Ceritinib exhibits X-ray powder diffraction peaks having maxima at diffraction angles (2.theta. degrees) at 5.1. degree., 5.5. degree., 5.6. degree., 9.5. degree., 9.6.degree., 10.1. degree., 11.0. degree., 1 1.8. degree., 12.1. degree., 12.6. degree.,

13.7. degree., 14.5. degree., 14.9. degree., 15.2. degree., 16.1. degree., 16.6. degree., 16.7. degree.,

17.0. degree., 17.1. degree., 17.5. degree., 17.7. degree., 18.0.degree., 18.8. degree., 19.0. degree., 19.3. degree., 19.5. degree., 20.5. degree., 20.9. degree., 21.5. degree., 21.9. degree., 22.1. degree., 22.4. degree., 22.8. degree., 23.2. degree., 23.7. degree., 23.9. degree., 24.3. degree., 24.5. degree.,

24.8. degree., 25.1. degree., 25.4.degree., 25.9. degree., 26.4.degree., 26.8. degree., 27.8. degree.,

28.1. degree., 28.6.degree., 29.1. degree., 29.6. degree., 29.8. degree., 30.6. degree., 31.6. degree., 32.7. degree., 33.5. degree., 34.2. degree., 35.4. degree., 35.6.degree. and 36.8. degree.

[0059] The present disclosure comprises a crystalline form of Ceritinib designated as Form Beta. The crystalline Form Beta of Ceritinib can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 12.3, 15.6, 18.1, 20.0, and 28.8 degrees 2 theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 1 ; ¹³ C NMR spectrum having peaks at 142.9, 137.5, 132.1, 33.8, and 18.7 ± 0.2 ppm; a solid state ¹³ C NMR spectrum having chemical shift differences between said characteristic peaks at 142.9, 137.5, 132.1, 33.8, and 18.7 ± 0.2 ppm and a reference peak at 125.7 ± 0.2 ppm of 17.2, 1 1.8, 6.4, -91.9 and -107.0 ± 0.1 ppm, respectively; a solid state ¹³ C NMR spectrum substantially as depicted in Figure 18; and combinations of these data.

[0060] Crystalline Form Beta of Ceritinib may be further characterized by an XRPD pattern having peaks at 12.3, 15.6, 18.1, 20.0, and 28.8 degrees two theta ± 0.2 degrees two theta; and also by the absence of one, two, three, four or five peaks selected from 5.5, 11.0, 16.6, 18.8, and 23.9 ± 0.2 degrees two-theta.

[0061] Crystalline Form Beta of Ceritinib may be further characterized by the XRPD pattern having peaks at 12.3, 15.6, 18.1, 20.0, and 28.8 degrees two theta ± 0.2 degrees two theta, and also having one, two, three or four additional peaks selected from 5.1, 12.7, 17.1, and 19.2 degrees two theta ± 0.2 degrees two theta; a DSC thermogram as depicted in Figure 2 or Figure 2A; an FTIR spectrum having one, two, three, four, five, six or seven peaks selected from 2798, 1541, 1465, 1066, 885, 771, and 505 ± 4 cm ^"1 ; an FTIR spectrum substantially as depicted in Figure 3; Raman peaks at 2797, 2730, 1482, 1223, 1 118 and 835 ± 4 cm ^"1 ; an FT- Raman spectrum substantially as depicted in Figure 19; and combinations of these data.

[0062] Crystalline Form Beta of Ceritinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at 12.3, 15.6, 18.1, 20.0, and 28.8 degrees two theta ± 0.2 degrees two theta and a DSC thermogram as depicted in Figure 2 or Figure 2A.

[0063] Crystalline Form Beta of Ceritinib may be an anhydrous form. Water and/or organic solvent content may be measured by any suitable method such as TGA, KF.

Preferably Form Beta may be characterized by a water content of below 0.3 wt%, or below 0.2 wt%, or below 0.1 wt% by Karl Fischer (KF).

[0064] Crystalline Form Beta of Ceritinib may be provided in a substantially pure form with no more than about 10% of any other form of Ceritinib present, preferably with no more than about 5% of any other form of Ceritinib as measured by XRPD. Preferably, crystalline Form Beta of Ceritinib may be provided in a relatively pure form with no more than about 10% of Ceritinib Form Gamma and/or of Ceritinib Form A, preferably with no more than about 5% of Ceritinib Form Gamma and/or of Form A as measured by XRPD.

[0065] Crystalline Ceritinib Form Beta is preferably polymorphically pure i.e., it is substantially free of any other forms, as described herein above. Particularly, it is substantially free of crystalline Ceritinib Form Gamma. Accordingly, the content of crystalline Ceritinib Form Gamma in crystalline Ceritinib Form Beta will be measured by detecting the described characteristic peaks of Form Gamma (or their absence in Form Beta). The characteristic peaks of crystalline Ceritinib Form Gamma used for the above described measurement can be selected from the following list of peaks at about: 11.8, 12.1, 16.1, 16.6, and 25.1 degrees two theta ± 0.2 degrees two theta.

[0066] In another embodiment Form Beta is substantially free of crystalline

Ceritinib Form A. Accordingly, the content of crystalline Ceritinib Form A in crystalline Ceritinib Form Beta will be measured by detecting the characteristic peaks of Form A (or their absence in Form Beta). The characteristic peaks of crystalline Ceritinib Form A used for the above described measurement can be selected from the following list of peaks at about: 7.2, 8.1, 10.8, and 13.4 degrees two theta ± 0.2 degrees two theta.

[0067] Depending on which other solid state form it is compared with, Form Beta of Ceritinib may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, wettability, dissolution rate, bioavailability, 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, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, or bulk density. Particularly, crystalline Form Beta of Ceritinib of the present disclosure has advantageous wettability compared to Form A. Wetting or wettability is the ability of a liquid to maintain contact with a solid surface. The solid surface can be active pharmaceutical ingredient (API). Many APIs, such as Ceritinib, exhibit low wettability due to their hydrophobic nature of the surface of the crystal, which may be overcome by developing new polymorphs with improved wettability properties. Polymorphs with enhanced wettability, such as Form Beta of the present disclosure, are advantageous during all formulation processes containing moisture e.g., wet granulation processes. In addition enhanced wettability ensure proper solubility measurement of the APIs per se and in formulation during dissolution studies, which are important in the pharmaceutical research and development.

[0068] Wettability of Ceritinib crystalline Form Beta and Form A were assessed by Washburn method (as describes for example in M. Lazghab et al, Powder Technology 157 (2005) 79-91 or in Y. Yuan, T. R. Lee, Contact Angle and Wetting Properties in G. Bracco, B. Hoist, Surface Science Techniques, Springer, 2013) using hexane for determination of the packing constant and water as the desired wetting agent . Obtained contact angles are presented in the table below: Ceritinib crystalline form Contact angle for water as determined

by the Washburn method

Form A 80.2°

Form Beta 67.4°

Significantly lower contact angle of Form Beta indicates higher wettability.

[0069] The present disclosure also comprises a crystalline form of Ceritinib designated as Form Gamma. The crystalline Form Gamma of Ceritinib can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.5, 12.5, 16.1, 16.5, and 18.7 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 5; and combinations of these data.

[0070] Crystalline Form Gamma of Ceritinib may be further characterized by the XRPD pattern having peaks at 5.5, 12.5, 16.1, 16.5, and 18.7 degrees two theta ± 0.2 degrees two theta, and also having one, two, three, four or five additional peaks selected from 9.4, 12.0, 17.5, 23.8, and 25.1 degrees two theta ± 0.2 degrees two theta; and combinations of these data.

[0071] Crystalline Form Gamma of Ceritinib may be further characterized by the XRPD pattern having peaks at 5.5, 12.5, 16.1, 16.5, and 18.7 degrees two theta ± 0.2 degrees two theta; and also by the absence of one, two or three peaks selected from 10.1, 13.7, and 18.1 ± 0.2 degrees two-theta.

[0072] Crystalline Form Gamma of Ceritinib may be an anhydrous form. Water and/or organic solvent content may be measured by any suitable method such as TGA, KF. Preferably Form Gamma may be characterized by a water content of below 0.3 wt%, or below 0.2 wt%, or below 0.1 wt% by Karl Fischer (KF).

[0073] Crystalline Form Gamma of Ceritinib may be provided in a substantially pure form with no more than about 10% of any other form of Ceritinib present, preferably with no more than about 5% of any other form of Ceritinib as measured by XRPD. Preferably, crystalline Form Gamma of Ceritinib may be provided in a relatively pure form with no more than about 10% of Ceritinib Form Beta, preferably with no more than about 5% of Ceritinib Form Beta as measured by XRPD.

[0074] Crystalline Ceritinib Form Gamma is preferably polymorphically pure i.e., it is substantially free of any other forms, as described herein above. Particularly, it is substantially free of crystalline Ceritinib Form Beta. Accordingly, the content of crystalline Ceritinib Form Beta in crystalline Ceritinib Form Gamma will be measured by detecting the described characteristic peaks of Form Beta (or their absence in form Gamma). The characteristic peaks of crystalline Ceritinib form Beta used for the above described measurement can be selected from the following list of peaks at: 10.1, 13.7, and 18.1 degrees two theta ± 0.2 degrees two theta.

[0075] The present disclosure also describes an amorphous form of Ceritinib. The amorphous form of Ceritinib may be characterized by a XRPD pattern substantially as depicted in Figure 4. The present disclosure also describes a solid dispersion of an amorphous form of Ceritinib with Hydroxypropyl cellulose (HPC). The solid dispersion of Ceritinib with hydroxypropylcellulose may be in a ratio of about 1 : 1 to about 1 :2 by weight.

[0076] The present disclosure further encompasses solid state forms of Ceritinib salts, in particular crystalline forms of Ceritinib dihydrochloride, Ceritinib hydrochloride and Ceritinib sodium.

[0077] The present disclosure comprises a crystalline form of Ceritinib

dihydrochloride designated as Form I. The crystalline Form I of Ceritinib dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.2, 8.1, 8.7, 12.1, and 20.8 degrees two theta ± 0.2 degrees two theta; a XRPD pattern substantially as depicted in Figure 9; and combinations of these data.

[0078] Crystalline Form I of Ceritinib dihydrochloride may be further characterized by the XRPD pattern having peaks at 5.2, 8.1, 8.7, 12.1, and 20.8 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 9.6, 12.7, 18.2, 20.0, and 26.5 degrees two theta ± 0.2 degrees two theta.

[0079] The present disclosure further comprises a crystalline form of Ceritinib dihydrochloride designated as Form II. The crystalline Form II of Ceritinib dihydrochloride can be characterized by data selected from one or more of the following: a XRPD pattern having peaks at 8.3, 14.5, 15.9, 19.4, and 20.9 degrees two theta ± 0.2 degrees two theta; a XRPD pattern substantially as depicted in Figure 10; and combinations of these data.

[0080] Crystalline Form II of Ceritinib dihydrochloride may be further

characterized by the XRPD pattern having peaks at 8.3, 14.5, 15.9, 19.4, and 20.9 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 9.8, 1 1.6, 16.5, 18.4, and 20.2 degrees two theta ± 0.2 degrees two theta.

[0081] The present disclosure comprises a crystalline form of Ceritinib

dihydrochloride designated as Form III. The crystalline Form III of Ceritinib dihydrochloride can be characterized by data selected from one or more of the following: a XRPD pattern having peaks at 7.4, 1 1.0, 12.7, 12.9, and 17.6 degrees two theta ± 0.2 degrees two theta; a XRPD pattern substantially as depicted in figure 1 1 ; and combinations of these data.

[0082] Crystalline Form III of Ceritinib dihydrochloride may be further characterized by the XRPD pattern having peaks at 7.4, 1 1.0, 12.7, 12.9, and 17.6 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 15.3, 15.8, 17.2, 19.2, and 21.6 degrees two theta ± 0.2 degrees two theta; an FTIR spectrum substantially as depicted in Figure 17; and combinations of these data.

[0083] Depending on which other solid state form it is compared with, Form III of Ceritinib dihydrochloride may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, 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, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, or bulk density. Particularly, crystalline Form III of Ceritinib

dihydrochloride of the present disclosure has higher crystallinity, compared for example, to Ceritinib dihydrochloride prepared according to example 7 of US 8,039,479 (form of US'479), which results in large crystals (hexagonal plate shaped) as can be seen in Figure 20. The form of US'479 on the other hand exhibits very small poorly defined particles which tend to form hard agglomerates, which are very hard to dry (See, e.g., Figure 21).

As is well known powder properties are greatly affected by the material's particle shape and size.

[0084] The large particle size (and hexagonal plate shape) of Form III of Ceritinib dihydrochloride decreases adhesive tendencies. Therefore, weighing and dispensing due to less electrostaticity is easier and better flowability and filterability are obtained. Powder properties such as powder flowability, cohesiveness or filterability are very important technological properties which influence successful material isolation, drying, blending, granulation, compaction, and the like.

[0085] The present disclosure describes a crystalline form of Ceritinib

dihydrochloride designated as Form IV. The crystalline Form IV of Ceritinib

dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 10.5, 12.1, 13.7, 18.2, and 22.2 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 12; and combinations of these data.

[0086] Crystalline Form IV of Ceritinib dihydrochloride may be further characterized by the XRPD pattern having peaks at 10.5, 12.1, 13.7, 18.2, and 22.2 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 6.1, 8.1, 14.7, 16.1, and 21.1 degrees two theta ± 0.2 degrees two theta.

[0087] The present disclosure further describes a crystalline form of Ceritinib dihydrochloride designated as Form V. The crystalline Form V of Ceritinib dihydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 8.2, 1 1.1, 12.5, 16.3, and 22.0 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 15; and combinations of these data.

[0088] Crystalline Form V of Ceritinib dihydrochloride may be further

characterized by the XRPD pattern having peaks at 8.2, 1 1.1, 12.5, 16.3, and 22.0 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 5.6, 10.4, 15.6, 18.8, and 20.9 degrees two theta ± 0.2 degrees two theta.

[0089] The present disclosure further describes a Ceritinib (mono-)hydrochloride salt. The Ceritinib hydrochloride salt may be in a crystalline form.

[0090] The present disclosure also describes a crystalline form of Ceritinib hydrochloride salt designated as Form I. The crystalline Form I of Ceritinib hydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.1, 10.4, 15.0, 16.6 and 23.3 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 16; and combinations of these data.

Crystalline Form I of Ceritinib hydrochloride salt may be further characterized by the XRPD pattern having peaks at 5.1, 10.4, 15.0, 16.6, and 23.3 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 15.7, 16.1, 20.8, 24.7, and 28.1 degrees two theta ± 0.2 degrees two theta.

[0091] In another aspect, the present disclosure further comprises a Ceritinib sodium salt. The Ceritinib sodium salt may be in a crystalline form.

[0092] The present disclosure further comprises a crystalline form of Ceritinib sodium salt designated as Form I. The crystalline Form I of Ceritinib sodium can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 6.5, 7.1, 10.1, 11.6, and 18.7 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 13; and combinations of these data. Crystalline Form I of Ceritinib sodium salt may be further characterized by the XRPD pattern having peaks at 6.5, 7.1, 10.1, 11.6 and 18.7 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 9.3, 9.8, 14.6, 19.5, and 19.7 degrees two theta ± 0.2 degrees two theta.

[0093] The present disclosure also comprises a crystalline form of Ceritinib sodium salt designated as Form II. The crystalline Form II of Ceritinib sodium can be characterized by data selected from one or more of the following: an XRPD pattern, having peaks at 6.4, 7.4, 10.7, 12.7, and 19.3 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 14; and combinations of these data. Crystalline Form II of Ceritinib sodium salt may be further characterized by the XRPD pattern having peaks at 6.4, 7.4, 10.7, 12.7, and 19.3 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 8.8, 10.3, 14.4, 14.9 and 23.2 degrees two theta ± 0.2 degrees two theta.

[0094] The present disclosure also provides the use of any one of the solid state forms of Ceritinib and of Ceritinib salts, specifically of Form Beta of Ceritinib or of Form III of Ceritinib dihydrochloride for preparing other solid state forms of Ceritinib, Ceritinib salts and solid state forms thereof.

[0095] The present disclosure further encompasses processes for preparing Ceritinib or solid state forms thereof, such as those described herein. The process for preparing Ceritinib or solid state forms thereof comprises preparing any one of the Ceritinib dihydrochloride, Ceritinib hydrochloride or Ceritinib sodium solid state forms, preferably, Form III of Ceritinib dihydrochloride, according to the present disclosure, and converting it to Ceritinib or solid state forms thereof. The conversion can be done, for example, by reacting any of the solid state forms of Ceritinib dihydrochloride or Ceritinib hydrochloride described herein with a suitable base or any one of the solid state forms of Ceritinib sodium described herein with a suitable acid, to obtain Ceritinib.

[0096] The present disclosure further encompasses a process for preparing Ceritinib salts or solid state forms thereof. The process comprises preparing any one of the solid state forms of Ceritinib of the present disclosure or preparing Ceritinib according to the above procedure, and converting it to a Ceritinib salt. The conversion can be done, for example, by a process comprising reacting the obtained Ceritinib with an appropriate acid or a base to obtain the corresponding acid addition or base addition salt. Alternatively, the Ceritinib salt can be prepared by salt switching, i.e., reacting Ceritinib dihydrochloride, Ceritinib hydrochloride or any of the solid state forms thereof, with an acid having a pK _a which is lower than the pK _a of dihydrochloride or reacting Ceritinib sodium or any of the solid state forms thereof, with a base having a pK _a which is higher than the pK _a of NaOH.

[0097] In another embodiment the present disclosure encompasses the use of any one of the above described solid state forms of Ceritinib, Ceritinib salts and/or combinations thereof for the preparation of pharmaceutical compositions and/or formulations.

[0098] The present disclosure further provides pharmaceutical compositions comprising any one of or a mixture of the solid state forms of Ceritinib or Ceritinib salts according to the present disclosure.

[0099] In yet another embodiment, the present disclosure encompasses

pharmaceutical formulations comprising any one of the above described solid state forms of Ceritinib, Ceritinib salts and/or combinations thereof or a pharmaceutical composition as described in the preceding paragraph, and at least one pharmaceutically acceptable excipient.

[00100] The present disclosure moreover encompasses a process to prepare said formulations of Ceritinib or Ceritinib salt comprising combining any one of the above solid state forms and/or combinations thereof and at least one pharmaceutically acceptable excipient.

[00101] In another embodiment, the present invention encompasses any one of the above described solid state forms of Ceritinib, Ceritinib salts and/or combinations thereof for use in medicine, preferably for the treatment of cancer, for example, the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib..

[00102] The present disclosure also provides a method of treating cancer, in particular lung cancer, for example, the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib, comprising administering a therapeutically effective amount of any one of the solid state forms of Ceritinib or Ceritinib salts of the present disclosure and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cancer, or otherwise in need of the treatment.

[00103] The present disclosure also provides the use of any one of the solid state forms of Ceritinib or Ceritinib salts of the present disclosure and/or combinations thereof, or at least one of the above pharmaceutical compositions or formulations for the manufacture of a medicament for treating cancer, in particular lung cancer, for example, the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), who have progressed on or are intolerant to Crizotinib. [00104] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.

Analytical Methods

X-ray Powder diffraction pattern ("XRPD") method:

[00105] The sample after being powdered in a mortar and pestle is applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with a Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom), and an X'Celerator (2.022° 2Θ) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan. The described peak positions were determined using silicon powder as an internal standard in an admixture with the sample measured.

DSC method

[00106] DSC analysis was performed on a Q 1000 MDSC (TA instruments) with heating rate of 10 °C/min, under nitrogen flow of 50 ml/min. A hermetic aluminium, closed pan with hole was used, and the sample mass was about 1-5 mg.

FTIR method

[00107] FTIR spectra were recorded on a Nicolet 6700 interferometer between 4000 cm ^"1 and 370 cm ^"1 with resolution of 4 cm ^"1 , in KBr technique.

Solid state NMR

[00108] Solid-state ¹³ C NMR spectra were recorded with variable amplitude cross polarization, magic angle spinning and high power proton decoupling using a BRUKER Avance 11+ spectrometer operating at 125MHz and ambient temperature (about 25°C - not controlled). A probe using 4mm o.d. zirconia rotors was employed. The operation conditions were: contact time: 2ms; recycle delay: 2s 1024 scans; spin rate of 11kHz. Chemical shifts were referenced via a reference sample of glycine (carboxyl carbon chemical shift assigned as 176.03 ppm relative to the signal of tetramethylsilane).

FT-Raman spectroscopy

[00109] Raman spectra were acquired on a Nicolet 6700 interferometer, equipped with an NXR FT-Raman modul. A Nd-YAG laser (1064 nm, 500 mW) was used to excite the sample. The spectrometer utilizes a CaF ₂ beamsplitter and a liquid nitrogen cooled Ge detector. The spectra were recorded at a resolution of 4 cm ^"1 .

Scanning Electron Microscopy (SEM) method

[00110] The images were obtained using Jeol JSM-5800 scanning microscope, sputtered with gold by Edwards SI 50 sputter coater

Wettability

[00111] Contact angle was determined using DataPhysics DCAT 1 1 Tensiometer by Washburn method (capillary rise). The experiments were performed using water as the wetting agent, in triplicates at 25°C. Packing constant was determined using hexane as the wetting agent, in triplicates at 25°C.

Examples

[00112] The starting materials 2-isopropoxy-5-mehyl-4-(piperdin-4-yl)aniline dihydrochloride and 2,5-dichloro-N-(2-(isopropyl sulfonyl) phenyl)pyrimidin-4-amine were commercially available.

Preparation of Ceritinib Form A

[00113] Form A of Ceritinib may be prepared according to the process described in Example 1 of WO2012/082972. Alternatively, Form A of Ceritinib may be prepared according to the following process:

[00114] Ceritinib dihydrochloride salt (34.0 g) was dissolved in acetone (102 mL) and water (34 mL) mixture by stirring at room temperature. The obtained solution was heated to 50-55°C and 10% solution of NaOH was added drop-wise during 20-25 minutes until pH 12.0 value was reached (40 mL of 10% NaOH was added). A suspension was obtained and stirring at 55°C was continued for additional 1 hour. Then, 170 mL of water was added drop- wise into the suspension while maintaining the temperature at 55 °C. The suspension was then cooled to room temperature and was additionally stirred for 1 hour. The solid product was filtered, washed with water (2x124 mL) and vacuum dried at 50-55°C for 6 hours. 27.2 g of Ceritinib form A was obtained. Example 1; Preparation of Ceritinib Form Beta

[00115] In a 3 -neck round bottom flask (100 mL) equipped with an thermometer, magnetic stirrer and reflux condenser Ceritinib dihydrochloride salt (2.0 g, 3.17 mmol) was dissolved in water (20 mL) and heated at 42°C. At a temperature of 42°C, 30 mL of 1% NaOH solution was added drop wise until pH 12.0 was reached. An off-white slurry was obtained and stirring at 42°C was continued for additional 6 hours. Then, the suspension was cooled to room temperature and stirred for additional 17 hours. The obtained product was filtered, washed twice with 10 mL of water and vacuum dried at 40°C for 6 hours. 1.53 g of Ceritinib Form Beta was obtained. Example 2; Preparation of Ceritinib Form Beta

[00116] In a 3 -neck round bottom flask (50 mL) equipped with thermometer, magnetic stirrer and reflux condenser Ceritinib dihydrochloride salt (1.6 g, 2.53 mmol) was dissolved in ¾0 (16 mL) at room temperature. To the obtained solution, 20.5 mL of 1% NaOH solution was added until pH 12.0 was reached. The slurry was obtained and suspension was heated at 42°C, stirred for 6 hours then cooled to room temperature and stirred for additional 17 hours. The obtained product was filtered and vacuum dried at 40°C for 6 hours. 1.16 g of Ceritinib Form Beta was obtained. Its XRPD pattern is presented in Figure 1, a DSC thermogram in Figure 2. Example 3; Preparation of amorphous Ceritinib

[00117] In a 3 -neck round bottom flask (100 mL) equipped with thermometer, magnetic stirrer and reflux condenser Ceritinib dihydrochloride salt (2.5 g, 3.96 mmol) was dissolved in deionised water (25 mL) at room temperature. To the obtained solution 35.4 mL of 1% NaOH was added until a pH value of 12.0 was reached. The obtained slurry was stirred at room temperature for additional 2 hours. The obtained product was filtered and washed twice with 20 mL of water and vacuum dried at 50°C for 6 hours. 2.08 g of amorphous Ceritinib was obtained, having XRPD pattern similar to that shown in Figure 4. Example 4; Preparation of amorphous Ceritinib

[00118] 1.0 g of Ceritinib Form A was dissolved in 20 mL of methanol while heating to about 60-65°C. A clear solution was formed and evaporated under reduced pressure while heating (bath temperature 40°C). 0.99 g of white foamy amorphous product was obtained. Its XRPD is presented in Figure 4.

Example 5; Preparation of amorphous Ceritinib

[00119] 0.5 g of Ceritinib Form A was dissolved in 10 mL of tert-butanol at room temperature. The obtained clear solution was frozen by cooling to -5°C and freeze-dried during 24 hours to obtain 0.49 g of amorphous Ceritinib, as confirmed by XRPD.

Example 6; Preparation of Ceritinib Form Beta

[00120] In a 3 -neck round bottom flask (50 mL) equipped with thermometer, magnetic stirrer and reflux condenser Ceritinib dihydrochloride salt (1.6 g, 2.53 mmol) was dissolved in a mixture of water (12.8 mL) and MeOH (3.2 mL) at RT. 17 mL of 0.3M NaOH solution was added drop wise until pH 12.0 was reached. An off- white slurry was obtained and stirring at RT was continued for an additional 17 hours. The obtained product was filtered, washed twice with 8 mL of water and dried at RT for 64 hours. 1.22 g of Ceritinib Form Beta was obtained.

Example 7; Preparation of Ceritinib Form Beta

[00121] In a 3-neck round bottom flask (100 mL) equipped with thermometer, magnetic stirrer and reflux condenser Ceritinib dihydrochloride salt (3.0 g, 4.75 mmol) was dissolved in a mixture of water (24 mL) and MeOH (6 mL) at RT. At RT 29 mL of 0.3M NaOH solution was added drop wise until pH 12.0 was reached. During NaOH addition, at pH=7.3, reaction mixture was seeded with 0.1 15 g of Form Beta. An off-white slurry was obtained, heated at 42°C and stirring at 42°C was continued for an additional 6 hours. Then, the suspension was cooled to room temperature and the product was filtered, washed twice with 8 mL of water and vacuum dried at 30°C for 6 hours. 2.43 g of Ceritinib Form Beta was obtained. Example 8; Preparation of Ceritinib Form Gamma

[00122] 0.45 g of Ceritinib base Form Beta was placed in a petri dish and dried in a vacuum drier under the following conditions: 100°C, 10 mbar, 2 hours.0.44 g of Ceritinib base Form Gamma was obtained as confirmed by XRPD.

Example 9; Preparation of Ceritinib Form Gamma

[00123] 0.25 g of Ceritinib base Form Beta was placed in a petri dish and dried without vacuum at 100°C for 1.5 hours. 0.25 g of Ceritinib base Form Gamma was obtained, as confirmed by XRPD.

Example 10; Preparation of an amorphous solid dispersion of Ceritinib combined with hydroxypropyl cellulose

[00124] Ceritinib (3.33 g) and hydroxypropyl cellulose (6.66 g) was dissolved in 200 ml aceton/water solution (80:20 v/v) at 50°C. The solution was spray dried under following conditions: Ti„i = 90°C, Aspirator= 100% and Pump = 20%. The resulting powder was analyzed by XRPD and found to be an amorphous solid dispersion as depicted in Figure 6.

Example 11; Preparation of an amorphous solid dispersion of Ceritinib combined with hydroxypropyl cellulose

[00125] Ceritibnib (2.6 g) and hydroxypropyl cellulose (5,2 g) was dissolved in 156 ml aceton/water solution (80:20 v/v) at 50°C. The solution was spray dried under following conditions: Ti„i = 80°C, Asiprator = 100% and Pump = 20%. The resulting powder was analyzed by XRPD and found to be amorphous solid dispersion as depicted in figure 7.

Example 12; Preparation of amorphous solid dispersion of Ceritinib combined with hydroxypropyl cellulose

[00126] Ceritinib (2,5 g) and hydroxypropyl cellulose (2,5 g) was dissolved in 100 ml aceton/water solution (80:20 v/v) at 50°C. The solution was spray dried under following conditions: Tinl = 80°C, Aspirator = 100% and Pump = 20%. The resulting powder was analyzed by XRPD and found to be an amorphous solid dispersion as depicted in Figure 8.

Example 13; Preparation of Ceritinib dihydrochloride Form I [00127] To a 3-neck round bottom flask (100 mL) equipped with a thermometer, mechanical stirrer and reflux condenser 2-isopropoxy-5-methyl-4-(piperdin-4-yl)aniline dihydrochloride (5.0 g) and 2,5-dichloro-N-(2-(isopropyl sulfonyl) phenyl)pyrimidin-4-amine (5.6 g ) were added. 50 mL of 2-Propanol (2-PrOH) was added and mixture was heated at reflux temperature and stirred for 22 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature for 1 hour followed by stirring in an ice bath for an additional 2 hours. The resulting solid was filtered, then suspended in 2-PrOH at room temperature for 1 hour. The obtained product was filtered, washed with 2-PrOH and dried at 50°C, 10 mbar for 16 hours. 6.87 g of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4- piperidinyl)phenyl]-N4-[2-(isopropyl-sulfonyl)phenyl]-2,4-py rimidinediamine

dihydrochloride salt Form I was obtained.

Example 14; Preparation of Ceritinib dihydrochloride Form II

[00128] 8 g of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]- N4- [2-(isopropyl-sulfonyl)-phenyl]-2,4-pyrimidinediamine dihydrochloride salt (Form I) was suspended in 50 mL of an acetone/FLO mixture (10: 1) and heated at reflux temperature. The obtained clear solution was stirred at reflux temperature for 30 minutes then cooled to room temperature when crystallization occurred. The obtained suspension was stirred at room temperature for 1 hour and then in an ice bath for additional 1 hour. The solid product was filtered and dried at 50°C, 10 mbar for 16 hours. 5.68 g of 5-chloro-N2-[2-isopropoxy-5- methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phe nyl]-2,4-pyrimidinediamine dihydrochloride salt Form II was obtained.

Example 15; Preparation of Ceritinib dihydrochloride Form III

[00129] To a 3-neck round bottom flask (100 mL) equipped with a thermometer, mechanical stirrer and reflux condenser 2-isopropoxy-5-mehyl-4-(piperdin-4-yl)aniline dihydrochloride (5.0 g) and 2,5-dichloro-N-(2-(isopropyl sulfonyl) phenyl)pyrimidin-4-amine (5.59 g) were added. 50 mL of 2-PrOH was added and the mixture was heated at reflux temperature and stirred for 8 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature for 1 hour. The resulting solid was filtered and dried at room conditions overnight. The dried product was then suspended in 2-PrOH at room temperature for 30 minutes. The obtained product was filtered, additionally washed with 2- PrOH and dried at 50°C, 10 mbar for 3 hours. 7.39 g of 5-chloro-N2-[2-isopropoxy-5- methyl-4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phe nyl]-2,4-pyrimidinediamine dihydrochloride salt Form III was obtained.

Example 16; Preparation of Ceritinib dihydrochloride Form IV

[00130] 6.58 g of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-

N4-[2-(isopropyl-sulfonyl)phenyl]-2,4-pyrimidinediamine dihydrochloride salt (Form III) was suspended in 40 mL of an acetone/FLO mixture (10: 1) and heated at reflux temperature. The obtained clear solution was stirred at reflux temperature for 30 minutes then cooled to room temperature. The obtained suspension was stirred at room temperature for 1 hour and then in ice bath for additional 1 hour. The solid product was filtered and dried at 50°C, 10 mbar for 3 hours. 5.18 g of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]- N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine dihydrochloride salt Form IV was obtained. Example 17; Preparation of Ceritinib sodium Form I

[00131] In a 3-neck round bottom flask (100 mL) equipped with an thermometer, magnetic stirrer and reflux condenser 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4- piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyr imidinediamine

dihydrochloride salt (5.5 g, Form II) was dissolved in 18.5 g of acetone:H ₂ 0 mixture (3: 1). The clear solution was heated to 55°C and then 8 mL of 58% NaOH was added dropwise during 30 minutes. An off-white slurry was obtained and stirred at 55 °C for additional 2 hours. New amount of 58% NaOH (5.5mL) was added dropwise over 30 minutes to the reaction mixture. The reaction mixture was cooled to room temperature and then 38 mL of deionized water was added dropwise. The slurry was stirred for additional 1 hour at room temperature. The obtained solid product was filtered, washed with water and dried at 50°C and 10 mbar for 16 hours. 4.07 g of the sodium salt of 5-chloro-N2-[2-isopropoxy-5-methyl- 4-(4-piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2, 4-pyrimidinediamine Form I was obtained. Example 18; Preparation of Ceritinib sodium Form II

[00132] 0.5 g of the sodium salt of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4- piperidinyl)phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyr imidinediamine Form I was dried in vacuum drier at 100°C, 10 mbar for period of 3 hours. The resulting material was Form II of sodium salt 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]- N4-[2- (isopropylsulfonyl) phenyl]-2,4-pyrimidinediamine.

Example 19; Preparation of Ceritinib dihydrochloride Form V

[00133] 0.5 g of Ceritinib base was suspended in 50 mL 2-PrOH at room

temperature. While heating, the starting material was dissolved and 2.5 eq of 5-6M HC1 in 2- PrOH (0.448 mL) was added at about 65°C. The clear solution was changed from colorless to light yellow and crystallization occurred while cooling the reaction mixture to about 55-60°C. The obtained suspension was stirred at 55°C for additional 1 hour, then cooled to room temperature and obtained product was filtered off under reduced pressure. 0.52 g of a light yellow crystalline product was obtained and identified as Form V by XRPD.

Example 20; Preparation of Ceritinib dihydrochloride Form V

[00134] 0.5 g of Ceritinib base was suspended in 50 mL 2-BuOH at room temperature. While heating, the starting material was dissolved and 2.5 eq of 5-6M HC1 in 2- PrOH (0.448 mL) was added at about 55-60°C. The clear solution was changed from colorless to light yellow and crystallization occurred while cooling reaction mixture to about 50°C. The obtained suspension was stirred at 50°C for additional 1 hour, then cooled to room temperature and the obtained product was filtered off under reduced pressure. 0.51 g of a light yellow crystalline product was obtained and identified as Form V by XRPD.

Example 21; Preparation of Ceritinib hydrochloride Form I

[00135] 1 g of Ceritinib base (Form Beta) was suspended in 1 mL of deionized H ₂ 0. The pH of the suspension was adjusted to pH = 1 by addition of 1M HC1 (6 ml). The obtained suspension was stirred at room temperature overnight and then filtered off. The obtained solid product was found to be Ceritinib hydrochloride Form I.

Example 22; Preparation of Ceritinib dihydrochloride Form III

[00136] To a 50 L glass reactor equipped with a thermometer, mechanical stirrer and reflux condenser 2-isopropoxy-5-mehyl-4-(piperdin-4-yl)aniline dihydrochloride (2.0 kg - dry and solvent free) and 2,5-dichloro-N-(2-(isopropyl sulfonyl) phenyl)pyrimidin-4-amine (2.59 kg) were added. 20 L of 2-PrOH and 3 L of DMF were added and the mixture was heated to 75-77°C and stirred for 30-40 hours. The reaction mixture was then cooled to room temperature and stirred at room temperature for 2 hours. The resulting solid was filtered on a filter dryer, washed with 2-PrOH and dried at 50°C under vacuum for 5 hours. 3.30 kg (dry and solvent free) of 5-chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]- N4-[2- (isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine [Ceritinib]dihydrochloride salt was obtained.

Example 23; Preparation of Ceritinib Form Beta

[00137] In a 1 liter reactor equipped with thermometer, mechanical stirrer and pH meter, Ceritinib dihydrochloride salt (30.0 g, 96.8%) was dissolved in a mixture of MeOH (231 ml) and water (58 ml) at room temperature while stirring. The obtained clear solution was filtered and 0.3M solution of KOH was added drop-wise through period of about 2 hours and 15 minutes until a pH value of 11.60 was achieved. During KOH addition, at pH=8.0, 0.5 g of seeding crystals (Form Beta) were added. At pH=l 1.6 obtained suspension was stirred for another three hours at room temperature. The obtained crystalline product was filtered off, washed twice with 60 mL of water and vacuum dried at 35°C for 15 hours to obtain Ceritinib Form Beta (24.2 g).

Example 24; Preparation of Ceritinib Form Beta

[00138] In a 1 liter reactor equipped with thermometer, mechanical stirrer and pH meter Ceritinib dihydrochloride salt (30.0 g, 96.8%) was dissolved in a mixture of MeOH (198 ml) and water (85 ml) at room temperature while stirring. The solution was filtered and 0.3M solution of KOH was added drop-wise through period of about 2 hours and 15 minutes until a pH value of 11.60 was achieved. At pH of 1 1.7 the obtained suspension was stirred for one hour at room temperature and crystalline product was filtered off, washed twice with 60 mL of water and vacuum dried at 35°C for 15 hours. Ceritinib Form Beta was obtained (20.3 g).

Example 25; Preparation of Ceritinib Form Beta

[00139] In a 1 liter reactor equipped with thermometer, mechanical stirrer and a pH meter, Ceritinib dihydrochloride salt (30.0 g, 94,3%) was dissolved in mixture of MeOH (246 ml) and water (27 ml) at room temperature while stirring. The solution was filtered and 0.3M solution KOH was added drop-wise through period of about 3 hours until pH value of 11.60 was achieved. During KOH addition, at pH=8.15, 0.48 g of seeding crystals (Form Beta) were added. After achieving pH=l 1.6 the obtained suspension was stirred for another three hours at room temperature. The obtained crystalline product was filtered off, washed twice with 60 mL of water and vacuum dried at 35°C for 15 hours. Ceritinib Form Beta was obtained (23.5 g).

Example 26; Preparation of Ceritinib Form Beta

[00140] In a 250 mL three neck round bottom flask equipped with mechanical stirrer and pH meter Ceritinib dihydrochloride salt (5.0 g, 95.0%) was dissolved in MeOH (47.5 ml ) at room temperature while stirring. The obtained clear solution was filtered and solution of 0.3M KOH was added drop-wise through period of around 2 hours until pH value of 1 1.60 was achieved. After pH=l 1.6 was obtained, the suspension was stirred for another hour at room temperature. The obtained crystalline product was filtered off, washed twice with 10 mL of water and dried at 25°C for 10 hours. Ceritinib Form Beta was obtained (4.02 g).