WO2020099483A1

WO2020099483A1 - Crystalline forms of brigatinib

Info

Publication number: WO2020099483A1
Application number: PCT/EP2019/081171
Authority: WO
Inventors: Nolwenn Martin; Arthur Pichler
Original assignee: Sandoz Ag
Priority date: 2018-11-15
Filing date: 2019-11-13
Publication date: 2020-05-22

Abstract

The present invention relates to new crystalline forms of 5-chloro-N4-[2- (dimethylphosphoryl)phenyl]-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1- yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib"), in particular to a crystalline hydrate system and to crystalline acid addition salts of brigatinib, and methods for preparing same. The invention also refers to a pharmaceutical composition comprising the said hydrate system or said acid addition salts of brigatinib. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC) and other diseases.

Description

Crystalline forms of Brigatinib

Field of the invention

The present invention relates to new crystalline forms of 5-chloro-N4-[2- (dimethylphosphoryl)phenyl]-N2-[2-methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1 - yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib"), in particular to a crystalline hydrate system and to crystalline acid addition salts of brigatinib, and methods for preparing same. The invention also refers to a pharmaceutical composition comprising the said hydrate system or said acid addition salts of brigatinib. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC) and other diseases.

Background of the invention

Brigatinib, also known under the chemical name 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]- N2-[2-methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1 -yl]phenyl]pyrimidine-2, 4-diamine, can be represented by the following chemical structure according to Formula (A):

Formula (A)

Brigatinib, previously also known as AP261 13, is a potent multi-targeted tyrosine-kinase inhibitor used in the treatment of non-small cell lung cancer (NSCLC) and other diseases. It acts as both as anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Brigatinib and its synthesis are described in WO 2009/143389 A1. In example 122 brigatinib is isolated after chromatographic purification, followed by an additional work-up consisting of suspending the yellow solid obtained after chromatography in ethyl acetate and refluxing the suspension for 30 minutes, cooling it to room temperature and filtering it. The obtained solid is then dissolved in dichloromethane, filtered and dried to afford brigatinib as an off-white solid. The physical form of brigatinib obtained from this example is not described.

WO 2016/065028 A1 discloses crystalline brigatinib and more particularly the crystalline forms of brigatinib designated as form A, form B, form C, form D, form E, form F, form G, form H, form J, form K and form L. Form A is described as an anhydrous and non-hygroscopic form. Form B is reported as a hydroscopic form and is obtained by dehydration of hydrated crystalline forms C or D. Form B reversibly converts to the hydrated crystalline forms C or D at relative humidity above 30% or transforms to form A, e.g., at elevated temperature (above 150 °C). Hydrated crystalline forms C and D easily dehydrate to anhydrous form B and convert to each other depending on the temperature and relative humidity. The crystalline forms E to H are solvated forms, which convert to form A upon storage under atmospheric conditions. The crystalline forms J to L are obtained in mixtures containing form J or form K or form L together with form A.

In WO 2016/065028 A1 , Table 27 summarizes the results of over 600 experiments and shows that most of the experiments (i.e. 98% of the experiments) led to the formation of crystalline form A of brigatinib as a pure form or in a mixture containing form A and one or two additional forms of brigatinib. Brigatinib form A is described as the most stable form of brigatinib and indeed form A is used as the active pharmaceutical ingredient in the marketed product “Alunbrig”, which was approved by the US FDA in April 2017.

Tablets comprising the crystalline form A of brigatinib have been approved by the US FDA for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). While the 30mg tablets have an approved shelf-life of 24 months, the 90mg tablets have interestingly been approved only with a shelf life of 18 months based on the provided stability data (Center for Drug Evaluation and Research, Approval Package for application number 2087720rig1s000, page 2).

IN201741014828 reports two crystalline forms of brigatinib designated as form SP3 and form SP4. According to IN201741014828, crystalline forms SP3 and SP4 may exist as a solvate. More specifically, crystalline form SP3 may exist as an acetic solvate and crystalline form SP4 may exist as a propionic solvate.

WO18077187 A1 relates two crystalline forms of brigatinib designated as form CS1 and form CS2. According to W018077187 A1 , crystalline forms CS1 and CS2 may be hydrated forms. Form CS1 readily convert to form CS2 upon storage at room temperature and a relative humidity in the range of 30 to 80%. Moreover, physical properties of form CS2, i.e. thermal stability, are unpredictable and strongly depend on the preparation process of this form, as illustrated by the differential scanning calorimetric (DSC) analyses in Figures 6 and 11. In W018077187 A1 it is reported that during the DSC analysis of CS2 crystal, which was prepared according to Example 7, three endothermic events were measured: first one started at about 45°C, the second one at about 72°C and the third one at about 210°C. On the other hand, during the DSC analysis of CS2 crystal, which was prepared according to Example 10, two endothermic events were measured: first one started at about 121 °C, the second one at about 214°C.

W018077187 A1 reported that crystalline form A of WO 2016/065028 A1 has a low solubility and slow dissolution rate, making its use for the preparation of pharmaceutical compositions unsuitable.

As reported above, crystalline hydrates forms C, D and CS1 are not moisture stable and readily convert to each other or to another crystalline form upon drying or exposure to relative humidity above 30%. Moreover, physical properties of form CS2 are unpredictable.

There remains thus a need for further polymorphs of brigatinib suitable for the development of pharmaceutical dosage forms, preferably polymorphs with improved properties. Moreover, as moisture sensitive solid forms pose a limitation to the types of pharmaceutical dosage forms which can be prepared from them, for the types of excipients which can be used in combination with them and for the conditions and processes, which can be employed during the preparation of a pharmaceutical dosage form, there is thus a need for a solid form of brigatinib, which is stable, and has consistent physical properties at a range of temperature and relative humidity which are typical of the regular working conditions encountered during finished dosage form preparation.

Summary of the invention

The present invention relates to new crystalline forms of brigatinib - more particularly to a crystalline hydrate system H1 and H2 and to an intermediate thereof, form S, as well as to crystalline acid addition salts of brigatinib. Additionally, the present invention further refers to methods for preparing the same, and to a pharmaceutical composition comprising said hydrate system or salts of brigatinib. The pharmaceutical composition of the present invention may be used as a medicament in particular for the treatment of anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer (NSCLC) and other diseases. The crystalline forms of the present invention have the advantages as demonstrated in the experimental section herein and as further detailed below. For examples, the present invention provides crystalline forms, which are stable during storage. The hydrate system of the invention is stable in the range of 0-80% RH, which makes the drug form less sensitive against presence of water during storage. For example, form H1 is stable under harsh conditions such as 40°C/75% RH for 8 weeks. In contrast, prior art form CS1 readily converts to CS2 at 30-80% RH. The acid addition salts of the invention may for example be less hygroscopic as compared with the known solid state forms.

Definitions

As used herein the term“room temperature” refers to a temperature in the range from 20 to 30 °C, preferably to a temperature in the range from 22 to 27 °C.

As used herein, the term“measured at a temperature in the range from 20 to 30 °C" refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range from 20 to 30 °C, i.e. at room temperature. A preferred temperature for measurements is 22 °C, Typically, standard conditions additionally mean a measurement at 20% to 75% RH (relative humidity), with about 25% to 40% RH being a preferred controlled humidity value for a measurement.

The term“reflection" with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 1 Q³ to 10²⁰ atoms, whereas short-range order is over a few atoms only (see“Fundamentals of Powder Diffraction and Structural Characterization of Materials’’ by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term “essentially the same” with reference to powder X-ray diffraction means that variabilities in peak positions and relative intensities of the peaks need to be taken into account. For example, a typical precision/accuracy of the 2-Theta values is in the range of ± 0.2° 2- Theta, preferably in the range of + 0. 2-Theta. Thus, a diffraction peak that usually appears at 13.0° 2-Theta for example can appear between 12.8° and 13.2° 2-Theta, preferably between 12.9° and 13. 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative peak intensities will show interapparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

An acid addition salt of brigatinib may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffractograms. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact peak positions and intensities.

The term“stable", as used herein, means that the respective crystalline form or the crystalline system is maintained in an amount of at least 90% when stored at 40% RH, preferably 80% RH (open conditions) for 1 week, 2 weeks preferably 4 weeks, or even 8 weeks. The amount of crystalline form can be determined by PXRD.

Abbreviations

PXRD powder X-ray diffractogram

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMSD gravimetric moisture sorption/ desorption

Am mass difference

RH relative humidity

w-% weight percent

TGMS thermogravimetric mass spectroscopy

Brief description of the figures (drawings)

Figure 1 : illustrates a representative PXRD of the crystalline dichloromethane solvate of brigatinib, form S, prepared according to the procedure described in Example 1 -1 . The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. Figure 2: Representative gravimetric moisture sorption/ desorption isotherms of the crystalline dichloromethane solvate of brigatinib, form S, prepared according to the procedure described in Example 1 -2. The X-axis shows the relative humidity / % and the Y-axis shows the mass difference Am / %. The sorption isotherm is represented by the square symbols (symbols:■); the desorption isotherm is represented by the triangle symbols (symbols: A ).

Figure 3: illustrates a representative PXRD of the crystalline hydrate H1 of brigatinib, prepared according to the procedure described in Example 2-1. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 4: illustrates a representative PXRD of the crystalline hydrate H2 of brigatinib, prepared according to the procedure described in Example 2-4. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 5: Representative DSC curve of the crystalline hydrate H1 of brigatinib, prepared according to the procedure described in Example 2-2. The X-axis shows the temperature / °C and the Y-axis shows peak heights / Wg-1 . Endothermic events are plotted up.

Figure 6: Representative TGA curve of the crystalline hydrate H1 of brigatinib, prepared according to the procedure described in Example 2-2. The X-axis shows the temperature / °C and the Y-axis shows sample mass / %. Endothermic events are plotted up.

Figure 7: Representative gravimetric moisture sorption/ desorption isotherms of the crystalline hydrate system of brigatinib, starting with form H1 prepared according to the procedure described in Example 2-1. The X-axis shows the relative humidity / % and the Y-axis shows the mass difference Am / %, The sorption isotherm is represented by the square symbols (symbols:■); the desorption isotherm is represented by the triangle symbols (symbols: A ).

Figure 8: illustrates a representative PXRD of the crystalline acid addition salt of brigatinib with fumaric acid, form M, prepared according to the procedure described in Example 3-3. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 9: Representative DSC curve of the crystalline acid addition salt of brigatinib with fumaric acid, form M, prepared according to the procedure described in Example 3-3. The X- axis shows the temperature / °C and the Y-axis shows peak heights / Wg-1. Endothermic events are plotted up.

Figure 10: Representative TGA curve of the crystalline acid addition salt of brigatinib with fumaric acid, form M, prepared according to the procedure described in Example 3-3. The X- axis shows the temperature / °C and the Y-axis shows sample mass / %. Endothermic events are plotted up.

Figure 11 : Representative gravimetric moisture sorption/ desorption isotherms of the crystalline acid addition salt of brigatinib with fumaric acid, form M, prepared according to the procedure described in Example 3-3. The X-axis shows the relative humidity / % and the Y- axis shows the mass difference Am / %. The sorption isotherm is represented by the square symbols (symbols: ■); the desorption isotherm is represented by the triangle symbols (symbols: A).

Figure 12: Thermogravimetric mass spectroscopy (TGMS) thermogram of brigatinib form A. The X-axis shows the time / min, which is correlated with the sample temperature (sample kept at 25°C for 2.5 min, then heated from 25°C to 250°C at a rate of 10°C/min; e.g. sample temperature: 100°C after 10 min, 200°C after 20 min). The Y-axis shows the ion current / A. “m/z" corresponds to the mass-to-charge ratio. At about 100°C the chemistry of the prior art form A sample changes.

Figure 13: Thermogravimetric mass spectroscopy (TGMS) thermogram of the crystalline acid addition salt of brigatinib with fumaric acid, form M, prepared according to the procedure described in Example 3-3. The X-axis shows the time / min, which is correlated with the sample temperature (sample kept at 25°C for 2.5 min, then heated from 25°C to 250°C at a rate of 10°C/min; e.g. sample temperature: 100°C after 10 min, 200°C after 20 min). The Y-axis shows the ion current / A.“m/z” corresponds to the mass-to-charge ratio. The chemistry of the sample remains unchanged at temperatures where the prior art form A sample changes its composition.

Figure 14: illustrates a representative PXRD of the crystalline acid addition salt of brigatinib with citric acid, form N, prepared according to the procedure described in Example 4. The x- axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X- ray beam in counts of detected photons. Figure 15: illustrates a representative PXRD of the crystalline acid addition salt of brigatinib with hydrochloric acid, form O, prepared according to the procedure described in Example 5. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 16: illustrates a representative PXRD of the crystalline acid addition salt of brigatinib with 1 ,5-naphthalenedisulfonic acid, form P, prepared according to the procedure described in Example 6. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Detailed description

Crystalline hydrate system

The present invention refers to a new crystalline hydrate system (also referred to herein as brigatinib form H1 and form H2) exhibiting improved physical properties e.g., with regard to stability, as well as to pharmaceutical compositions comprising the same.

Crystalline acid addition salts of brigatinib

The present invention also relates to crystalline acid addition salts of brigatinib.

In a particular embodiment, the acid addition salts of brigatinib with an acid, in particular with a pharmaceutically acceptable acid such as fumaric acid, citric acid, hydrochloric acid and 1 ,5- naphtha!enedisulfonic acid, is characterized by having a molar ratio of brigatinib and acid in the range of from 1 .0 : 0.8 to 1 .0 : 5.0, preferably of from 1.0 : 0.9 to 1 .0 : 4.0 and most preferably the molar ratio is 1 .0 : 3.0.

The present inventors have surprisingly found that crystalline acid addition salts of brigatinib of the present invention are stable and have a higher thermal stability than the marketed brigatinib form A. Moreover the crystalline acid addition salt of brigatinib with fumaric acid of the present invention, is less hygroscopic than marketed brigatinib form A. Pharmaceutical compositions with the crystalline acid addition salt of brigatinib with fumaric acid of the present invention is advantageous compared to pharmaceutical compositions comprising crystalline brigatinib form A in that its lower hygroscopicity and higher thermal stability can improve storage stability, for example under high temperature conditions or for a longer storage period.

Additionally, crystalline acid addition salts of brigatinib of the present invention are crystalline forms wherein brigatinib is chemically stable. By“chemically stable” it is meant that crystalline acid addition salts of brigatinib of the present invention show very little degradation (e.g., less than 5-%) when analyzed by thermogravimetric mass spectroscopy (TGMS) from 25°C to 170°C at a heating rate of 10°C/min, preferably crystalline acid addition salts of brigatinib with fumaric acid, hydrochloric acid and 1 ,5-naphthalenedisulfonic acid of the present invention show very little degradation when analyzed by thermogravimetric mass spectroscopy (TGMS) from 25°C to 200°C at a heating rate of 10°C/min. The chemistry of the crystalline acid addition salt of brigatinib with fumaric acid, hydrochloric acid and 1 ,5-naphthalenedisulfonic acid of the present invention, remains unchanged at temperatures where prior art forms, e.g., crystalline form A of brigatinib, changes its composition, as the chemistry of prior art brigatinib form A changes at about 100°C. By“chemically stable upon storage under stress conditions” it is meant that crystalline acid addition salts of brigatinib of the present invention show very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days. Very little degradation means that the TGMS thermogram shows no relevant decomposition process or an HPLC (high performance liquid chromatography) analysis of brigatinib shows no impurity of more than 0.1 area%.

Embodiments:

Form H1 and H2 and hydrate system:

Form H1

In a first aspect, the present invention refers to crystalline hydrate form H1 of brigatinib, and a method of preparing the same. In the following, preferred embodiments of form H1 are described:

H 1 -1. Crystalline hydrate form H1 of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") as the free base characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (13.0+ 0.2)°, (18.8± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal ,2 radiation having a wavelength of 0.15419 nm.

In a preferred embodiment, the crystalline hydrate form H1 of brigatinib is a“wet hydrate”. H1 -2. Crystalline hydrate form of brigatinib according to item H 1 -1 , further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (13.0 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2),“when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (13.0 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (20.9 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (20.9 ± 0.2)°, (21.1 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

H1 -3. Crystalline form of brigatinib according to item H1 -1 or H1-2, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1 .

H1 -4. Crystalline hydrate form of brigatinib according to any one of items H1 -1 to H1 -3, characterized by having a powder X-ray diffractogram essentially the same as shown in Figure 3 herein, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 n . H 1 -5. DSC analyses of the crystalline hydrate form of brigatinib according to any one of Items H1 -1 to H1 -4, characterized by showing a first endotherm event between a temperature of about 32±2°C and about 108±2°C. By heating further, a second endotherm event is observed at onset temperature of about 120±2°C and a peak maximum at about 128±2°C and a third endotherm event, corresponding to the final melting, is observed at onset temperature of about 21 1 ±2°C and a peak maximum at about 214±2°C.

A representative DSC curve of the crystalline hydrate form of brigatinib according to any one of items H1 -1 to H1 -5, is shown in Figure 5.

H1-6. Therefore, alternatively or additionally, the crystalline hydrate form of brigatinib according to any one of items H1-1 to H1 -5, can be characterized by a DSC curve comprising a first endotherm event between a temperature of about 32±2°C and about 108±2°C, a second endotherm event - a transition endotherm - with an onset temperature of about 120±2°C and a peak maximum at about 128±2°C and a third endotherm event, corresponding to the final melting, with an onset temperature of about 21 1 ±2°C and a peak maximum at about 214±2°C, when measured at a heating rate of 10°C/min.

H1 -7. In addition, a representative TGA curve of the crystalline hydrate form of brigatinib according to any one of items H1 -1 to H1 -6, is shown in Figure 6, TGA curve shows a continuous weight loss of 4.0 w-% from 25 to about 120°C (1 .0 mole equivalent of water corresponds to about 3.0 w-%).

H1 -8. Crystalline hydrate form of brigatinib according to any one of items H1 -1 to H1 -7, characterized in that it is stable at ambient conditions and upon storage at 40°C and 75% RH for a time period of 8 weeks.

H1-9. Crystalline hydrate form of brigatinib according to any one of items H1-1 to H1-8, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%.

The (chemical) purity as referred to herein can be determined by HPLC -analysis.

H1 -10. Crystalline hydrate form of brigatinib according to any one of items H1-1 to H1 -9, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w- %, further preferred at least 98 w-%.

The polymorphic purity as referred to herein can be determined by PXRD -analysis. H1 -1 1 . Crystalline form according to any one of items H1-1 to H1 -10, which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The“impurities" are other compounds than brigatinib and water as well as other crystalline or non-crystalline forms of brigatinib.

Preparation of brigatinib form H1 :

The present invention also refers to a process for the preparation of crystalline form H1 of brigatinib. In the following, preferred embodiments of the preparation of form H1 are described:

H1-12. Process for the preparation of the crystalline hydrate form of brigatinib as defined in any one of items H1 -1 to H 1-1 1 , comprising the following steps:

(i) providing a crystalline form of brigatinib (form S) as defined herein;

(ii) storing the crystalline form of brigatinib provided in step (i) at a temperature in the range of 25-40°C and a relative humidity in the range of from 25-80, e.g., 50-75%, thereby obtaining the crystalline form of brigatinib as defined in any of items H1 -1 to H1 -11 .

H1 -13. Process according to item H1-12, wherein step (i) comprises the steps defined in item S-9.

Form H2:

In a further aspect, the present invention refers to crystalline hydrate form H2 of brigatinib, and a method of preparing the same. In the following, preferred embodiments of form H2 are described:

H2-1. Crystalline hydrate form H2 of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1 -yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") as the free base characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (12.3 ± 0.2)°, (19.1 ± 0.2)° and (20.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm. In a preferred embodiment, the crystalline hydrate form H2 of brigatinib is a“dry hydrate”.

H2-2. Crystalline hydrate form of brigatinib according to item H2-1 , further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (12.3 ± 0.2)°, (18.7 ± 0.2), (19.1 ± 0.2)° and (20.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (12.3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)° and (20.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)° and (20.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (12,3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (10.4 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (10.4 ± 0.2)°, (12.3 ± 0.2)°, (12.9 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.8 ± 0.2)°, (8.3 ± 0.2)°, (10.4 ± 0.2)°, (12.3 ± 0.2)°, (12.9 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

H2-3. Crystalline form of brigatinib according to item H2-1 or H2-2, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1 .

H2-4. Crystalline hydrate form of brigatinib according to any one of items H2-1 to H2-3, characterized by having a PXRD essentially the same as shown in Figure 4 herein, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai_,2 radiation having a wavelength of 0.15419 nm.

H2-5. Crystalline hydrate form of brigatinib according to any one of items H2-1 to H2-4, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%.

H2-6. Crystalline hydrate form of brigatinib according to any one of items H2-1 to H2-5, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w- %, further preferred at least 98 w-%.

The polymorphic purity as referred to herein can be determined by PXRD -analysis,

H2-7. Crystalline form according to any one of items H2-1 to H2-6, which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The“impurities” are other compounds than brigatinib and water as well as other crystalline or non-crystalline forms of brigatinib.

Preparation of brigatinib Form H2:

The present invention also refers to a process for the preparation of crystalline form H2 of brigatinib. In the following, preferred embodiments of the preparation of form H2 are described:

H2-8. Process for the preparation of the crystalline form of brigatinib as defined in any one of items H2-1 to H2-7, comprising the following steps:

(i) providing a crystalline form of brigatinib (form S) as defined herein;

(ii) drying crystalline brigatinib form S provided in step (i) at room temperature and a pressure being in the range of from 5-30 bar, thereby obtaining the crystalline form H2 as defined in any one of items H2-1 to H2-7.

H2-9. Process according to item H2-8, wherein step (i) comprises the steps defined in item S-9. Hydrate system:

The invention also refers to a hydrate system H1/H2 as follows:

H3-1 . Crystalline hydrate system comprising, preferably consisting of, form H1 according to any of items H1 -1 to H1 -11 and/or form H2 according to any of items H2-1 to H2-7.

The crystalline hydrate forms H1 and H2 can interconvert, which means that H1 can change to H2 and vice versa. For example, the hydrate system may only comprise form H1 , which, after dehydration converts to H2 to some extent. Accordingly, the hydrate system may contain a varying molar ratio of forms H1 and H2 over time. The molar ratio of forms Hi and H2 also vary with respect to the relative humidity.

H3-2. Crystalline hydrate system of brigatinib of the present invention, i.e. crystalline hydrates H1 and H2, reversibly converts to crystalline hydrate H1 , e.g. when exposed to relative humidity in the range of from 40 to 80%, or to crystalline hydrate H2, e.g. when exposed to relative humidity in the range of from 0 to 20% or to drying in vacuum.

H3-3. Moreover, representative gravimetric moisture sorption/desorption (GMSD) isotherms of the crystalline hydrate system of brigatinib of the present invention measured at 25 ± 0.1 °C are displayed in Figure 7 herein. The measurement was started using crystalline hydrate H1 of brigatinib containing 3.7 ± 0.1 w-% water at 25% RH. After desorption cycle until 0% RH and increasing relative humidity until 25%, crystalline hydrate H2 of brigatinib containing 2.6 ± 0.1 w-% water at 25% RH was obtained. The crystalline hydrate system of brigatinib, for example, shows a water content of 0.0 ± 0.1 w-% at about 0% RH and a water content of 7.5 ± 0.1 w-% at about 80% RH (1 .0 mole equivalent of water corresponds to ca. 3.0 w-%).

H3-4. Alternatively or additionally, the crystalline system of brigatinib can be characterized by being stable upon storage under normal conditions, preferably under storage at a relative humidity of 45% at 23°C for at least two six months, more preferably for at least one year, most preferably for at least two years. Alternatively or additionally, the crystalline system of brigatinib can be characterized by being stable upon storage under accelerated conditions, preferably under storage at a relative humidity of 70% at 40°C for at least one month, more preferably for at least three months, most preferably for at least six months. Form S: Crystalline dichloromethane solvate

In a further aspect, the present invention refers to crystalline solvate form S of brigatinib, and a method of preparing the same. In the following, preferred embodiments of form S are described:

S-1. Crystalline dichloromethane solvate form S of 5-chloro-N4-[2- (dimethylphosphoryl)phenyl]-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1- yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") as the free base characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2- Theta angles of (5.7 ± 0.2)°, (12.3 ± 0.2)° and (18.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

Form S is an intermediate of the hydrates of form H1 and H2. The presence of dichloromethane is the sample was confirmed by thermogravimetric mass spectroscopy (TGMS) thermogram, recorded during the thermogravimetric analysis, as well as by nuclear magnetic resonance (NMR) measurement.

Form S contains bonded and/or non-bonded dichloromethane molecules in its structure, for example 0.1 -0.5 mol of dichloromethane, preferably 0.1 -0.3 mol of dichloromethane (per mol of brigatinib). Form S might also contain some water.

S-2. Crystalline hydrate form of brigatinib according to item S-1 , further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (12.3 + 0.2)°, (17.6 ± 0.2)° and (18.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2)° and (18.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2)°, (18.8 ± 0.2)° and (21.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 ± 0.2)°, (12.3 ± 0.2)°, (17.2 ± 0.2)°, (17.6 ± 0.2)°, (18.8 ± 0.2)° and (21.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 + 0.2)°, (12.3 ± 0.2)°, (17.2 ± 0.2)°, (17.6 ± 0.2)°, (18.8 ± 0.2)°, (20.6 ± 0.2)° and (21 .8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 ± 0.2)°, (12.3 ± 0.2)°, (16.7 ± 0.2)°, (17.2 ± 0.2)°, (17.6 ± 0.2)°, (18,8 ± 0.2)°, (20.6 ± 0.2)° and (21.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.7 ± 0.2)°, (8.6 ± 0.2)°, (12.3 ± 0.2)°, (16.7 ± 0.2)°, (17.2 ± 0.2)°, (17.6 ± 0.2)°, (18.8 ± 0.2)°, (20.6 ± 0.2)°, (21.2 ± 0.2)° and (21.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

S-3. Crystalline form of brigatinib according to item S-1 or S-2, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1.

S-4. Crystalline dichloromethane solvate form S of brigatinib according to any one of items S-1 to S-3, characterized by having a PXRD essentially the same as shown in Figure 1 herein, when measured at a temperature in the range of from 20 to 30 °C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

S-5. Crystalline form of brigatinib according to any one of items S-1 to S-4, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w -%.

The“impurities” are other compounds than brigatinib, water and dichloromethane as well as other crystalline or non-crystalline forms of brigatinib,

S-6. Crystalline form of brigatinib according to any of items S-1 to S-5, characterized by a first endotherm with an onset temperature of about 32±2°C and a peak maximum at about 75+2°C and a second endotherm with an onset temperature of about of about 117±2°C and a peak maximum at about 128±2°C, and a third endotherm with an onset temperature in the range of 203-210°C, when determined by differential scanning calorimetry (DSC).

The DSC can be measured at a heating rate of 10°C/min. S-7. Crystalline form of brigatinib according to any of items S-1 to S-6, characterized by a continuous weight loss of 4.0 w-% from 25 to about 135°C (1.0 mole equivalent of dichloromethane corresponds to about 12.7 w-%), when carrying out thermogravimetric analysis (TGA).

S-8. Crystalline form of brigatinib according to any one of items S-1 to S-7, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%.

The polymorphic purity as referred to herein can be determined by PXRD -analysis.

Representative gravimetric moisture sorption/desorption (GMSD) isotherms of crystalline dichloromethane solvate of brigatinib, form S, measured at 25 ± 0.1 °C are displayed in Figure 2 herein. PXRD measurement performed at the end of the GMSD experiment reported in Figure 2 shows that crystalline dichloromethane solvate of brigatinib, form S, converts to the hydrate system of the present invention under the conditions used for the GMSD experiment as reported in the example part.

Crystalline dichloromethane solvate of brigatinib, form S, can convert to crystalline hydrate H1 of brigatinib of the present invention upon storage at a temperature of about 40°C and a relative humidity of about 75% RH for a period of time of 1 to 24 hours.

Preparation of brigatinib form S:

The present invention also refers to a process for the preparation of crystalline form S of brigatinib. In the following, preferred embodiments of the preparation of form S are described:

S-9. Process for the preparation of the crystalline form of brigatinib as defined in any one of items S-1 to S-8, comprising the following steps:

(i) providing brigatinib in amorphous or crystalline form,

(ii) dissolving said amorphous or crystalline brigatinib in a suitable solvent, including or consisting of dichloromethane, at a suitable temperature, preferably at a temperature of 25- 40°C, thereby obtaining a solution;

(iii) optionally, filtering the solution obtained in step (ii);

(iv) optionally seeding the solution,

(v) optionally, adding n-heptane; (vi) subjecting the mixture provided in any of (iii)-(v) to crystallization conditions leading to the formation of crystalline form S of brigatinib, preferably keeping the solution at room temperature without stirring for a time period of 1 to 30 days, slightly open to allow solvent evaporation, thereby leading to the formation of dichloromethane solvate of brigatinib, form S;

(vii) optionally, carrying out a filtration step after step (vi) in order to isolate the crystals, and (viii) obtaining crystalline form S of brigatinib.

In step (i) brigatinib may be provided by any method known to the person skilled in the art, such as, e.g., the methods described in WO2016/065028.

Brigatinib may be provided in any form, such as in crystalline, in amorphous form, or as a mixture thereof. Brigatinib may be present in crystalline form, e.g. in form A or form B or form C or form D or as a mixture of two or more thereof. Brigatinib may also be provided as a crystalline solvate reported in WO2016/065028.

In step (ii) solvent is added at a temperature in the range of from 10 to 40°C, more preferably in the range of from 20 to 30°C, preferably at ambient pressure.

A suitable organic solvent, in which crystallization of dichloromethane solvate of brigatinib, form S, is dichloromethane or a mixture of dichloromethane with an anti-solvent. Regarding the anti-solvents, no specific restrictions exist, provided that dichloromethane solvate of brigatinib, form S, is not soluble and is stable.

Optionally, seed crystals may be added in step (iv). The seed crystals are prepared using the same process steps as for the preparation of the dichloromethane solvate of brigatinib, form S. The seed crystals are typically added in an amount of 0.1 w-% to 10 w-%, preferably in an amount of 0.5 w-% to 7.0 w-%, most preferably 1.0 wt.% 5.0 w-%, on the basis of the total amount of the starting material used in step (i).

In step (vi) the mixture is kept slightly open at a temperature in the range of 10 to 30°C, preferably in the range of from 15 to 25 °C without stirring, allowing really slow solvent evaporation in order to promote crystallization.

Optionally, isolation in step (vii) may be performed by using procedures known in the art, such as by filtration, centrifugation, or evaporation of solvent. Moreover, the isolated crystals may be used for preparing forms H1 and H2.

Form M: Crystalline fumaric acid addition salt of brigatinib

In a further aspect, the present invention refers to crystalline addition salt form M of brigatinib with fumaric acid, and a method of preparing the same. In the following, preferred embodiments of form M are described: M-1. Crystalline acid addition salt of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") with fu marie acid.

M-2. Crystalline form according to item M-1 , characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (9.3 ± 0.2)°, (10.4 ± 0.2)° and (14.7 ± 0.2), when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

Form M may have a molar ratio of brigatinib and fumaric acid in the range from 1 .0 : 2.0 to 1.0 : 3.5, preferably from 1 .0 : 2.5 to 1 .0 : 3.0. It may be in the form of an anhydrate.

M-3. Crystalline form of brigatinib according to item M-1 or M-2, further characterized (I) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (14.7 ± 0.2)° and (17.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (14.7 ± 0.2)°, (17.0 ± 0.2)° and (19.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (17.0 ± 0.2)° and (19.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)° and (19.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 + 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (19.0 ± 0.2)° and (19.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14,7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (19.0 ± 0.2)° and (19.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; (vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (19.0 ± 0.2)°, (19.2 ± 0.2)° and (23.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

M-4. Crystalline form of brigatinib according to any of items M-1 to M-3, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1.

M-5. Crystalline form of brigatinib according to any of items M-1 to M-4, characterized by having a powder X-ray diffractogram essentially the same as shown in Figure 8 herein, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

M-6. Crystalline form of brigatinib according to any of items M-1 to M-5, characterized by a single endotherm with an onset temperature of about 217°C, e.g., 217± 2°C, and a peak maximum at about 221 °C, e.g., 221 + 2°C, when determined by differential scanning calorimetry (DSC).

The DSC can be measured at a heating rate of 10°C/min.

A representative DSC curve of the crystalline acid addition salt of brigatinib with fumaric acid, form M, is displayed in Figure 9.

M-7. Crystalline form of brigatinib according to any of items M-1 to M-6, characterized by having a melting point of about 217°C, when measured with DSC at a heating rate of 10°C/min.

M-8, Crystalline form of brigatinib according to any of items M-1 to M-7, characterized by having a DSC curve essentially the same as displayed in Figure 9.

M-9. Crystalline form of brigatinib according to any of items M-1 to M-8, characterized by a weight loss of 0.4 w-% from 25 to about 190°C (corresponding to loss of unbound residual organic solvent or atmospheric moisture), when carrying out thermogravimetric analysis (TGA).

A representative TGA curve of the crystalline acid addition salt of brigatinib with fumaric acid, form M, is provided in Figure 10 herein. M-10. Crystalline form of brigatinib according to any of items M-1 to M-9, characterized by comprising about £ 1.0 w-%, preferably about £ 0.8 w-%, more preferably about £ 0.6 w-% and most preferably about £ 0.4 w-% organic solvent.

The organic solvent can be determined e.g, by TGA and TGMS.

M-1 1 . Crystalline form of brigatinib according to any of items M-1 to M-10, characterized by a water content of 0.0 w-% at about 0% RH and a water content of 0.9 w-% at about 80% RH (GMSD).

M-12. Crystalline form of brigatinib according to any of items M-1 to M-1 1 , characterized by comprising £ 1 .0 w-% water when measured at 0 to 80% RH and 25 ± 0.1 °C (GMSD).

A representative gravimetric moisture sorption/desorption (GMSD) isotherms of the crystalline acid addition salt of brigatinib with fumaric acid, form M, measured at 25 ± 0.1 °C are displayed in Figure 1 1 herein. According to the GMSD isotherms displayed in Figure 1 1 the crystalline acid addition salt of brigatinib with fumaric acid, Form M, is an anhydrate of acid addition salt of brigatinib with fumaric acid with low hygroscopicity. Hence, alternatively or additionally, the crystalline acid addition salt of brigatinib with fumaric acid, Form M, can be characterized as being an anhydrate.

M-13. Crystalline form of brigatinib according to any of items M-1 to M-12, characterized in that it is stable under normal conditions for at least two years.

Alternatively or additionally, the crystalline acid addition salt of brigatinib with fumaric acid, form M, can be characterized by being stable upon storage under normal conditions, preferably under storage at a relative humidity of 45% at 23°C for at least two six months, more preferably for at least one year, most preferably for at least two years. Alternatively or additionally, the crystalline acid addition salt of brigatinib with fumaric acid, form M, can be characterized by being stable upon storage under accelerated conditions, preferably under storage at a relative humidity of 70% at 40°C for at least one month, more preferably for at least three months, most preferably for at least six months. In a preferred embodiment, the crystalline acid addition salt of brigatinib with fumaric acid of the present invention is a crystalline form wherein brigatinib is chemically stable.

By“chemically stable" it is meant that the crystalline acid addition salt of brigatinib with fumaric acid of the present invention (form M) shows very little degradation when analyzed by thermogravimetric mass spectroscopy (TGMS) from 25°C to about 200°C at a heating rate of 10°C/min, as illustrated in Figure 13. The chemistry of the crystalline acid addition salt of brigatinib with fumaric acid, form M, remains unchanged at temperatures where prior art forms, e.g., crystalline form A of brigatinib, changes its composition. The chemistry of brigatinib form A changes at about 100°C, as illustrated in Figure 12.

By“chemically stable upon storage under stress conditions" it is meant that crystalline acid addition salt of brigatinib with fumaric acid of the present invention shows very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days. Very little degradation means that the TGMS thermogram shows no relevant decomposition process or an HPLC analysis of brigatinib shows no impurity of more than 0.1 area%.

M-14. Crystalline form of brigatinib according to any one of items M-1 to M-13, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%.

M-15. Crystalline form of brigatinib according to any one of items M-1 to M-14, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%.

M-16. Crystalline form M according to any one of items M-1 to M-15, which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The “impurities” are other compounds than brigatinib and fumaric acid as well as other crystalline or non-crystalline forms of brigatinib.

Form N: Crystalline citric acid addition salt of brigatinib

In a further aspect, the present invention refers to crystalline addition salt form N of brigatinib with citric acid, and a method of preparing the same. In the following, preferred embodiments of form N are described: N-1 . Crystalline acid addition salt of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") with citric acid.

The crystalline acid addition salt may have a molar ratio of brigatinib and citric acid in the range from 1 .0 : 0.5 to 1 .0 : 2.0, preferably of from 1 .0 : 1 .0 to 1.0 : 2.0.

N-2. Crystalline form according to item N-1 , characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (8.6 ± 0.2)°, (1 1 .3 ± 0.2)° and (12.7 ± 0.2)°, when measured at a temperature in the range from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

N-3. Crystalline form of brigatinib according to item N-1 or N-2, further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (11 .3 ± 0.2)°, (12.7 ± 0.2)° and (14.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1.3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)° and (16.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1 .3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)°, (16.4 ± 0.2)° and (17.0± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1 .3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)°, (16.4 ± 0.2)°, (17.0± 0.2)° and (18.5 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1.3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)°, (16.4 ± 0.2)°, (17.0± 0.2)°, (18.5 ± 0.2)° and (20.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1.3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)°, (16.4 ± 0.2)°, (17.0± 0.2)°, (18.5 ± 0,2)°, (20.1 ± 0.2)° and (21 .4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; (vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.6 ± 0.2)°, (1 1.3 ± 0.2)°, (12.7 ± 0.2)°, (14.4 ± 0.2)°, (16.4 ± 0.2)°, (17.0± 0.2)°, (18.5 ± 0.2)°, (20.1 + 0.2)°, (21 .4 + 0.2)° and (21.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

N-4. Crystalline form of brigatinib according to any one of items N-1 to N-3, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1 .

N-5. Crystalline form of brigatinib according to any one of items N-1 to N-4, characterized by having a powder X-ray diffractogram essentially the same as shown in Figure 14 herein, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

N-6. Crystalline form of brigatinib according to any one of items N-1 to N-5, characterized by a first endotherm between about 50 and 125 °C, corresponding to dehydration, and a multiple endotherm event between about 170 and 205 °C, when determined by differential scanning calorimetry (DSC).

The DSC can be measured at a heating rate of 10°C/min.

N-7. Crystalline form of brigatinib according to any one of items N-1 to N-6, characterized by a weight loss of 2.6 w-% from 25 to about 130°C - corresponding to sample dehydration and loss of eventual unbound residual organic solvent, when carrying out thermogravimetric analysis (TGA).

N-8. Crystalline form of brigatinib according to any one of N-1 to N-7, characterized by a water content of about 2.0 w-% at about 10% RH and about 3.7 w-% at 80% RH, measured at 25 ± 0.1 °C (GMSD).

According to the GMSD isotherms, the crystalline acid addition salt of brigatinib with citric acid is a hydrate with low to medium hygroscopicity. Hence, alternatively or additionally, the crystalline acid addition salt of brigatinib with citric acid can be characterized as being a hydrate.

N-9. Crystalline form of brigatinib according to any one of items N-1 to N-8, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%. The (chemical) purity as referred to herein can be determined by HPLC -analysis.

N-10. Crystalline form of brigatinib according to any one of items N-1 to N9, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%.

N-1 1 . Crystalline form according to any one of items N-1 to N-10, which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The“impurities” are other compounds than brigatinib, water and citric acid as well as other crystalline or non-crystalline forms of brigatinib.

Form 0: Crystalline hydrochloric acid addition salt of brigatinib

In a further aspect, the present invention refers to crystalline addition salt form O of brigatinib with hydrochloric acid, and a method of preparing the same. In the following, preferred embodiments of form O are described:

0-1. Crystalline acid addition salt of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") with hydrochloric acid.

The crystalline acid addition salt may have a molar ratio of brigatinib and hydrochloric acid in the range from 1.0 : 0.5 to 1 .0 : 2.0. It may be a hydrate at ambient conditions, e.g., at 25°C and 25-45%RH.

0-2. Crystalline form according to item 0-1 , characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (4.5 ± 0.2)°, (10.6 ± 0.2)° and (14.1 ± 0.2)°, when measured at a temperature in the range from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm. 0-3. Crystalline form of brigatinib according to item 0-1 or 0-2, further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)° and (14.1 ± 0,2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)° and (14.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)°, (12.2 ± 0.2)° and (14.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)°, (12.2 ± 0.2)°, (14.1 ± 0.2)° and (17.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)°, (12.2 ± 0.2)°, (14.1 ± 0.2)°, (17.3 ± 0.2)° and (18.7 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)°, (12.2 ± 0.2)°, (14.1 ± 0.2)°, (17.3 ± 0.2)°, (18.7 ± 0.2)° and (19.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (9.0 ± 0.2)°, (10.6 ± 0.2)°, (1 1.7 ± 0.2)°, (12.2 ± 0.2)°, (14.1 ± 0.2)°, (17.3 ± 0.2)°, (18.7 ± 0.2)°, (19.1 ± 0.2)° and (19.8 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

0-4. Crystalline form of brigatinib according to any one of items 0-1 to 0-3, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1.

0-5. Crystalline form of brigatinib according to any one of items 0-1 to 0-4, characterized by having a powder X-ray diffractogram essentially the same as shown in Figure 15 herein, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm. 0-6. Crystalline form of brigatinib according to any one of items 0-1 to 0-5, characterized by a first endotherm with an onset temperature of about 53°C and a peak maximum at about 80°C, corresponding to dehydration and loss of eventual unbound residual organic solvent, and a melting endotherm with an onset temperature of about 231 °C and a peak maximum at about 233°C, when determined by differential scanning calorimetry (DSC).

The DSC can be measured at a heating rate of 10°C/min.

0-7. Crystalline form of brigatinib according to any one of items 0-1 to 0-6, characterized by a weight loss of 4.4 w-% from 25 to about 95°C - corresponding to sample dehydration and loss of eventual unbounded residual organic solvent, when carrying out thermogravimetric analysis (TGA).

0-8. Crystalline form of brigatinib according to any one of items 0-1 to 0-7, characterized by a water content of 0.0 ± 0.5 w-% at about 0% RH, and/or of 4.4 + 0.3 w-% at about 35-55% RH (sorption isotherm) and/or at about 20-45% RH (desorption isotherm) and/or a water content of 12.4 ± 0.5 w-% at about 70-90% RH, measured at 25 ± 0.1 °C (GMSD).

According to the measured GMSD isotherms, the crystalline acid addition salt of brigatinib with hydrochloric acid of the present invention contains about 4.4 ± 0.3 w-% at ambient conditions and reversibly dehydrates at relative humidity below 10% or takes more water above 55-60% RH. Hence, alternatively or additionally, the crystalline acid addition salt of brigatinib with hydrochloric acid of the present invention can be characterized as being a hydrate at ambient conditions.

0-9. Crystalline form of brigatinib according to any one of items 0-1 to 0-8, characterized in that it is (chemically) stable under normal conditions, preferably for at least two years.

By "chemically stable" it is meant that crystalline acid addition salt of brigatinib with hydrochloric acid of the present invention shows very little degradation when analyzed by thermogravimetric mass spectroscopy (TGMS) from 25°C to about 200°C at a heating rate of 10°C/min. The chemistry of the crystalline acid addition salt of brigatinib with hydrochloric acid, form O, remains unchanged at temperatures where prior art forms, e.g. crystalline form A of brigatinib, changes its composition.

By“chemically stable upon storage under stress conditions” it is meant that crystalline acid addition salt of brigatinib with hydrochloric acid of the present invention shows very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40°C for 14 days, preferably after storage for 50 days. Very little degradation means that the TGMS thermogram shows no relevant decomposition process or an HPLC analysis of brigatinib shows no impurity of more than 0.1 area%.

0-10. Crystalline form of brigatinib according to any one of items 0-1 to 0-9, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%.

0-1 1 . Crystalline form of brigatinib according to any one of items 0-1 to H1 -10, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%.

0-12. Crystalline form according to any one of items 0-1 to 0-1 1 , which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The“impurities" are other compounds than brigatinib, water and HCI as well as other crystalline or non-crystalline forms of brigatinib.

Form P: Crystalline 1 ,5-naphthalenedisulfonic acid addition salt of brigatinib

In a further aspect, the present invention refers to crystalline addition salt form P of brigatinib, and a method of preparing the same. In the following, preferred embodiments of form P are described:

P-1 . Crystalline acid addition salt of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine (also referred to as "brigatinib") with 1 ,5-naphthalenedisulfonic acid.

The crystalline acid addition salt may have a molar ratio of brigatinib and 1 ,5- naphthalenedisulfonic acid in the range of from 1.0 : 0.5 to 1 .0 : 2.0, preferably of 1.0 : 1 .0. It may be a hydrate (containing 2.5-3.0 mol of water at ambient conditions). P-2. Crystalline form according to item P-1 , characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (5.5 ± 0.2)°, (6.6 ± 0.2)° and (13.6 ± 0.2)°, when measured at a temperature in the range from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

P-3. Crystalline form of brigatinib according to item P-1 or P-2, further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (13.6 ± 0.2)° and (14.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10.7 ± 0.2)°, (13.6 ± 0.2)° and (14.4 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10.7 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)° and (17.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10.7 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)°, (16.5 ± 0.2)° and (17.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10,7 ± 0.2)°, (13.3 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)°, (16.5 ± 0.2)° and (17.1 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10.7 ± 0.2)°, (13.3 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)°, (16.5 ± 0.2)°, (17.1 ± 0.2)° and (18.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.5 ± 0.2)°, (6.6 ± 0.2)°, (10.7 ± 0.2)°, (13.3 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)°, (16.5 ± 0.2)°, (17.1 ± 0.2)°, (18.3 + 0.2)° and (19.7± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

P-4, Crystalline form of brigatinib according to any one of items P-1 to P-3, wherein the peaks are not defined by an accuracy of ± 0.2 but by an accuracy of ± 0.1. P-5. Crystalline form of brigatinib according to any one of items P-1 to P-4, characterized by having a powder X-ray diffractogram essentially the same as shown in Figure 16 herein, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

P-6. Crystalline form of brigatinib according to any one of items P-1 to P-5, characterized by a first multiple endotherm event between about 30 and 110 °C, corresponding to dehydration, and a second endotherm event with an onset temperature of about 215°C and a peak maximum at about 255°C, when determined by differential scanning calorimetry (DSC).

The DSC can be measured at a heating rate of 10°C/min.

P-7. Crystalline form of brigatinib according to any one of items P-1 to P-6, characterized by a weight loss of 5.6 w-% from 30 to about 170°C - corresponding to sample dehydration and loss of eventual unbound residual organic solvent (1.0 mole equivalent of water corresponds to about 2.0 w-%), when carrying out thermogravimetric analysis (TGA).

P-8. Crystalline form of brigatinib according to any one of items P-1 to P-7, characterized by a water content of about 0.9 w-% at about 0% RH and 8.5 ± 0.5 w-% at 80% RH, measured at 25 + O.rC (GMSD).

According to the GMSD isotherms, the crystalline acid addition salt of brigatinib with 1 ,5- naphthalenedisulfonic acid of the present invention is a hydrate of acid addition salt of brigatinib with 1 ,5-naphthalenedlsulfonic acid. Hence, alternatively or additionally, the crystalline acid addition salt of brigatinib with 1 ,5-naphthalenedisulfonic acid of the present invention can be characterized as being a hydrate.

P-9. Crystalline form of brigatinib according to any one of items P-1 to P-8, which is in substantially pure form, preferably has a purity of at least 95 w-%, further preferred at least 98 w-%.

The (chemical) purity as referred to herein can be determined by GC (gaschromatography) - analysis.

P-10. Crystalline hydrate form of brigatinib according to any one of Items P-1 to P-9, which is in substantially pure polymorphic form, preferably has a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%. The polymorphic purity as referred to herein can be determined by PXRD -analysis.

P-1 1. Crystalline form according to any one of items P-1 to P-10, which has a chemical purity of at least 95 w-%, preferably at least 98%, as determined by HPLC-analysis, and a polymorphic purity of at least 95 w-%, further preferred at least 98 w-%, as determined by PXRD analysis.

The“impurities" are other compounds than brigatinib, water and 1 ,5-naphthalenedisulfonic acid as well as other crystalline or non-crystalline forms of brigatinib.

Preparation of brigatinib acid addition salts:

The present invention also refers to a process for the preparation of crystalline addition salts of brigatinib, forms M, N, O, and P, as defined and disclosed above. In the following, preferred embodiments of for the preparation of forms M, N, O and P are described:

MNOP-1 . Process for the preparation of the crystalline acid addition salts of brigatinib as defined in any one of items M-1 to M-16, N-1 to 1 1 , 0-1 to 0-12, and P-1 to P-11 , comprising the following steps:

(i) providing brigatinib;

(ii) adding the respective acid and at least one organic solvent to obtain a solution or a suspension,

(iii) optionally seeding the mixture with the crystalline acid addition salt of brigatinib and

(iv) subjecting the mixture provided in (iii) to crystallization conditions leading to the formation of the crystalline acid addition salt of brigatinib

(v) optionally isolating the crystalline acid addition salt of brigatinib,

(vi) optionally drying the crystalline acid addition salt of brigatinib, and

(vii) obtaining the crystalline acid addition salt of brigatinib.

In step (i) brigatinib may be provided by any method known to the person skilled in the art, such as, e.g., the methods described in WO2016/065028. Furthermore, brigatinib may be provided in any form, such as in crystalline, in amorphous form, or as a mixture thereof. Brigatinib may be present in crystalline form, e.g. in form A or form B or form C or form D or as a mixture of two or more thereof. Brigatinib may also be provided as a crystalline solvate reported in WO2016/065028. In step (ii) the acid and the at least one organic solvent can be added in any order. Moreover, the acid can be added neat or can be first dissolved or diluted in the at least one organic solvent. In step (ii), the mole ratio of brigatinib and acid is preferably in the range of from 1 .0:0.9 to 1.0:4.0, more preferably in the range of from 1 .0:1.0 to 1.0:3.0. In step (ii), the solvent or a solution containing the acid dissolved in the solvent is added at a temperature in the range of from 10 to 80°C, more preferably in the range of from 20 to 50°C, preferably at ambient pressure.

A suitable organic solvent, in which the acid base reaction of step (ii) may be carried out is selected from the group consisting of acetonitrile, C3-C5 ketones, C1 -C2 halogenated hydrocarbons, C2-C4 alcohols, C2-C6 ethers, C3-C5 esters or a combination of two or more thereof. Preferably, the solvent is selected from the group consisting of dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, 2-propanol, ethyl acetate, isopropyl acetate, acetone, acetonitrile or mixtures of two or more thereof.

Optionally, seed crystals may be added in step (iii). The seed crystals are prepared according to the same process as the one reported in MNOP-1 . In particular, the seed crystals are prepared using the same process steps as the specific crystalline acid addition salt of brigatinib of the present invention. The seed crystals are typically added in an amount of 0.1 w-% to 10 w-%, preferably in an amount of 0.5 w-% to 7.0 w-%, most preferably 1.0 wt.% 5.0 w-%, on the basis of the total amount of the starting material used in step (i).

In step (iv) the mixture is stirred at a temperature in the range of from 15 to 60°C, preferably in the range from 20 to 50°C, typically for a period of time from 2 to 24 hours, under stirring conditions or without stirring, in order to promote crystallization. After crystallization, the mixture can optionally be cooled to a temperature in the range from 0 to 20°C, preferably in the range from 5 to 15°C and/or one or more anti-solvents can be added to the mixture to increase the process yield. Regarding the anti-solvents, no specific restrictions exist, provided that the crystalline acid addition salt of brigatinib is not soluble and is stable.

Optionally, isolation in step (v) may be performed by using procedures known in the art, such as by filtration, centrifugation, or evaporation of solvent. Moreover, the isolated crystals may optionally be dried in step (vi), e.g. under reduced pressure, typically at room temperature, or heated up to a temperature between 25°C and 40°C or the crystals may directly be used in further processes.

Compositions comprising the crystalline forms H1, H2, the hydrate system H1/H2, crystalline forms S, M, N, 0, and/or P of brigatinib In a further aspect, the present invention also refers to compositions comprising, preferably consisting of,

- crystalline forms H1 and/or H2 as defined herein;

- the hydrate system H1/H2 as defined herein;

- form S of brigatinib as defined herein; and/or

- crystalline additions salts forms M, N, O and/or P of brigatinib as defined herein.

Preferred embodiments of compositions comprise crystalline forms H1 and/or H2 as defined herein.

Further preferred embodiments of compositions comprise the hydrate system H1/H2 as defined herein.

Further preferred embodiments of compositions comprise form M, optionally in addition to crystalline forms H1 and/or H2, or optionally in addition to the hydrate system H1/H2, respectively as defined herein.

The present invention also refers to a method of preparing the same.

In the following, preferred embodiments of compositions comprising crystalline form H1 , H2, hydrate system H1/H2 and/or form S or crystalline addition salts form M, N, O, or P are described:

C-1 . Composition comprising

- crystalline forms H1 according to any one of items H1 -1 to H1-1 1 and/or H2 according to any one of items H2-1 to H2-7;

- the hydrate system H1/H2 according to item H3-1 to H3-4; and/or

- crystalline form S of brigatinib according to any one of items S-1 to S-8; and/or

- crystalline additions salts form M according to any one of items M-1 to M-16, or form N according to any one of items N-1 to N-1 1 , or form O according to any one of items O- 1 to 0-12, or form P according to any one of items P-1 to P-1 1 ;

preferably, the composition is essentially free of any other physical form of brigatinib.

The composition can also comprise two or more forms selected from the forms disclosed herein. In one embodiment the composition comprises both form H1 and form H2 or form M. In a preferred embodiment, the composition comprises one of form H1 , form H2 or form M.

C-2. Composition according to C-1 , or composition comprising the crystalline form of brigatinib according to any one of items H1 -1 to H 1 -1 1 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S- 8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , characterized by comprising at most 20% by weight of any other physical form of brigatinib, based on the weight of the composition, preferably as determined by PXRD.

C-3. Composition according to C-1 , or composition comprising the crystalline form of brigatinib according to any one of items H1-1 to H1 -11 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S- 8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , characterized by comprising at most 10% by weight of any other physical form of brigatinib, based on the weight of the composition.

C-4. Composition according to C-1 , or composition comprising the crystalline form of brigatinib according to any one of items H1 -1 to H 1-11 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S- 8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , characterized by comprising at most 5% by weight of any other physical form of brigatinib, based on the weight of the composition.

C-5. Composition according to C-1 , or composition comprising the crystalline form of brigatinib according to any one of items H 1 -1 to H 1-11 , H2-1 to H2-7, H3-1 to H 3-4, S-1 to S- 8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , characterized by comprising at most 2% by weight of any other physical form of brigatinib, based on the weight of the composition.

C-6. Composition according to C-1 , or composition comprising the crystalline form of brigatinib according to any one of items H1 -1 to H1 -1 1 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S- 8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , characterized by comprising at most 1 % by weight of any other physical form of brigatinib (e.g., including other crystalline and amorphous forms), based on the weight of the composition.

C-7. Composition comprising the crystalline form of brigatinib according to any one of items C-1 to C-6, wherein any other physical form of brigatinib is amorphous.

C-8. Composition comprising the crystalline form of brigatinib according to any one of items C-1 to C-6, wherein any other physical form of brigatinib, which is not present, is

Form A characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 9.6, 17.2, 19.4, 20.1 , 23.1 and 27.7, when measured as disclosed in paragraphs [0090], [0091], [0092], and [0093] of WO 2016/065028;

Form B characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 1 1.5, 14.5, 16.9, 19.2 and 23.2, when measured as disclosed in paragraphs [0090], [0091 ], [0092], and [0093] of WO 2016/065028;

Form C characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 5.4, 14.9, 15.9, 17.3, 19.2 and 23.9, when measured as disclosed in paragraphs [0090], [0091], [0092], and [0093] of WO 2016/065028;

Form D characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 9.7, 1 1 .1 , 17.4, 18.9 and 23.7, when measured as disclosed in paragraphs [0090], [0091 ], [0092], and [0093] of WO 2016/065028;

Form E characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 9.1 , 10.2, 15.8, 19,2 and 23.9, when measured as disclosed in paragraphs [0090], [0091 ], [0092], and [0093] of WO 2016/065028;

Form F characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 9.8, 17.0, 19.4, 20.3 and 27.1 , when measured as disclosed in paragraphs [0090], [0091], [0092], and [0093] of WO 2016/065028;

Form G characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 8.3, 9.7, 12.9, 15.8, 18.1 , 20.7, 22.8 and 26.8, when measured as disclosed in paragraphs [0090], [0091], [0092], and [0093] of WO 2016/065028;

Form H characterized by having a powder X-ray diffraction pattern with at least two peaks expressed in degrees 2-Theta chosen from 4.2, 5.2, 8.4, 10.9, 12.7 and 21.3, when measured as disclosed in paragraphs [0090], [0091], [0092], and [0093] of WO 2016/065028.

C-9. Composition comprising the crystalline form of brigatinib according to any one of items C-1 to C-6, wherein any other physical form of brigatinib is form CS2 characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (17.1 ± 0.2)°, (22.9 ± 0.2)° and (28.7 ± 0.2)°, as depicted in table 8 of WO 2018/077187.

The composition defined in any one of C-1 to C-9 can further comprise pharmaceutically acceptable excipient(s). The choice of said excipient(s) depends on the intended administration of the brigatinib. For example, if a form of brigatinib as disclosed herein is intended to be administered in solid form, such as a tablet, then suitable pharmaceutically acceptable excipients can for instance be selected from the group consisting of carriers, fillers, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavouring agents, binders, colorants, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials and combinations thereof.

Use of crystalline forms and compositions

In a further aspect, the present invention also refers to the use of the crystalline forms of brigatinib disclosed herein, and the compositions comprising said crystalline forms.

U-1 . Use of the crystalline form as defined in any one of items H1 -1 to H1 -1 1 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S-8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , or the composition as defined in any one of items C-1 to C-9, for the preparation of a pharmaceutical composition.

U-2. Use according to item U-1 , wherein the pharmaceutical composition is prepared by a dry or wet processing method.

U-3. Use according to item U-2, wherein the dry processing method comprises dry granulation or dry compaction, and the wet processing method comprises wet granulation.

U-4. Pharmaceutical composition comprising the crystalline form as defined in any one of items H1-1 to H1 -1 1 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S-8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-1 1 , or the composition as defined in any one of items C-1 to C-9, and at least one pharmaceutically acceptable excipient.

U-5. Pharmaceutical composition according to item U-4, comprising predetermined and/or effective amount of the crystalline form defined in any of items H1-1 to H1 -1 1 , H2-1 to H2-7, H3-1 to H3-4, S-1 to S-8, M-1 to M-16, N-1 to N-1 1 , 0-1 to 0-12, or P-1 to P-11 , or the composition as defined in any one of items C-1 to C-9, and at least one pharmaceutically acceptable excipient.

U-6. Pharmaceutical composition according to items U-4 or U-5, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of carriers, fillers, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavouring agents, binders, colorants, osmotic agents, buffers, surfactants, disintegrants, granulating agents, coating materials and combinations thereof. Methods

Powder X-rav diffraction

Powder X-ray diffraction (PXRD) was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Ka1 ,2 radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector. Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels).

Differential scanning calorimetry

Differential scanning calorimetry (DSC) was performed on a Mettler Polymer DSC R instrument. The sample was heated in a 40 microL aluminum pan with pierced aluminum lid from 25 to 250°C or from 25 to 300°C at a rate of 10°C/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.

Thermogravimetric mass spectroscopy (TGMS)

Thermogravimetric analysis (TGA) was performed on a Mettler Toledo TGA/DSC 1 instrument. Samples were heated in 100 pi aluminium pans closed with aluminium lids. Lids were automatically pierced at the beginning of the measurement. Samples were initially kept at 25°C for 2.5 minutes and then heated from 25 to 250°C or from 25 to 300°C at a rate of 10°C/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.

Mass spectrometry (MS) measurements, coupled with thermogravimetric analysis (TGA), were performed with a Pfeiffer GSD 320 ThermoStar Gas Analysis System. A part of the headspace was evacuated with a capillary placed near the TG sample pan, and mass fragments between 1 - 100 atomic mass units (amu) were analyzed simultaneously without further separation applying a secondary electron multiplier (SEM) for signal amplification. Since samples were kept at 25°C for 2.5 minutes and then heated with a heating rate of 10°C/min, the ordinate of mass trace printouts, displayed in minutes, can be directly related to temperatures applying a factor of 10 (e.g. 10 minutes correspond to 100°C in the TGA experiment).

Gravimetric moisture sorption/desorption Gravimetric moisture sorption/desorption (GMSD) isotherms were recorded with an SPSx-I m moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at relative humidity (RH) between 3% and 45%. Relative humidity was then decreased to 5% RH in 5% steps, followed by a further decrease to 3% RH and to 0% RH. For this isotherm, a black filled square with a white plus (“+”) inside is used in the respective figures. Afterwards RH was increased from 0% to 80% RH or form 0% to 90% RH in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally RH was increased to ambient relative humidity, i.e. a relative humidity in the range of from 25% to 45%, in 5% steps. As to the isotherm obtained by the last step, a black filled square with a white“x" inside is used in the respective figures.

The time per step was set to a minimum of 2 hours and a maximum of 6 hours. If an equilibrium condition with a constant mass of ± 0.01 % within 1 hour was reached before the maximum time for all examined samples the sequential humidity step was applied before the maximum time of 6 hours. If no equilibrium was achieved the consecutive humidity step was applied after the maximum time of 6 hours. The temperature was 25 ± 0.1 °C.

Determination of the moisture stability

Moisture stability at accelerated stability conditions was performed in a Memmert constant climate chamber HPP1 10. 50-70 mg of crystalline sample were exposed to an atmosphere having a relative humidity of 75±1 % and a temperature of 40±0.5°C for a certain period of time.

Examples

Example 1 : preparation of dichloromethane solvate of brigatinib. form S

Example 1 -1

Brigatinib (200 mg, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V) was dissolved in 4.0 mL of dichloromethane. The solution was filtered. The filtrate was put into a test tube - with a slightly unscrewed cap to allow really slow solvent evaporation - and let stand at room temperature without stirring. After 14 days, all the solvent was evaporated and remaining solid material appear to be a crystalline dichloromethane solvate of brigatinib (form S). Characteristic PXRD pattern of the obtained crystalline dichloromethane solvate of brigatinib, form S, is shown in Figure 1. The corresponding reflection list is provided in Table 1 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 1 : PXRD reflection list of crystalline dichloromethane solvate of brigatinib, form S:

Example 1 -2

Brigatinib (202 mg, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V) was dissolved in 3.0 mL of dichloromethane. The solution was filtered and additional 1 .0 mL of dichloromethane was used to wash the filter. The filtrate was put into a test tube - with a slightly unscrewed cap to allow really slow solvent evaporation - and let stand at room temperature without stirring. After 8 days, solid material was obtained. The solvent was evaporated at ambient conditions overnight (20-3Q°C and 20-30% RH), yielding crystalline dichloromethane solvate of brigatinib, form S. The PXRD pattern of the obtained crystalline dichloromethane solvate of brigatinib, form S, was essentially identical to the one shown in Figure 1.

Example 2; preparation of the crystalline hydrate system, forms H1 -H2, of briaatinib Example 2-1 : preparation of hydrate H1

Crystalline dichloromethane solvate of brigatinib, form S (50 mg prepared according to Example 1 -1 herein) was stored at a temperature of about 40 °C and a relative humidity of about 75% for 14 hours, yielding crystalline hydrate system of brigatinib, and more particularly, crystalline hydrate form H1 of brigatinib. Characteristic PXRD pattern of the obtained crystalline hydrate H1 of brigatinib is shown in Figure 3. The corresponding reflection list is provided in Table 2 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 2: PXRD reflection list of the crystalline hydrate H1 of Brigatinib:

Example 2-2: preparation of hydrate H1

Brigatinib (102 mg, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V) was dissolved in 2.0 ml_ of dichloromethane. The solution was filtered. The filtrate was put into a test tube and 1.0 ml_ n-heptane was slowly added under manual shaking. The mixture was heated to reflux for a few seconds and let stand at a temperature of 25 to 35 °C and a relative humidity of 45 to 65% without stirring (tube cap slightly unscrewed to allow slow solvent evaporation). After 4 days, all the solvent was evaporated. The remaining solid material, which was exposed to a temperature of 25-35 °C and a relative humidity of 45-65%, was the crystalline hydrate H1 of brigatinib. The PXRD pattern of the obtained crystalline hydrate H1 of brigatinib was essentially identical to the one shown in Figure 3.

Example 2-3: preparation of hydrate H1

Crystalline hydrate H2 of brigatinib (40 mg, e.g. prepared according to Example 2-4 herein) was stored at a temperature of about 40 °C and a relative humidity of about 75% for 15 hours, yielding crystalline hydrate form H1 of brigatinib. The PXRD pattern of the obtained crystalline hydrate H1 of brigatinib was essentially identical to the one shown in Figure 3.

Example 2-4: preparation of hydrate H2

Crystalline hydrate H1 of brigatinib (50-70 mg prepared according to Example 2-1 herein) was subjected to gravimetric moisture sorption/desorption (GMSD) experiment as shown in Figure 7. The measurement cycle was started at 25% RH. The relative humidity was first decreased to 0% RH. Afterwards, it was increased from 0% to 80% RH in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally, the relative humidity was increased to ambient relative humidity, i.e. 25% RH, in 5% steps, yielding crystalline hydrate form H2 of brigatinib. Characteristic PXRD pattern of the obtained crystalline hydrate H1 of brigatinib is shown in Figure 4. The corresponding reflection list is provided in Table 3 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 3: PXRD reflection list of the crystalline hydrate H2 of Brigatinib:

Example 2-5: preparation of hydrate H2

Crystalline dichloromethane solvate of brigatinib, form S (50-70 mg prepared according to Example 1 -2 herein) was subjected to gravimetric moisture sorption/desorption (GMSD) experiment as shown in Figure 7. The measurement cycle was started at 25% RH. The relative humidity was first decreased to 0% RH. Afterwards, it was increased from 0% to 80% RH in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally, the relative humidity was increased to ambient relative humidity, i.e. 25% RH, in 5% steps, yielding crystalline hydrate form H2 of brigatinib. The PXRD pattern of the obtained crystalline hydrate H2 of brigatinib was essentially identical to the one shown in Figure 4.

Example 2-6: preparation of hydrate H2

Crystalline hydrate H1 of brigatinib (45 mg, e.g. prepared according to Example 2-1 herein) was dried in vacuum at a temperature of about 25 °C and a pressure of about 30 mbar for 16 hours, yielding crystalline hydrate form H2 of brigatinib. The PXRD pattern of the obtained crystalline hydrate H2 of brigatinib was essentially identical to the one shown in Figure 4. Example 3: preparation of the crystalline acid addition salts of brigatinib with fumaric acid (Form M)

Example 3-1

Fumaric acid (10.4 mg, 1.04 equivalent) was dissolved in 1.0 mL ethanol under sonication. The obtained solution was added to brigatinib (50.3 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by dissolution in water- acetonitrile (50:50 w-%), solution freezing in a liquid nitrogen bath and lyophilization at room temperature and a pressure of 0.1-0.5 mbar). Additional 1.0 mL ethanol was added. The mixture was heated to about 40-50 °C to accelerate dissolution of solid material. After complete dissolution of brigatinib, the clear solution was stirred at room temperature. After one hour, a suspension was formed and it was further stirred at room temperature for about 20 hours. Afterwards, the solid material was collected by filtration and dried at room temperature under vacuum (about 30 mbar) for 16 hours to yield the crystalline acid addition salts of brigatinib with fumaric acid, form M. The PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with fumaric acid, form M, was essentially identical to the one shown in Figure 8.

Example 3-2

Fumaric acid (20.4 mg, 2.04 equivalent) was dissolved in 0.5 mL ethanol under sonication and heating. The obtained solution was taken with a syringe - additional 0.5 mL ethanol was added to wash the vial, i.e. fumaric acid dissolve in 1 .0 mL of ethanol - and added to brigatinib (50.4 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by lyophilization process to obtain amorphous brigatinib, as described in Example 3-1 ). The mixture was heated to about 40-50 °C under manual shaking, leading to direct precipitation and the formation of a dense suspension. To allow better stirring, 0.5 mL ethanol was added. The suspension was stirred at room temperature for about 2 hours. Afterwards, the solid material was collected by filtration, washed with ethanol and dried at room temperature under vacuum (about 30 mbar) for 18 hours to yield the crystalline acid addition salts of brigatinib with fumaric acid, form M. The PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with fumaric acid, form M, was essentially identical to the one shown in Figure 8.

Example 3-3 Fumaric acid (1 19.7 mg, 2.98 equivalent) was dissolved in 3.5 ml- ethanol under sonication and heating. The obtained warm solution was taken with a syringe - additional 1.0 ml_ ethanol was added to wash the vial, i.e. fumaric acid dissolve in 4.5 ml_ of ethanol - and added to brigatinib (202.0 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by lyophilization process to obtain amorphous brigatinib, as described in Example 3-1 ), leading to direct precipitation. The obtained white suspension was stirred at room temperature for about 15 hours. Afterwards, the solid material was collected by filtration, washed with ethanol and dried at room temperature under vacuum (about 30 mbar) for 20 hours to yield 268 mg of the crystalline acid addition salts of brigatinib with fumaric acid, form M, as a white-off powder. Characteristic PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with fumaric acid, form M, is shown in Figure 8. The corresponding reflection list is provided in Table 4 below (relative peak intensities can vary due to e.g. interapparatus variability, sample crystallinity, sample preparation, etc.).

Table 4: PXRD reflection list of the crystalline acid addition salt of brigatinib with fumaric acid (Form M):

Example 4: preparation of the crystalline acid addition salts of brigatinib with citric acid (Form N)

To a solid mixture containing brigatinib (201.0 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by lyophilization process to obtain amorphous brigatinib, as described in Example 3-1 ) and citric acid (69.1 mg, 1.05 equivalent) were added 3.5 ml_ of warm ethanol, leading to the formation of a gel on the vial wall. The obtained mixture was vigorously stirred at room temperature for about 18 hours, leading to the formation of a white suspension with some remaining gel pasted on the vial wall. Afterwards, the suspension was filtered. The collected solid material was washed with ethanol and dried at room temperature under vacuum (about 30 mbar) for 48 hours to yield the crystalline acid addition salts of brigatinib with citric acid, form N, as a white-off powder. Characteristic PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with citric acid is shown in Figure 14. The corresponding reflection list is provided in Table 5 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 5: PXRD reflection list of the crystalline acid addition salt of brigatinib with citric acid (Form N):

Example 5: preparation of the crystalline acid addition salts of briaatinib with hydrochloric acid (Form 01

HCI (36.0 mg of a 37% aqueous solution, 1.05 equivalent) was diluted in 4.0 mL of warm ethanol. The solution was added to brigatinib (200.8 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by lyophilization process to obtain amorphous brigatinib, as described in Example 3-1 ). The mixture was sonicated and heated to about 40-50 °C to accelerate dissolution of solid material. The solution was stirred at room temperature. After about 30 minutes, formation of soli material was observed. The mixture was further stirred at room temperature for 17 hours, yielding a beige suspension. Afterwards, the suspension was filtered. The collected solid material was washed with ethanol and dried at room temperature under vacuum (about 30 mbar) for 20 hours to yield the crystalline acid addition salts of brigatinib with hydrochloric acid, Form O, as a white-off powder. Characteristic PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with hydrochloric acid is shown in Figure 15. The corresponding reflection list is provided in Table 6 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 6: PXRD reflection list of the crystalline acid addition salt of brigatinib with hydrochloric acid of the present invention (Form O):

Example 6: preparation of the crystalline acid addition salts of brigatinib with 1.5- naphthalenedisulfonic acid (Form P)

To a solid mixture containing brigatinib (202.0 mg, amorphous, e.g. prepared according to the procedures disclosed in WO 2016/065028 A1 , part V, followed by lyophilization process to obtain amorphous brigatinib, as described in Example 3-1 ) and 1 ,5-naphthalenedisulfonic acid tetrahydrate (136.0 mg, 1 .01 equivalent) were added 4.0 ml_ of warm ethanol, leading to the formation of a gel on the vial wall. The gel was removed from the vial wall and the mixture was vigorously stirred at room temperature for about 18 hours, leading to the formation of a white suspension. Afterwards, the suspension was filtered. The collected solid material was washed with ethanol, dried at room temperature under vacuum (about 30 mbar) for 48 hours and then stored at 40 °C and 75% RH for six days to yield the crystalline acid addition salts of brigatinib with 1 ,5-naphthalenedisulfonic acid, Form P. Characteristic PXRD pattern of the obtained the crystalline acid addition salts of brigatinib with 1 ,5-naphthalenedisulfonic acid is shown in Figure 16. The corresponding reflection list is provided in Table 7 below (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.).

Table 7: PXRD reflection list of the crystalline acid addition salt of brigatinib with 1 ,5- naphthalenedisulfonic acid (Form P):

Claims

1 . Crystalline hydrate system comprising form H1 and/or form H2,

wherein H1 is a crystalline hydrate form of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2- [2-methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1 -yl]phenyl]pyrimidine-2, 4-diamine as the free base characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (13.0± 0.2)°, (18.8± 0.2)° and (22.3 ± 0.2)°, and

wherein H2 is a crystalline hydrate form of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2- [2-methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine as the free base characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (12.3 ± 0.2)°, (19.1 ± 0.2)° and (20.4 ± 0.2)°, and

wherein PXRD-measurements are performed at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

2. The crystalline hydrate system of claim 1 , wherein the crystalline hydrate form H1 is further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (13.0 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)° and (22.3 ± 0.2),“when measured at a temperature in the range of from 20 to 30“C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (13.0 ± 0.2)°, (17.5 ± 0.2)“, (18.8 ± 0.2)“ and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)“ and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (13.0 + 0.2)“, (16.7 ± 0.2)°, (17.5 ± 0.2)“, (18.8 ± 0.2)° and (22.3 ± 0.2)“, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)“ and (22.3 ± 0.2)“, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)“, (16.7 ± 0.2)“, (17.5 ± 0.2)“, (18.8 ± 0.2)°, (20.9 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (4.5 ± 0.2)°, (12.0 ± 0.2)°, (12.3 ± 0.2)°, (13.0 ± 0.2)°, (16.7 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (20.9 ± 0.2)°, (21.1 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm,

3. The crystalline hydrate system of claim 1 or claim 2, wherein the crystalline hydrate form H2 is further characterized

(iv) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (8.3 ± 0.2)°, (10.4 ± 0.2)°, (12.3 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 ± 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (5.8 ± 0.2)°, (8.3 ± 0.2)°, (10.4 ± 0.2)°, (12.3 ± 0.2)°, (12.9 ± 0.2)°, (17.6 ± 0.2), (18.7 ± 0.2), (19.1 ± 0.2)°, (20.4 + 0.2)° and (22.3 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

4. Crystalline acid addition salt of 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-[2- methoxy-4-[4-(4-methylpiperazin-1 -yl)piperidin-1-yl]phenyl]pyrimidine-2, 4-diamine with fumaric acid.

5. Crystalline acid addition salt according to claim 4, further characterized by having a powder X-ray diffractogram (PXRD) comprising reflections at 2-Theta angles of (9.3 ± 0.2)°, (10.4 ± 0.2)° and (14.7 ± 0.2), when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

6. Crystalline addition salt according to claim 4 or 5, further characterized

(i) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (14.7 ± 0.2)° and (17.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(ii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (14.7 ± 0.2)°, (17.0 + 0.2)° and (19.0 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm; or

(v) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (19.0 ± 0.2)° and (19.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphal ,2 radiation having a wavelength of 0.15419 nm;

(vi) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (19.0 ± 0.2)° and (19.2 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm;

(vii) by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of: (9.3 ± 0.2)°, (10.4 ± 0.2)°, (13.9 ± 0.2)°, (14.7 ± 0.2)°, (16.3 ± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (19.0 ± 0.2)°, (19.2 ± 0.2)° and (23.9 ± 0.2)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalpha1 ,2 radiation having a wavelength of 0.15419 nm.

7. Composition comprising the crystalline hydrate system comprising form H1 and/or form H2 as defined in any one of claims 1 to 3.

8. Composition comprising the crystalline acid addition salt as defined in any one of claims 4 to 6.

9. Pharmaceutical composition, comprising the crystalline hydrate system comprising form H1 and/or form H2 as defined in any one of claims 1 to 3 and one or more pharmaceutically acceptable excipients.

10. Pharmaceutical composition, comprising the crystalline acid addition salt as defined in any one of claims 4 to 6 and one or more pharmaceutically acceptable excipients.

1 1 . The composition as defined in claim 7 or claim 8, or the pharmaceutical composition as defined in claim 9 or claim 10, wherein the respective crystalline forms contained therein are substantially pure, preferably have a purity of at least 95 w-%, further preferred at least 98 w- %.

12, Crystalline hydrate system comprising form H1 and/or form H2 as defined in any one of claims 1 to 3, crystalline acid addition salt as defined in any one of claims 4 to 6, composition as defined in claim 7 or claim 8, or pharmaceutical composition as defined in claim 9 or claim 10, for use in a method of treating lung cancer.

13, Crystalline hydrate system, crystalline acid addition salt, composition or pharmaceutical composition for use according to claim 12, wherein the lung cancer is anaplastic lymphoma kinase positive metastatic non-small cell lung cancer (NSCLC).

14, Dosage form comprising the pharmaceutical composition as defined in claim 9 or claim 10.