WO2016098070A1

WO2016098070A1 - Crystalline form of 5-chloro-n2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-n4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine

Info

Publication number: WO2016098070A1
Application number: PCT/IB2015/059779
Authority: WO
Inventors: Celine GALLAND; Arnaud Grandeury; Jerzy Antoni Budz; Benjamin Martin; Flavien SUSANNE; Michel Aubry; Serbuelent SEVINC; Andrea Decker
Original assignee: Novartis Ag
Priority date: 2014-12-19
Filing date: 2015-12-18
Publication date: 2016-06-23

Abstract

The present invention is directed to a new form of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine. The present disclosure also generally relates to a pharmaceutical composition comprising the form, as well of methods for obtaining such form, and methods of using the form as a medicine.

Description

CRYSTALLINE FORM OF 5-CHLORO-N2-(2-ISOPROPOXY-5-METHYL-4-

PIPERIDIN-4-YL-PHENYL)-N4-r2-(PROPANE-2-SULFONYL)-PHENYLl-

PYRIMIDINE-2. 4-DIAMINE

Field of the Disclosure

The present invention is directed to a new form of 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4- [2-(propane-2-sulfony l)-phenyl] -pyrimidine-2, 4-diamine. The present disclosure also generally relates to a pharmaceutical composition comprising the form, as well of methods for obtaining such form, and methods of using the form as a medicine.

Background

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. Genetic alterations of ALK have been implicated in oncogenesis in hematopoietic and non-hematopoietic tumors. The gene has been found to be rearranged, mutated, or amplified in a series of tumors, including non-small cell lung cancer (NSCLC). The identification of ALK as an oncogene has led to the development of ALK tyrosine kinase inhibitors, such as crizotinib, or ceritinib, and their deployment in a treatment of cancers harboring ALK mutations, rearrangements or amplifications, in particular NSCLC. Thus, ceritinib has been approved by the US FDA as Zykadia® for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approved dosage is a daily dose of 750 mg administered orally, with possible dose reduction in 150 mg increment(s) to 600 mg and 450 mg as needed. The minimum treatment dose is 300 mg. The approved dosage form is a capsule of size 00 containing a 150 mg dose of ceritinib.

Ceritinib was originally described in WO 2008/073687. Two crystalline forms ceritinib, Form A and Form B, and methods of their preparation have been described in WO 2012/082972. Preparation of Form A has been described in Example 1 of WO 2012/082972, and preparation of Form B has been described in Example 2 of WO 2012/082972. Summary of the Disclosure

The present invention provides a new crystalline form of ceritinib, also referred to as Form C. In one aspect, the present invention relates to the compound ceritinib obtained in a distinct crystalline form.

The present invention provides a crystalline ceritinib, preferably in substantially pure form, characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising five or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C, substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.

The present invention provides the crystalline ceritinib, preferably is in substantially pure form, having a differential scanning calorimetry thermogram substantially the same as that shown in shown in FIG.2, and having a melting point of 162.4° C, as determined by differential scanning calorimetry.

The present invention also provides a pharmaceutical composition comprising the crystalline ceritinib, and a pharmaceutically acceptable carrier.

The present invention also provides a method for the preparation of the crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent, preferably isopropanol, to a first reactor at about 20° C; and (ii) providing base solution to a second reactor at about 5° C; followed by (iii) mixing the solutions (i) withand (ii), wherein preferably the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2.

The present invention also provides another method for the preparation of the crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent mixture, wherein preferably the solvent mixture is composed of 29.0% of water, 12.0% of Isopropanol and 59.0% of Tetrahydrofuran; (ii) adding 5% Brine solution; (iii) performing extraction using n-heptane; followed by crystallization. The present invention also provides the crystalline ceritinib for use as a medicine. The present invention further provides the crystalline ceritinib for use as a medicine for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK.

The present invention also provides the use of the crystalline ceritinib for the preparation of a medicament for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK.

The present invention also provides a method for the treatment of proliferative disorders, preferably cancer, more preferably cancers mediated by ALK, comprising administering to a patient in need of such treatment an effective amount of the crystalline ceritinib.

Brief Description of the Drawings

Figure 1 depicts the x-ray powder crystal diffraction results of 5-Chloro-N2-(2-isopropoxy-5- methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine Form C.

Figure 2 depicts differential scanning calorimetry results of Form C of 5-Chloro-N2-(2- isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2, 4-diamine.

Figure 3 Comparison of XRPD patterns for the three 5-Chloro-N2-(2-isopropoxy-5-methyl-4- piperidin-4-yl-phenyl)-N4- [2-(propane-2-sulfonyl)-phenyl] -pyrimidine-2, 4-diamine forms (Form A, Form B, and Form C).

Figure 4 depicts first equilibration: 2 mL Ethanol and 200 mg of Form C of 5-Chloro-N2-(2- isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2, 4-diamine. Figure 5 depicts second equilibration: 2 rriL Ethanol and 150 mg of Form C + 150 g Form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine.

Figure 6 depicts third equilibration: 2 rriL Isopropanol and 200 mg of Form C of 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2, 4-diamine.

Figure 7 depicts fourth equilibration: 2 mL Isopropanol and 150 mg of Form C + 150 g Form A of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine. Figure 8 depicts IR spectrum of ceritinib form C.

Detailed Description of the Disclosure

Although ceritinib is a very promising drug, it is a difficult compound to formulate. In water, it exhibits solubility of only 0.02 mg/mL (at 25°C), and together with its low permeability according to the Biopharmaceutics Classification System qualifies for a class IV compound. In addition, physical characteristics of ceritinib cause sticking and picking during tableting or encapsulation of the drug and make it poorly compressible.

As a chemical substance can exhibit different physical properties being in one or another crystalline form, this polymorphism of the drug molecule can affect the shelf life, solubility, formulation properties, processing properties, and the action of a drug. Different polymorphs, in addition, can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity.

Understanding and controlling polymorphism, then, gives a decided advantage in bringing new drugs to the marketplace, which may be more active, more stable, or more cheaply

manufactured. However, even though polymorphism has been a subject for intensive investigations, understanding and controlling this phenomenon represents a substantial scientific challenge. It is hard to predict whether a given molecule will crystallize in one or several crystal forms, and to find conditions leading to such crystallization. Two crystalline forms of ceritinib, form A and form B, and methods of their preparation have been described in WO 2012/082972. However, both of these crystalline forms of ceritinib are difficult to formulate due to their low solubility, high stickiness and poor compressibility. For example, Form A has good solubility at pH 1, however only fair solubility in water and good solubility in organic solvents (11 mg/mL in pH 1, 0.21 mg/mL in water and 40 mg/mL in methanol, respectively). Therefore, there remains a need for other crystalline forms of ceritinib, which exhibit physical properties which may be advantageous for drug formulation and solubility, and which also may have positive impact on the shelf life, processing properties, uptake in the body and the action of the drug.

Unexpectedly, a new crystalline form of ceritinib was found. The present invention provides a new crystalline form of ceritinib, also referred to as Form C.

Ceritinib is 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, in the form of a free base, of formula

Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor. ALK is a member of the insulin receptor super family of receptor tyrosine kinases. Compound I was originally described in WO 2008/073687 Al as Example 7, compound 66.

The terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

As used herein, the term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. The crystalline form(s) differ with respect to thermodynamic stability, physical parameters, x-ray structure and methods of preparation. In addition, "amorphous" refers to a disordered solid state.

Crystalline ceritinib of the present invention is hydroscopic, and 24-h solubility of crystalline ceritinib is 1.3 at 10°C in ethanol/water 40/40 v/v. The equilibration and competitive

equilibration with the Form A suggests that the Form C is less stable than Form A or Form B.

However, Form C can be advantageously obtained in a fast, continuous precipitation process.

The crystalline ceritinib (Form C) of the present invention differs from previously described

Forms A and B in that it gives rise to a different polymorph of the HCl salt. Crystalline ceritinib of the present invention in HCl solution pH 1 gives a different polymorph of the HCl salt compared to the forms A and B in similar conditions. Crystalline ceritinib of the present invention (Form C) is highly crystalline powder with XRPD pattern uniquely different from that of previous polymorphs (Forms A and B).

It should be noted that different samples of a particular crystalline form will share the same major X-ray powder diffraction (XRPD) peaks, but that there can be variation in powder patterns with regard to minor peaks. In addition, the term "about" with regard to XRPD maxima values (in degrees) generally means within 0.3°, more preferably within 0.2°, and most preferably within 0.1° of the given value. Alternatively, the term "about" means (in this and all contexts) within an accepted standard of error of the mean, when considered by one of ordinary skill in the art. In addition, the term "about" or "approximately" shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

In one aspect, the present invention relates to the crystalline ceritinib characterized by a X-ray powder diffraction (XRPD) pattern obtained by using Cu K-alpha radiation comprising five or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C. The XRPD pattern is summarized in FIG. 1.

In another embodiment, the crystalline ceritinib is characterized by a XRPD pattern obtained by using Cu K-alpha radiation comprising eight or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

In another embodiment, the crystalline ceritinib is characterized by XRPD pattern obtained by using Cu K-alpha radiation comprising twelve or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

In a further embodiment, the crystalline ceritinib is characterized by XRPD pattern obtained by using Cu K-alpha radiation comprising all 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

In one aspect, the present invention relates to the crystalline ceritinib having a X-ray diffraction spectrum, obtained by using Cu K-alpha radiation at a temperature of about 25°C, substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.

In another aspect, the present invention relates to the HC1 salt of the new crystalline form disclosed herein.

The term "substantially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2Θ) will show some inter-apparatus variability, typically as much as 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.

In one aspect, the present invention relates to the crystalline ceritinib exhibiting the following thermal parameters: melting point, Tm (onset) 162.4° C as determined by differential scanning calorimetry at a scanning rate of 10° C/min (as shown in FIG. 2).

In one aspect, the present invention relates to the crystalline ceritinib having a differential scanning calorimetry thermogram which is substantially the same as that shown in shown in FIG.2.

The crystalline form C of ceritinib can have infrared absorption spectra as depicted in Figure 8. Specifically, the infrared absorption bands can be at 3416, 3310, 2798, 1065, 1022, 1009, 942, 885, 863, 769 and 678 (in units of wavenumbers, cm^"1). The most significant differences observed between the spectra of forms C compared to forms A and B were in the range of 4000- 3000 cm^"1 and 800-600 cm^"1

In one embodiment of the above mentioned aspects, the crystalline ceritinib is in

substantially pure form. As used herein, the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation. For example, the crystalline ceritinib may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of ceritinib and/or reaction impurities and/or processing impurities. The presence of reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance

spectroscopy, mass spectrometry, or infrared spectroscopy.

In one embodiment of the above mentioned aspects, crystalline ceritinib has less than 1.0 % by weight total impurities, in another embodiment of the above mentioned aspects, crystalline ceritinib has less than 0.5 % by weight total impurities. In a further embodiment of the above mentioned aspects, crystalline ceritinib has less than 0.1 % by weight total impurities.

In one aspect, the present invention relates to a pharmaceutical composition comprising a crystalline ceritinib of the present invention, and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, buffering agents (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, and the like), and the like and combinations thereof, as would be known to those skilled in the art (see, for example,

Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the crystalline ceritinib its use in the pharmaceutical compositions or medicaments is contemplated. In one aspect, the present invention relates to a method for the preparation of a crystalline ceritinib. Considering the challenge to crystallize ceritinib in a continuous production mode, preferably in a single step continuous mode, the reactive precipitation is one of the selected processes of the present invention.

As used herein, the term "continuous production", also called "continuous process" or "continuous flow process", refers to a flow production method used to manufacture, produce, or process materials without interruption. In continuous production mode the materials being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production. The term "batch production' is a technique used in manufacturing, in which the object in question is created stage by stage over a series of workstations, and different batches of products are made. Batch crystallization is widely used in pharmaceutical processing. However, use of continuous crystallization due to employment of continuous crystallizers allows more flexibility in control of temperature, supersaturation, nucleation, crystal growth and all the other process parameters that influence crystal size distribution. Furthermore, continuous production can avoid scale-up difficulties, and improve quality while maintaining or reducing manufacturing costs.

The term "reactive precipitation" refers to precipitation which occurs through the mixing of solutions which react together (e.g. acid plus base solutions). The term "continuous reactive precipitation" refers to reactive precipitation which occurs continuously due to a continuous flow of reactive solutions. Compared to a batch reactive crystallization, continuous reactive precipitation results in a very high uniform supersaturation conditions, so that the end result is formation of small particles with a narrow size distribution.

In one embodiment, the present invention relates to a method for the preparation of a crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 15°C to about 25° C, preferably at about 20° C; and (ii) providing base solution to a second reactor at about 0°C to about 10°C, preferably at about 5° C; followed by (iii) mixing the solutions (i) and (ii), preferably wherein the ratio of 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2.

In one embodiment, the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib which comprises steps: (i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 15°C to about 25° C, preferably at about 20° C; and (ii) providing base solution to a second reactor at about 0°C to about 10°C, preferably at about 5° C; followed by (iii) mixing the solutions (i) and (ii), preferably wherein the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4- piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine

dihydrochloride to the base is at least 2.

In one embodiment, the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib, which comprises steps:

(i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 20° C; and (ii) providing base solution to a second reactor at about 5° C; followed by (iii) mixing the solutions (i) and (ii),preferably wherein the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4- piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine

dihydrochloride to the base is at least 2.

The term "about" or "approximately" shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine dihydrochloride is suspended and/or stirred in a suitable solvent to afford a slurry, which is heated to promote dissolution. The term "slurry", as used herein, means a compound suspension, which is a heterogeneous mixture of the compound and a solvent at a given temperature. In one embodiment, the solvent is isopropanol.

While isopropanol is a preferred solvent, other solvents are possible. Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.

However, as isopropanol is also used during the synthesis of ceritinib, it may have some advantages to use the same solvent (isopropanol) for the production of the crystalline ceritinib. In a continuous manufacturing, the preparation of the drug is performed in a single continuous flow, and thus it would be advantageous to use the same solvent for all steps. In one embodiment, the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl- phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2. The amount of the base solution of the step (ii) used in step (iii) depends on the base used and may vary, however the amount of base must be sufficient to convert 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2, 4-diamine dihydrochloride to 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4- yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.

In one embodiment, the base solution is aqueous alkali hydroxide selected from the list consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and caesium hydroxide. In a further embodiment, the base solution is aqueous potassium hydroxide. In a preferred embodiment, the base solution is aqueous sodium hydroxide. In one embodiment, the base solution is aqueous alkali hydroxide, and 5-Chloro-N2-(2-isopropoxy-5- methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of the step (i) mixed with at least two equivalents of the base of the step (ii).

In another embodiment, the base solution is aqueous alkaline earth hydroxide selected from the list consisting of beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, and radium hydroxide. In a further embodiment, the base solution is magnesium hydroxide or calcium hydroxide. In one embodiment, the base solution is aqueous alkaline earth hydroxide, and 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)- N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of the step (i) mixed with at least one equivalent of the base of the step (ii).

While sodium hydroxide is a preferred base, other strong bases, such as hydroxides of alkali or alkaline earth metals, or other weak bases, such as N¾, CH₃NH₂, C₅H₅N may be used. The amount of base must be sufficient to convert 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin- 4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride to 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine.

In a preferred embodiment, the present invention relates to a method, suitable for a continuous production mode, for the preparation of a crystalline ceritinib, which comprises steps:

(i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in isopropanol to a first reactor at about 20° C; and

(ii) providing 1 N NaOH to a second reactor at about 5° C;

followed by

(iii) mixing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in isopropanol from the step (i) with at least two equivalents of the base of the step (ii). In order to ensure a good mixing during step (iii) between dissolved 5-Chloro-N2-(2- isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine- 2, 4-diamine dihydrochloride in isopropanol from the step (i) with the base solution of the step (ii), a roughton mixer is the most adapted equipment. Thus, in one embodiment, mixing is done using a roughton mixer. Different flow speeds are suitable for the method of invention, preferably from 50 to 400 mL/min.

While a roughton mixer is preferred equipment for mixing, other mixers and processes, which provide a fast precipitation, are possible, preferably other micro mixers, such as Y-mixer.

The above described method for the preparation of a crystalline ceritinib is suitable for a continuous production mode. This continuous crystallization technique has many advantages. Most notably a significant reduction in equipment footprint can be realized for higher volume products. Furthermore, this method for the preparation of a crystalline ceritinib is carried out in one step instead of two steps (recrystallization and dry milling), because the grains produced are already smaller, and thus it provides an additional significant manufacturing advantage. While the above describe method for the preparation of the crystalline ceritinib is preferred due to its suitability in a continuous production, other methods are also possible. Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, and addition of antisolvents (counters olvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.

Thus, in one aspect, the present invention relates to a method for the preparation of the crystalline ceritinib which comprises steps:

(i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent mixture; (ii) adding 5% Brine solution;

(iii) performing extraction using n-heptane; followed by crystallization.

In one embodiment, the solvent mixture is composed of about 29.0% of water, about 12.0% of isopropanol and about 59.0% of tetrahydrofuran. In a further embodiment, the solvent mixture has a pH of approximately 1. The term "about" or "approximately" shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

In one embodiment, the Brine solution is sodium chloride solution. However, other salt solutions can also be used. The concentration of Brine solution can be at least 5%. In one embodiment the reaction mixture of step (i) is diluted with 5% Brine solution.

In one embodiment, the extraction using n-heptane is six-step extraction. While in a preferred embodiment, the extraction is performed using Heptane as it provides the most efficient extraction, other solvents also can be used.

In one embodiment, particle precipitation is performed by adding ethanol, and adjusting pH to 13 by stirring in NaOH.

The isolated solids obtained in any of the above described methods for the preparation of the crystalline ceritinib may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70 weight % isolated yield, preferably greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.

In one aspect, the present invention relates to the crystalline ceritinib for use as a medicine.

In one embodiment, the present invention relates to the crystalline ceritinib for use in the treatment of proliferative disorders. In one embodiment, the present invention relates to the use of the crystalline ceritinib for the preparation of a medicament for the treatment of proliferative disorders.

In one embodiment, the present invention relates to a method for the treatment of proliferative disorders, comprising administering to a patient in need of such treatment an effective amount of the crystalline ceritinib.

In one embodiment, proliferative disorder is a cancer. In a further embodiment, the proliferative disorder is mediated by ALK. In another embodiment, the proliferative disorder is a cancer mediated by ALK.

Disorders mediated by ALK are in particular disorders characterized by amplification of ALK, or somatic mutation of ALK, in particular activation mutations in the fill-length receptor that result in ligand-independent constitutive activation, or rearrangement of ALK, in particular through genetic aberrations involving translocation of the kinase domain with multiple fusion partners. The medicament is useful in treating diseases which respond to inhibition of anaplastic lymphoma kinase activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70) insulin-like growth factor (IGF-1R and combinations thereof. The diseases are selected from benign or malignant tumor; a cancer selected from anaplastic large cell lymphoma; non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; and melanoma.

In one embodiment, the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of cancers selected from anaplastic large cell lymphoma; non- Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma; sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma;

glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; and melanoma.

In another embodiment, the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of disorders mediated by ALK, in particular neuroblastoma, anaplastic thyroid cancer or non-small cell lung carcinoma (NSCLC). In a further embodiment, the present invention relates to the crystalline ceritinib for use as a medicine for the treatment of NSCLC refractory to crizotinib.

The term "treating" or "treatment" is defined herein to refer to a treatment relieving, reducing or alleviating at least one symptom in a subject or affecting a delay of progression of a disorder. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.

The term "subject" or "patient" as used herein includes animals, which are capable of suffering from or afflicted with disorders mediated by anaplastic lymphoma kinase. Examples of subjects include mammals, e.g., humans, dogs, horses, cats, mice, rats and transgenic non-human animals. In the preferred embodiment, the subject is a human, e.g., a human suffering from a cancer.

The term "therapeutically effective amount" is intended to mean the amount of the inventive crystalline form that, when administered to a subject in need thereof, is sufficient to effect treatment for disorder conditions alleviated by the inhibition of protein kinase activity. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the disorder condition and the severity thereof, the identity of the subject in need thereof, etc., which amount may be routinely determined by artisans of ordinary skill in the art. Preferably, more than 80%, more preferably at least 85%, still more preferably at least 90%, and most preferably at least 95%, of the crystalline form administered is of one of the inventive forms. As noted above, illustrative modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal. Administration of the crystalline form may be accomplished by administration of a pharmaceutical composition of this invention or via any other effective means.

In one embodiment, the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful as medicine. In one embodiment , the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful for treatment of proliferative disorders, in particular cancers, in particular disorders mediated by ALK, in particular disorders characterized by amplification of ALK, or somatic mutation of ALK, or rearrangement of ALK. In one embodiment, the present invention relates to the crystalline ceritinib for use as an intermediate for preparing crystalline or amorphous forms of ceritinib that are useful for treatment of cancers mediated by ALK.

The following Examples illustrates the invention described above, but are not, however, intended to limit the scope of the invention in any way. Other test models known as such to the person skilled in the pertinent art can also determine the beneficial effects of the claimed invention.

Examples

Analytical Methods

ATR-FTIR: PerkinElmer Spectrum BX II; "Golden Gate" diamond ATR cell (from Graseby- Specac Ltd., U.K.), DTGS detector, 12-20 scans, 4000-600 cm^"1 range, 4 cm^"1 resolution.

DSC: PerkinElmer DSC 7; hermetically closed gold crucible or an aluminum crucible with a pinhole in the lid, variable heating rates (from 2-20 K/min) and temperature ranges (see the figures for details). The multiscan experiments involve either quench cooling at -500°C/min to - 50°C or cooling at -10°C/min between heating scans. Heating rate Sample pan Melting onset / Melting enthalpy /

T_g of amorphous in 2^nd scan AC_P of amorphous in 2^nd scan

K/min C C

20 with pinhole 162.0°C^a 76.8 J/g⁹

10 with pinhole 161.8°C^b 76.3 J/g⁹

5 with pinhole 161 .6°C^C 75.8 J/g⁹

2 with pinhole 161.2°C^d 78.7 J/g⁹

20 closed 162.4°C^e 76.6 J/g⁹

10 closed 161.8°C^f 64.5 J/g

a also broad endotherm at T_onSet = 66.3°C (ΔΗ = 20.3 J/g) & small endotherm at T_onSet =

174.6°C (ΔΗ = 7.2 J/g)

b also broad endotherm at T_onSet = 57.4°C (ΔΗ = 12.6 J/g), small exotherm at T_onSet = 165.9°C (ΔΗ = -3.1 J/g), and sharp endotherm at T_onSet = 174.5°C (ΔΗ = 12.7 J/g)

0 also broad endotherm at T_onSet = 62.3°C (ΔΗ = 6.4 J/g), small exotherm at T_onSet = 164.3°C (ΔΗ = -13 J/g), and sharp endotherm at T_onSet = 174.3°C (ΔΗ ~ 25 J/g)

d also broad endotherm at T_onSet = 51 .6°C (ΔΗ = 8.2 J/g), small exotherm at T_onSet = 163.4°C (ΔΗ ~ -23 J/g), and sharp endotherm at T_onSet = 174.2°C (ΔΗ ~ 51 J/g)

e also broad endotherm at T_onSet = 52.1 °C (ΔΗ = 8.2 J/g) & small endotherm at T_onSet = 175.0°C (ΔΗ = 7.0 J/g)

f also broad endotherm at T_onSet = 52.4°C (ΔΗ = 4.7 J/g) & small exotherm at T_onSet = 167.1 °C (ΔΗ = -2.5 J/g)

⁹ sum of endotherms (and exotherm when present) in the region of the main melting peak

XRPD: Bruker D8 Advance; LynxEye detector; Cu-Κα radiation; standard measurement conditions: Bragg -Brentano reflection, 40 kV and 40 mA tube power, 0.02°2Θ step size, 37 s step time, 2.5-50.0°2 Θ scanning range; sample holder: 0.1 -mm deep silicon single crystal; standard sample preparation: slight pressure was applied to get a flat surface; the sample was rotated during the measurement. Example 1

Preparation of crystalline form of ceritinib (Form C) by fast precipitation through the Roughton mixer

The compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride (200 g), isopropanol

(583.3 g, 742.11 ml) and water (249.7 g, 249.7 ml) were added in a 2L reactor. The mixture was stirred at 400 rpm and heated up to 20°C until the compound is totally dissolved.

IN NaOH (750 ml) solution was added into a second reactor. The reactor jacket was cooled down to 5°C. With the help of two HNP micro gear pumps, the API solution and the anti-solvent were introduced simultaneously into the Roughton mixer respecting the flow rate ratio between the solvent and the anti-solvent of 1.5 (in order to get 2.3 equivalents of NaOH compared to 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2, 4-diamine dihydrochloride ). Table 1 summarizes the flow rates through the roughton mixer, which were tested and all led to the formation of Form C. Let the process run over approx. 1 min for each flow rate. The precipitation occurred directly at the outlet of the mixer. The collected suspensions were filtered over a glass Nutsche filter. The solids were dried at 50°C with p<25 mbar overnight. Form C was identified and confirmed by its corresponding XRPD pattern (Figure 1) and thermal parameters (Figure 2). Obtained form C was a yellowish to yellow, highly crystalline powder with XRPD pattern uniquely different from that of previous polymorph Forms A and B (Figure 3).

Table 1. Tested flow rates of the Roughton mixer.

Example 2

Preparation of crystalline form of ceritinib (Form C)

The compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl] -pyrimidine-2, 4-diamine dihydrochloride was synthetized in a solvent mixture composed of 29.0% of water, 12.0% of Isopropanol and 59.0% of

Tetrahydrofuran. The solvent mixture had a pH of approximately 1.

A six-step extraction was performed at 20°C: first a 5% Brine solution was added, followed by a six step extraction with heptane. 5 % Brine solution was prepared by diluting 92.6 g of sodium chloride solution (27%) diluted with 407.4 g of demineralized water. A clear, colorless 5% Brine solution was obtained.

For the extraction with 5% Brine solution, 400 ml (381.7 g) of reaction solution of 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl] -pyrimidine-2, 4-diamine dihydrochloride synthesis was mixed with 400 ml (414.7 g) of 5% Brine in a 21 vessel. The mixture was stirred for 1 minute. A clear brown solution was obtained.

The solution was transferred into a separating funnel, and 400 ml (269.9 g) of n-heptane was added. The mixture was shaken well for 30 seconds. After approximately 2min, 2 phases were separated. The upper phase represented an organic phase, and was a clear, colorless solution. The upper phase was discarded. The lower phase represented an aqueous phase, and was a dark-brown, clear solution. The lower phase was separated, and 400 ml (269.9 g) of n- heptane was again added to it. This procedure was repeated six times (see Table 2). After the last separation, the retained aqueous phase was a brown, clear solution.

Table 2. Six-step n-heptane extraction. extraction : separation ratio

[sec] [ml] [g] org/aq. phase

org Phase 1 100 540.0 397.0 1.0

aq. Phase 1 100 655.0 663.8 1.2

org Phase 2 55 445.0 311.5 1.0

aq. Phase 2 55 505.0 617.3 1.1

org Phase 3 56 420.0 288.2 1.0

aq. Phase 3 56 580.0 594.5 1.4

org Phase 4 180 410.0 277.5 1.0

aq. Phase 4 180 570.0 583.1 1.4

org Phase 5 180 410.0 274.8 1.0

aq. Phase 5 180 560.0 575.0 1.4

org Phase 6 200 400.0 272.8 1.0

aq. Phase 6 200 560.0 568.2 1.4

After the 6 step n-heptane extraction, 100 ml (103.4 g) of aqueous phase was filled into a 250ml bottle, and 100 ml (78.9 g) of 99.8% ethanol was added under stirring conditions. A clear, brown solution was obtained. The pH of the mixture was adjusted to 13, under constant stirring, with 32% NaOH. White solids precipitated out. Form C of ceritinib was identified and confirmed by its corresponding XRPD pattern.

Example 3

Conversion of Form C of ceritinib to Form A of ceritinib Competitive equilibrations of the new form C of ceritinib were performed at room temperature over 2 days under the following conditions. The first equilibration was performed with 2 mL Ethanol and 200 mg of Form C of ceritinib (Figure 4). The second equilibration was performed with 2 mL Ethanol and 150 mg of Form C of ceritinib and 150 g of Form A of ceritinib (Figure 5). The third equilibration was performed with 2 mL Isopropanol and 200 mg of Form C of ceritinib (Figure 6). The fourth equilibration was performed with 2 mL Isopropanol and 150 mg of Form C of ceritinib and 150 g Form A of ceritinib (Figure 7).

All samples were filtered, dried under vacuum for 5 hours at 50 °C and analyzed with XRPD. All samples turned to Form A of ceritinib.

Claims

Claims:

1. A crystalline ceritinib characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising five or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2, 27.8±0.2, 28.4±0.2,

28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

2. The crystalline ceritinib according to claim 1 characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising eight or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2,

25.9±0.2, 27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

3. The crystalline ceritinib according to claim 1 characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising twelve or more 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2,

4. The crystalline ceritinib according to claim 1 characterized by a X-ray powder diffraction pattern obtained by using Cu K-alpha radiation comprising all 2Θ values selected from the group consisting of 5.0±0.2, 9.6±0.2, 10.1±0.2, 12.3±0.2, 13.7±0.2, 14.45±0.2, 15.1±0.2, 15.55±0.2, 17.1±0.2, 18.1±0.2, 19.3±0.2, 20.0±0.2, 20.55±0.2, 21.9±0.2, 24.4±0.2, 25.9±0.2,

27.8±0.2, 28.4±0.2, 28.85±0.2, and 31.7±0.2 at a temperature of about 25°C.

5. A crystalline ceritinib having a X-ray diffraction spectrum, obtained by using Cu K-alpha radiation at a temperature of about 25°C, substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.

6. A crystalline ceritinib having a differential scanning calorimetry thermogram substantially the same as that shown in shown in FIG.2.

7. A crystalline ceritinib having a melting point of 162.4° C, as determined by differential scanning calorimetry.

8. The crystalline ceritinib of any one of the preceding claims, wherein the said crystalline ceritinib is in substantially pure form.

9. The crystalline ceritinib of any one of the preceding claims, having less than 1.0 % by weight total impurities.

10. The crystalline ceritinib of any one of the preceding claims, having less than 0.5 % by weight total impurities.

11. The crystalline ceritinib of any one of the preceding claims, having less than 0.1 % by weight total impurities.

12. A pharmaceutical composition comprising the crystalline ceritinib of any one of the preceding claims, and a pharmaceutically acceptable carrier.

13. A method for the preparation of a crystalline ceritinib which comprises the steps of:

(i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent to a first reactor at about 20° C to form a first solution; and

(ii) providing base solution to a second reactor at about 5° C; followed by

(iii) mixing the first solution of step (i) with the base solution of step (ii).

14. The method of claim 13, wherein said solvent is isopropanol.

15. The method of claim 13, wherein the ratio of 5-Chloro-N2-(2-isopropoxy-5-methyl-4- piperidin-4-yl-pheny 1)-N4- [2-(propane-2-sulfonyl)-phenyl] -pyrimidine-2, 4-diamine dihydrochloride to the base is at least 2.

16. The method of claim 13, wherein the base solution is an aqueous alkali hydroxide selected from the list consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, and caesium hydroxide.

17. The method of claim 15, wherein the base solution is aqueous sodium hydroxide.

18. The method of claim 15, wherein the base solution is aqueous potassium hydroxide.

19. The method of any one of claims 13 to 18, wherein 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of the step (i) is mixed with at least two equivalents of the base of step (ii).

20. The method of claim 13, wherein the base solution is an aqueous alkaline earth hydroxide selected from the list consisting of beryllium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide, and radium hydroxide.

21. The method of claim 20, wherein the base solution is aqueous magnesium hydroxide or aqueous calcium hydroxide.

22. The method of any one of claims 20 to 21, wherein 5-Chloro-N2-(2-isopropoxy-5-methyl- 4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride of step (i) solution is mixed with at least one equivalent of the base of step (ⁱⁱ).

23. The method of any one of claims 13 to 22, wherein step (iii) of claim 14 is done using a roughton mixer.

24. A method for the preparation of a crystalline ceritinib which comprises steps:

(i) providing 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine dihydrochloride in a solvent mixture; (ii) adding a 5% Brine solution;

(iii) performing extraction using n-heptane; followed by crystallization.

25. The method of claim 24, wherein the solvent mixture is composed of 29.0% of water, 12.0% of Isopropanol and 59.0% of Tetrahydrofuran.

26. The method of claim 24, wherein the brine solution is a sodium chloride solution.

27. The method of any one of claims 24 to 26, wherein the extraction using n-heptane is a six- step extraction.

28. The crystalline ceritinib according to any one of claims 1 to 11 for use as a medicine.

29. The crystalline ceritinib according to any one of claims 1 to 11 for use in the treatment of proliferative disorders.

30. Use of the crystalline ceritinib according to any one of claims 1 to 11 for the preparation of a medicament for the treatment of proliferative disorders.

31. A method for the treatment of proliferative disorders, comprising administering to a patient in need of such treatment an effective amount of the crystalline ceritinib according to any one of claims 1 to 11.

32. The crystalline ceritinib of claim 29, the use of claim 30 or the method of claim 31,

wherein the proliferative disorder is a cancer.

33. The crystalline ceritinib of claim 29, the use of claim 30 or the method of claim 31,

wherein the proliferative disorder is a cancer mediated by ALK.

34. The crystalline ceritinib of claim 29, the use of claim 30 or the method of claim 31,

wherein the proliferative disorder is a cancer selected from anaplastic large cell lymphoma; non-Hodgkin's lymphoma; an inflammatory myofibrolastic tumor; a neuroblastoma;

sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden disease); pancreas; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; kidney; renal pelvis; urinary bladder; uterine corpus; uterine cervix; vagina; ovary; multiple myeloma;

esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; and melanoma.