WO2022117448A1

WO2022117448A1 - Crystalline forms of pralsetinib

Info

Publication number: WO2022117448A1
Application number: PCT/EP2021/083135
Authority: WO
Inventors: Hannes Lengauer; Arthur Pichler; Renate MARGREITER
Original assignee: Sandoz Ag
Priority date: 2020-12-03
Filing date: 2021-11-26
Publication date: 2022-06-09

Abstract

The present invention relates to crystalline forms of pralsetinib and to processes for their preparation. Furthermore, the invention relates to a pharmaceutical composition comprising one of the crystalline forms of pralsetinib of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of RET-associated cancers, such as non-small cell lunc cancer and thyroid cancer.

Description

CRYSTALLINE FORMS OF PRALSETINIB

FIELD OF THE INVENTION

The present invention relates to crystalline forms of pralsetinib and to processes for their preparation. Furthermore, the invention relates to a pharmaceutical composition comprising one of the crystalline forms of pralsetinib of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of .KET-associated cancers, such as non-small cell lune cancer and thyroid cancer.

BACKGROUND OF THE INVENTION Pralsetinib is an oral kinase inhibitor indicated for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic EE /'-mutant medullary thyroid cancer (MTC) and advanced or metastatic EE /'-fusion positive thyroid cancer. The chemical name of pralsetinib is (15,4E)-7\/-((5)-l-(6-(4-fluoro-lJ/-pyrazol-l- yl)pyridin-3-yl)ethyl)-l -methoxy -4-(4-methyl-6-(5-methyl-l ZEpyrazol-3-ylamino)pyrimidin- 2-yl)cyclohexanecarboxamide. Pralsetinib can be represented by the following chemical structure according to Formula (A)

Formula (A). WO 2017/079140 Al, Example 5 discloses the preparation of pralsetinib, which is obtained as a “white solid”. CN 111777595 A discloses crystalline forms of pralsetinib designated as forms CM-I, CM-II, CM-III, CM-IV, CM-V, CM- VI, CM- VII and CM- VIII, whereas Form CM-I, CM-II and CM-III are mentioned to be preferred.

Different solid-state forms of an active pharmaceutical ingredient often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid-state forms.

The crystalline forms disclosed in CN 111777595 A suffer from certain drawbacks, which may to a certain extent compromise their use for pharmaceutical purpose. In particular, they show significant mass losses during TGA experiments, which might be an indication of thermal instability connected to chemical degradation and/or desolvation events due to loss of organic solvent(s) and/or water. Since there is no therapeutic benefit from residual solvents, or they might even be toxic, they should be removed to the extent possible. In addition, phase transitions upon temperature stress e.g. via desolvation/dehydration can affect safety and efficacy of the drug product.

Furthermore, some of the crystalline pralsetinib forms disclosed in CN 111777595 A are hygroscopic. The tendency of a drug substance to absorb water from the environment can negatively affect the pharmaceutical behavior and quality of a drug product. Water absorption for example can lead to chemical degradation, trigger changes of the physical form, lead to changes in dissolution behavior and influence powder properties such as flowability, compactability, tableting and compression behavior etc.

There is thus a need for the provision of a solid-state form of pralsetinib having improved physicochemical properties. In particular, there is a need for a solid-state form of pralsetinib, which is non-hygroscopic or only slightly hygroscopic. Furthermore, there is a need for a solid- state form of pralsetinib, which possesses physicochemical properties allowing for the reliable production of a safe and efficacious drug product comprising pralsetinib. In particular, there is a need for a solid-state form of pralsetinib which is stable upon storage of the active pharmaceutical ingredient, during formulation of a pharmaceutical drug product containing pralsetinib and throughout the whole shelf-life of the drug product comprising pralsetinib.

SUMMARY OF THE INVENTION

The present invention solves one or more of the above mentioned problems by providing a crystalline form of pralsetinib, which is hereinafter also referred to as “Form II”. Form II of pralsetinib of the present invention possesses one or more favorable physicochemical properties for a drug substance intended for use in an oral solid dosage form. Said properties may be selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, chemical purity, organic solvent content, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.

For example, Form II of the present invention shows no significant mass loss in the TGA curve until the sample melts, which indicates good thermal stability as well as low residual solvent content (see Example 8 and Comparative Example 1 herein).

Furthermore, the inventors of the present invention surprisingly found that crystalline Form II of pralsetinib of the present invention practically shows no interaction with water vapor, thus the physicochemical properties of Form II are preserved regardless the relative humidity of the surrounding atmosphere, which facilitates easier and more reliable manufacturing processes as well as easier storage of a pharmaceutical product containing said form, (see Example 9 and Comparative Example 2 herein).

This unique combination of advantageous properties renders pralsetinib Form II of the present invention the preferred solid-state form of pralsetinib for the preparation of a reliable safe and efficacious drug product containing pralsetinib.

Abbreviations

PXRD powder X-ray diffractogram

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption DMSO dimethylsulfoxide

RH relative humidity w-% weight percent

Definitions

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:

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

As used herein, the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature. Standard conditions can mean a temperature of about 22°C. Typically, standard conditions can additionally mean a measurement under 20-60% RH, preferably 30-50% RH, more preferably 40% RH.

The term “Form CM-I” as used herein, when talking about a solid-state form of pralsetinib refers to the crystalline form of pralsetinib, which is disclosed in CN 111777595 A. Form CM- I of pralsetinib can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (4.9 ± 0.2)°, (12.7 ± 0.2)° and (14.8 ± 0.2)°, 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.

The term “reflection” with regard 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 100 to 1000 atoms, whereas short-range order is over a few atoms only (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials ” by Vitalij K. P echar sky 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 reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 9.6° 2-Theta for example can appear between 9.4° and 9.8° 2-Theta, preferably between 9.5° and 9.7° 2- Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

A crystalline form of pralsetinib of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. 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. However, a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid-state form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.

The term “solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound.

The terms “anhydrous” or “anhydrate” as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

The term “non-solvated” as used herein, when talking about a crystalline solid indicates that no organic solvent is cooperated in or accommodated by the crystal structure. Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. The term “solvate” as used herein, refers to a crystalline solid where either one or more organic solvent(s) is/are cooperated in or accommodated by the crystal structure e.g. is/are part of the crystal structure or entrapped into the crystal (solvent inclusions). Thereby, the one or more organic solvent(s) can be present in a stoichiometric or non-stoichiometric amount. When the one or more organic solvent(s) is/are present in stoichiometric amount(s), the solvate may be referred to by adding greek numeral prefixes. For example, a solvate may be referred to as a Aemzsolvate or as a /w/wsolvate depending on the solvent(s)/compound stoichiometry. The solvent content can be measured, for example, by GC, NMR, SXRD and/or TGA/MS.

The terms “desolvating” or “desolvation” as used herein, describe the at least partial removal of organic solvent from the crystal structure of the host molecule.

A “predetermined amount” as used herein with regard to pralsetinib refers to the initial amount of pralsetinib used for the preparation of a pharmaceutical composition having a desired dosage strength of pralsetinib.

The term “effective amount” as used herein with regard to pralsetinib encompasses an amount of pralsetinib, which produces the desired therapeutic and/or prophylactic effect.

As used herein, the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

The term “pharmaceutically acceptable excipient” as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer, acidifying agent or a manufacturing aid among others.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates a representative PXRD of pralsetinib Form II of the present invention. 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: illustrates a representative DSC curve of pralsetinib Form II of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 3: illustrates a representative TGA curve of pralsetinib Form II of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in weight percent (w-%).

Figure 4: illustrates a representative PXRD of pralsetinib Form SDMSO of the present invention. 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: illustrates a representative DSC curve of pralsetinib Form SDMSO of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in Watt per gram (W/g) with endothermic peaks going up.

Figure 6: illustrates a representative TGA curve of pralsetinib Form SDMSO of the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the mass (loss) of the sample in weight percent (w-%).

Figure 7: illustrates representative GMS isotherms of pralsetinib Form II of the present invention in the range of 0 to 90% RH. The x-axis displays the RH in percent (%) measured at a temperature of (25.0 ± 0.1)°C, the y-axis displays the equilibrium mass change in weight percent (w-%). Sample weight at 0% RH at the start of the sorption curve is used as reference weight. Sorption curve points are displayed as triangles, desorption curve points as squares.

Figure 8: illustrates a representative PXRD of pralsetinib Form HyB of the present invention. 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 OF THE INVENTION

The present invention concerns crystalline forms of pralsetinib which are useful for pharmaceutical purpose.

Crystalline Form II of pralsetinib and compositions comprising the same

One aspect of the present invention relates to a crystalline form of pralsetinib, herein also designated as “Form II”.

Crystalline Form II of pralsetinib of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods include but are not limited to powder X-ray diffraction, DSC, TGA and GMS. Pralsetinib Form II of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form II of pralsetinib of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

In one embodiment the invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.5 ± 0.2)°, (9.6 ± 0.2)° and (11.6 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)° and (17.5 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)° and (17.5 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)° and (17.5 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)° and (19.6 ±

0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)°, (19.6 ± 0.2)° and (22.2 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)°, (19.6 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)°, (19.6 ± 0.2)°, (20.2 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (19.6 ± 0.2)°, (20.2 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°; or

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (19.6 ± 0.2)°, (20.2 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°;

(5.5 ± 0.2)°, (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (15.1 ± 0.2)°, (17.0 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (19.6 ± 0.2)°, (20.2 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°; 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.

In another embodiment, the invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (9.6 ± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (17.0 ± 0.2)°, (17.5 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (19.6 ± 0.2)°, (21.0 ± 0.2)° and (22.2 ± 0.2)°, 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. In a further embodiment the invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.5 ± 0.1)°, (9.6 ± 0.1)° and (11.6 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)° and (17.5 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)° and (17.5 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)° and (17.5 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)° and (19.6 ±

0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)°, (19.6 ± 0.1)° and (22.2 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)°, (19.6 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)°, (19.6 ± 0.1)°, (20.2 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)°, (18.8 ± 0.1)°, (19.6 ± 0.1)°, (20.2 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°; or

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.5 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (19.6 ± 0.1)°, (20.2 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°;

(5.5 ± 0.1)°, (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (15.1 ± 0.1)°, (17.0 ± 0.1)°, (17.5 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (19.6 ± 0.1)°, (20.2 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°; 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.

In yet another embodiment, the invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (9.6 ± 0.1)°, (11.6 ± 0.1)°, (13.4 ± 0.1)°, (17.0 ± 0.1)°, (17.5 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (19.6 ± 0.1)°, (21.0 ± 0.1)° and (22.2 ± 0.1)°, 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.

The PXRD of pralsetinib Form II of the present invention can be readily distinguished from the PXRD of pralsetinib Form CM-I of CN 111777595 A (compare Figure 1 of the present invention and Figure 1 of CN 111777595 A). Form II for example possesses characteristic reflections at (5.5 ± 0.2)° and (11.6 ± 0.2)° 2-Theta, whereas Form CM-I shows no reflection in the same ranges. On the other hand the diffractogram of Form CM-I of CN 111777595 A displays reflections at 2-Theta angles of (4.9 ± 0.2)° and (12.7 ± 0.2)°, whereas Form II of the present invention shows no reflection in these ranges.

Hence, in another embodiment the present invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD as defined in any one of the above described embodiments, but comprising no reflections at 2-Theta angles of (4.9 ± 0.2)° and (12.7 ± 0.2)°, 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.

In a further embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, 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.

In another embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak onset at a temperature of (205 ± 5)°C, preferably of (205 ± 3)°C, more preferably of (205 ± 1)°C, when measured at a heating rate of 10 K/min.

In a further embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak maximum at a temperature of (206 ± 5)°C, preferably of (206 ± 3)°C, more preferably of (206 ± 1)°C, when measured at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib, characterized by having a TGA curve showing a mass loss of not more than 1.0 w- %, based on the weight of the crystalline form, when heated from 25 to 220°C at a rate of 10 K/min.

In a further embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib, characterized by having a TGA curve showing a mass loss of not more than 0.5 w- %, based on the weight of the crystalline form, when heated from 25 to 200°C at a rate of 10 K/min.

In yet another embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib, characterized by having a TGA curve showing a mass loss of not more than 0.5 w- %, 0.4 w-%, 0.3 w-%, 0.2 w-% or 0.1 w-% based on the weight of the crystalline form, when heated from 25 to 150°C at a rate of 10 K/min.

In a further embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib characterized by showing a mass change of not more than 2.0 w-%, preferably of not more than 1.5 w-%, such as 1.3 w-% or 1.2 w-% based on the weight of the crystalline form, when measured with GMS at a RH in the range of from 0 to 90% and a temperature of (25.0 ± 0.1°C).

In one embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form II) of pralsetinib characterized in being non-solvated.

In a further aspect, the present invention relates to a composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid-state form of pralsetinib. For example, a composition comprising the crystalline Form II of pralsetinib of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid-state form of pralsetinib, based on the weight of the composition. Preferably, the any other solid-state form of pralsetinib is Form CM-I of CN 111777595 A. Form CM-I of pralsetinib exhibits a PXRD comprising amongst others characteristic reflections at 2-Theta angles of (4.9 ± 0.2)°and (12.7 ± 0.2)°, 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. Therefore, the absence of reflections at 2-Theta angles of (4.9 ± 0.2)° and/or (12.7 ± 0.2)° in the PXRD excludes the presence of Form CM-I of pralsetinib in the composition.

Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at 2-Theta angles of (4.9 ± 0.2)° and/or (12.7 ± 0.2)°, 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. In another embodiment, the invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the crystalline form (Form II) of pralsetinib as defined in any one of the above described embodiments, based on the total weight of the composition. The remaining material may comprise other solid-state form(s) of pralsetinib, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.

Pharmaceutical compositions comprising pralsetinib Form II and medical use

In a further aspect, the present invention relates to the use of the crystalline form (Form II) of pralsetinib of the present invention, or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.

In a further aspect, the present invention relates to a pharmaceutical composition comprising the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.

Preferably, the effective and/or predetermined amount of the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments is in the range of from about 100 to 400 mg, calculated as pralsetinib (water free). For example, the effective and/or predetermined amount is selected from the group consisting of 100 mg, 200 mg, 300 mg and 400 mg, calculated as pralsetinib (water free). Preferably, the effective and/or predetermined amount is 100 mg, calculated as pralsetinib (water free).

The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, binders, acidifiers, lubricants, glidants and any combinations thereof.

Preferably, the pharmaceutical composition of the present invention as described above is an oral solid dosage form. More preferably, the pharmaceutical composition of the present invention as described above is a tablet or a capsule.

The pharmaceutical compositions of the present invention as defined in any one of the above described embodiments may be produced by standard manufacturing processes, which are well- known to the skilled person including e.g. milling, sieving, blending, granulation (wet or dry granulation), tablet compression or capsule filling.

In a further aspect, the present invention relates to the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In a further aspect, the present invention relates to the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of .KET-associated cancer.

In another aspect, the present invention relates to a method of treating 7?ET-associated cancer, said method comprising administering an effective amount of the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form II) of pralsetinib of the present invention or the composition comprising the crystalline form (Form II) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment.

In one embodiment, the ^>A7'-accociated cancer is selected from the group consisting of lung cancer, small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, lung adenocarcinoma, thyroid cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple enocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa and cervical cancer. In a particularly preferred embodiment, the ^>A7'-associated cancer is selected from the group consisting of advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic 7: /'-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

Crystalline DMSO solvate (Form SDMSO) of pralsetinib

Another aspect of the present invention relates to a crystalline DMSO solvate of pralsetinib, herein also designated as “Form SDMSO”.

Crystalline Form SDMSO of pralsetinib of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods include but are not limited to powder X-ray diffraction, DSC, TGA and GMS. Pralsetinib Form SDMSO of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form SDMSO of pralsetinib of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

In one embodiment the invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of: (8.0 ± 0.2)°, (10.9 ± 0.2)° and (19.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)° and (19.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (16.1 ± 0.2)° and (19.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (16.1 ± 0.2)° and (19.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (16.1 ± 0.2)° and (19.7 ±

0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (16.1 ± 0.2)° and (19.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (15.0 ± 0.2)°, (16.1 ± 0.2)° and (19.7 ± 0.2)°; or (5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (15.0 ± 0.2)°, (16.1 ± 0.2)°, (19.7 ± 0.2)° and (20.6 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (15.0 ± 0.2)°, (16.1 ± 0.2)°, (19.7 ± 0.2)°, (20.6 ± 0.2)° and (21.7 ± 0.2)°; or

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (15.0 ± 0.2)°, (16.1 ± 0.2)°, (19.7 ± 0.2)°, (20.6 ± 0.2)°, (21.7 ± 0.2)° and (22.4 ± 0.2)°;

(5.3 ± 0.2)°, (8.0 ± 0.2)°, (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (14.1 ± 0.2)°, (15.0 ± 0.2)°, (16.1 ± 0.2)°, (19.7 ± 0.2)°, (20.6 ± 0.2)°, (21.7 ± 0.2)°, (22.4 ± 0.2)° and (23.2 ± 0.2)°; 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.

In another embodiment, the invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (10.9 ± 0.2)°, (11.9 ± 0.2)°, (13.3 ± 0.2)°, (16.1 ± 0.2)°, (19.1 ± 0.2)°, (19.7 ± 0.2)°, (20.4 ± 0.2)°, (20.6 ± 0.2)°, (21.7 ± 0.2)° and (22.4 ± 0.2)°, 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.

In a further embodiment the invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of: (8.0 ± 0.1)°, (10.9 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (16.1 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (16.1 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (16.1 ± 0.1)° and (19.7 ±

0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (16.1 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (15.0 ± 0.1)°, (16.1 ± 0.1)° and (19.7 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (15.0 ± 0.1)°, (16.1 ± 0.1)°, (19.7 ± 0.1)° and (20.6 ± 0.1)°; or

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (15.0 ± 0.1)°, (16.1 ± 0.1)°, (19.7 ± 0.1)°, (20.6 ± 0.1)° and (21.7 ± 0.1)°; or (5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (15.0 ± 0.1)°, (16.1 ± 0.1)°, (19.7 ± 0.1)°, (20.6 ± 0.1)°, (21.7 ± 0.1)° and (22.4 ± 0.1)°;

(5.3 ± 0.1)°, (8.0 ± 0.1)°, (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (14.1 ± 0.1)°, (15.0 ± 0.1)°, (16.1 ± 0.1)°, (19.7 ± 0.1)°, (20.6 ± 0.1)°, (21.7 ± 0.1)°, (22.4 ± 0.1)° and (23.2 ± 0.1)°; 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.

In yet another embodiment, the invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (10.9 ± 0.1)°, (11.9 ± 0.1)°, (13.3 ± 0.1)°, (16.1 ± 0.1)°, (19.1 ± 0.1)°, (19.7 ± 0.1)°, (20.4 ± 0.1)°, (20.6 ± 0.1)°, (21.7 ± 0.1)° and (22.4 ± 0.1)°, 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.

In a further embodiment, the present invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized by having a PXRD essentially the same as shown in Figure 4 of the present invention, 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.

In another embodiment, the present invention relates to a crystalline DMSO solvate (Form SDMSO) of pralsetinib characterized in being a /w/wsolvate.

In a further aspect, the present invention relates to a composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid- state form of pralsetinib. For example, a composition comprising the crystalline DMSO solvate of pralsetinib of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid-state form of pralsetinib, based on the weight of the composition. Preferably, the any other solid-state form of pralsetinib is Form CM-I of CN 111777595 A. Form CM-I of pralsetinib exhibits a PXRD comprising amongst others characteristic reflections at 2-Theta angles of (4.9 ± 0.2)°and (12.7 ± 0.2)°, 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. Therefore, the absence of reflections at 2-Theta angles of (4.9 ± 0.2)°and/or (12.7 ± 0.2)° in the PXRD excludes the presence of Form CM-I of pralsetinib in the composition. Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at (12.7 ± 0.2)° 2-Theta, 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.

In another embodiment, the invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the crystalline DMSO solvate (Form SDMSO) of pralsetinib as defined in any one of the above described embodiments, based on the total weight of the composition. The remaining material may comprise other solid-state form(s) of pralsetinib, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.

Pharmaceutical compositions comprising pralsetinib Form SDMSO and medical use

In a further aspect, the present invention relates to the use of the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention, or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.

In a further aspect, the present invention relates to a pharmaceutical composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.

Preferably, the effective and/or predetermined amount of the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments is in the range of from about 100 to 400 mg, calculated as pralsetinib (water and solvent free). For example, the effective and/or predetermined amount is selected from the group consisting of 100 mg, 200 mg, 300 mg and 400 mg calculated as pralsetinib (water and solvent free). Preferably, the effective and/or predetermined amount is 100 mg calculated as pralsetinib (water and solvent free). The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, binders, acidifiers, lubricants, glidants and any combinations thereof.

Preferably, the pharmaceutical composition of the present invention as described above is an oral solid dosage form.

More preferably, the pharmaceutical composition of the present invention as described above is a tablet or a capsule.

In a further aspect, the present invention relates to the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In a further aspect, the present invention relates to the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of RET associated cancer.

In another aspect, the present invention relates to a method of treating RET associated cancer, said method comprising administering an effective amount of the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention or the composition comprising the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment.

In one embodiment, the ^>A7'-accociated cancer is selected from the group consisting of lung cancer, small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, lung adenocarcinoma, thyroid cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple enocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa and cervical cancer. In a particular preferred embodiment, the ’A’/'-associated cancer is selected from the group consisting of advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic 7: /'-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

Crystalline Form HyB of pralsetinib and compositions comprising the same

One aspect of the present invention relates to a crystalline form of pralsetinib, herein also designated as “Form HyB”.

Crystalline Form HyB of pralsetinib of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods include but are not limited to powder X-ray diffraction, DSC, TGA and GMS. Pralsetinib Form HyB of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, Form HyB of pralsetinib of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

In one embodiment the invention relates to a crystalline form (Form HyB) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of: (2.9 ± 0.2)°, (8.7 ± 0.2)° and (14.8 ± 0.2)°; or

(2.9 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)° and (14.8 ± 0.2)°; or

(2.9 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)° and (14.8 ± 0.2)°; or (2.9 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)°, (14.8 ± 0.2)° and (19.4 ± 0.2)°; or (2.9 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)°, (14.8 ± 0.2)°, (19.4 ± 0.2)° and (20.9 ± 0.2)°; or

(2.9 ± 0.2)°, (5.3 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)°, (14.8 ± 0.2)°, (19.4 ± 0.2)° and (20.9 ± 0.2)°; or

(2.9 ± 0.2)°, (5.3 ± 0.2)°, (8.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)°, (14.8 ± 0.2)°, (16.2 ± 0.2)°, (19.4 ± 0.2)° and (20.9 ± 0.2)°; or

(2.9 ± 0.2)°, (5.3 ± 0.2)°, (8.7 ± 0.2)°, (10.7 ± 0.2)°, (11.5 ± 0.2)°, (12.9 ± 0.2)°, (14.8 ± 0.2)°, (16.2 ± 0.2)°, (19.4 ± 0.2)° and (20.9 ± 0.2)°; 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.

In another embodiment, the invention relates to a crystalline form (Form HyB) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (11.5 ± 0.2)°, (14.8 ± 0.2)°, (19.1 ± 0.2)°, (19.4 ± 0.2)°, (19.8 ± 0.2)°, (20.3 ± 0.2)°, (20.9 ± 0.2)°, (21.8 ± 0.2)°, (22.3 ± 0.2)° and (23.1 ± 0.2)°, 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.

In a further embodiment the invention relates to a crystalline form (Form HyB) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of:

(2.9 ± 0.1)°, (8.7 ± 0.1)° and (14.8 ± 0.1)°; or

(2.9 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)° and (14.8 ± 0.1)°; or

(2.9 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)° and (14.8 ± 0.1)°; or

(2.9 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)°, (14.8 ± 0.1)° and (19.4 ± 0.1)°; or

(2.9 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)°, (14.8 ± 0.1)°, (19.4 ± 0.1)° and (20.9 ±

0.1)°; or

(2.9 ± 0.1)°, (5.3 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)°, (14.8 ± 0.1)°, (19.4 ± 0.1)° and (20.9 ± 0.1)°; or

(2.9 ± 0.1)°, (5.3 ± 0.1)°, (8.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)°, (14.8 ± 0.1)°, (16.2 ± 0.1)°, (19.4 ± 0.1)° and (20.9 ± 0.1)°; or

(2.9 ± 0.1)°, (5.3 ± 0.1)°, (8.7 ± 0.1)°, (10.7 ± 0.1)°, (11.5 ± 0.1)°, (12.9 ± 0.1)°, (14.8 ± 0.1)°, (16.2 ± 0.1)°, (19.4 ± 0.1)° and (20.9 ± 0.1)°; 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. In yet another embodiment, the invention relates to a crystalline form (Form HyB) of pralsetinib characterized by having a PXRD comprising reflections at 2-Theta angles of (11.5 ± 0.1)°, (14.8 ± 0.1)°, (19.1 ± 0.1)°, (19.4 ± 0.1)°, (19.8 ± 0.1)°, (20.3 ± 0.1)°, (20.9 ± 0.1)°, (21.8 ± 0.1)°, (22.3 ± 0.1)° and (23.1 ± 0.1)°, 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.

The PXRD of pralsetinib Form HyB of the present invention can be readily distinguished from thePXRDs of pralsetinib Forms CM-Ito CM- VIII of CN 111777595 A. Form HyB for example possesses a characteristic reflection at (2.9 ± 0.2)° 2-Theta, whereas Forms CM-I to CM- VI don’t show reflections in the same range. Furthermore, the PXRD of Form HyB displays e.g. a further characteristic reflection at (8.7 ± 0.2)° 2-Theta, whereas the PXRD of Form CM- VII of CN 111777595 A has no reflection in the same range. Finally, Form HyB possesses additional characteristic reflections e.g. at 2-Theta angles of (11.5 ± 0.2)° and (14.8 ± 0.2)°, at ranges where the PXRD of Form CM- VIII of CN 111777595 A displays no reflections.

In a further embodiment, the present invention relates to a crystalline form (Form HyB) of pralsetinib characterized by having a PXRD essentially the same as shown in Figure 8 of the present invention, 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.

In a further aspect, the present invention relates to a composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition being essentially free of any other solid-state form of pralsetinib. For example, a composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5, 4, 3, 2 or 1 w-% of any other solid-state form of pralsetinib, based on the weight of the composition. Preferably, the any other solid-state form of pralsetinib is Form CM- I of CN 111777595 A. Form CM-I of pralsetinib exhibits a PXRD comprising amongst others characteristic reflections at 2-Theta angles of (4.9 ± 0.2)°and (12.7 ± 0.2)°, 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. Therefore, the absence of reflections at 2-Theta angles of (4.9 ± 0.2)°and/or (12.7 ± 0.2)° in the PXRD excludes the presence of Form CM-I of pralsetinib in the composition. Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described embodiments, said composition having a PXRD comprising no reflections at (4.9 ± 0.2)° 2-Theta, 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.

In another embodiment, the invention relates to a composition comprising at least 90 w-%, including at least 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 w-%, and also including equal to about 100 w-% of the crystalline form (Form HyB) of pralsetinib as defined in any one of the above described embodiments, based on the total weight of the composition. The remaining material may comprise other solid-state form(s) of pralsetinib, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.

Pharmaceutical compositions comprising pralsetinib Form HyB and medical use

In a further aspect, the present invention relates to the use of the crystalline form (Form HyB) of pralsetinib of the present invention, or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.

In a further aspect, the present invention relates to a pharmaceutical composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.

Preferably, the effective and/or predetermined amount of the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments is in the range of from about 100 to 400 mg, calculated as pralsetinib (water free). For example, the effective and/or predetermined amount is selected from the group consisting of 100 mg, 200 mg, 300 mg and 400 mg calculated as pralsetinib (water free). Preferably, the effective and/or predetermined amount is 100 mg calculated as pralsetinib (water free). The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, binders, acidifiers, lubricants, glidants and any combinations thereof.

In a further aspect, the present invention relates to the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In a further aspect, the present invention relates to the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of RET associated cancer.

In another aspect, the present invention relates to a method of treating RET associated cancer, said method comprising administering an effective amount of the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention, or the pharmaceutical composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention or the composition comprising the crystalline form (Form HyB) of pralsetinib of the present invention as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment.

In one embodiment, the ^>A7'-accociated cancer is selected from the group consisting of lung cancer, small cell lung carcinoma, non-small cell lung cancer, bronciolus lung cell carcinoma, lung adenocarcinoma, thyroid cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple enocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa and cervical cancer. In a particular preferred embodiment, the AET-associated cancer is selected from the group consisting of advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic 7: /'-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

EXAMPLES

The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention.

Example 1: Preparation of pralsetinib Form II

Pralsetinib (50 mg, e.g. prepared according to the procedure disclosed in WO 2017/079140 Al, Example 5) was dissolved in dimethylcarbonate (1 mL) upon heating to reflux temperature. The resulting clear solution was allowed to cool to room temperature and kept without stirring for 4 days, whereupon crystallization occured. Subsequently, the crystals were collected by centrifugation and air dried to obtain crystalline Form II of pralsetinib of the present invention.

Example 2: Preparation of pralsetinib Form II

Pralsetinib (196 mg, e.g. prepared according to the procedure disclosed in WO 2017/079140 Al, Example 5) was dissolved in dimethylcarbonate (4 mL) upon heating to reflux temperature. The resulting clear solution was allowed to cool to room temperature and seeded with a small spatula of Form II crystals obtained from Example 1 hereinabove. The mixture was further stirred at room temperature for 22 hours, whereupon a suspension was obtained. Subsequently, the crystals were collected by filtration and the wet product was dried under vacuum at 50°C for 6 hours in order to obtain 132 mg of crystalline Form II of pralsetinib of the present invention.

Example 3: Preparation of pralsetinib Form SDMSO

Pralsetinib (50 mg, e.g. prepared according to the procedure disclosed in WO 2017/079140 Al, Example 5) was dissolved in DMSO (1 mL) at room temperature. The resulting clear solution was allowed to open stand on a watchglass at room temperature for several days. The obtained crystals were collected and air dried to give crystalline Form SDMSO of pralsetinib of the present invention.

Example 4: Preparation of pralsetinib Form SDMSO

Pralsetinib (196 mg, e.g. prepared according to the procedure disclosed in WO 2017/079140 Al, Example 5) was suspended in diethyl ether (2 mL) followed by the addition of DMSO (50 microliter). The mixture was seeded with a small spatula of Form SDMSO crystals obtained from Example 3 hereinabove and further stirred at room temperature for 2 hours. Subsequently, the crystals were collected by filtration and air dried to obtain 117 mg of crystalline Form SDMSO of pralsetinib of the present invention.

Example 5: Preparation of pralsetinib Form HyB

Pralsetinib Form SDMSO (20 mg, prepared according to the procedure disclosed in Example 4 hereinabove) was suspended in water (0.5 mL) and stirred at room temperature for 30 minutes. Subsequently, the crystals were collected by centrifugation and air dried to obtain the crystalline Form HyB of pralsetinib of the present invention.

Example 6: Powder X-ray diffraction

Powder X-ray diffraction was performed with a PANalytical X’Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, Cu-Kalphai,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) in the angular range of 2° to 40° 2-Theta at ambient conditions. A typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. A representative diffractogram of the crystalline Form II of pralsetinib of the present invention is displayed in Figure 1 herein. The corresponding reflection list is provided in Table 1 below.

Table 1: Reflection positions of crystalline Form II of pralsetinib in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0.1° 2-Theta. A representative diffractogram of the crystalline DMSO solvate (Form SDMSO) of pralsetinib of the present invention is displayed in Figure 4 herein. The corresponding reflection list is provided in Table 2 below.

Table 2: Reflection positions of crystalline Form SDMSO of pralsetinib in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0. 1° 2- Theta.

A representative diffractogram of the crystalline Form HyB of pralsetinib of the present invention is displayed in Figure 8 herein. The corresponding reflection list is provided in Table 3 below.

Table 3: Reflection positions of crystalline Form HyB of pralsetinib in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.2° 2-Theta, preferably of ± 0. 1° 2- Theta.

Example 7: Differential scanning calorimetry

DSC was performed on a Mettler Toledo Polymer DSC R instrument. Pralsetinib (about 2.2 mg Form II, about 2.5 mg Form SDMSO) was heated in a 40 microliter aluminium pan with a pierced aluminium lid from 25 to 250°C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.

A representative DSC curve of pralsetinib Form II of the present invention is displayed in Figure 2 hereinafter and shows a single sharp endotherm with an onset temperature of about 205°C and a peak maximum at a temperature of about 206°C, which is due to the melting of the sample.

A representative DSC curve of the pralsetinib Form SDMSO is displayed in Figure 5 hereinafter and shows multiple thermal events including a first endotherm with an onset temperature of about 103 °C and a peak maximum at a temperature of about 107°C, followed by a broad second endotherm with an onset temperature of about 111°C and a peak maximum at a temperature of about 132°C. While these first two events can be assigned to a desolvation process which goes along with a transformation to Form CM-I of CN 111777595 A, the third endotherm with an onset temperature of about 204°C and a peak maximum at a temperature of about 206°C is due to melting of Form CM-I.

Example 8: Thermogravimetric analysis

TGA was performed on a Mettler Toledo TGA/DSC 1 instrument. Pralsetinib (about 4.3 mg Form II, about 4.7 mg Form SDMSO) was weighed into a 100 microliter aluminum pan closed with an aluminum lid. The lid was automatically pierced at the beginning of the measurement. The sample was initially kept at 25°C for 2 minutes and 30 seconds and then heated from 25 to 250°C at a rate of 10 K/min. Nitrogen (purge rate 30 mL/min) was used as purge gas.

A representative TGA curve of pralsetinib Form II of the present invention is displayed in Figure 3 hereinafter and shows no significant mass loss until the sample melts. No significant mass loss was observed for Form II of the present invention up to about 150°C and only about 0.4 w-% mass loss was observed up to a temperature of about 200°C, indicating the anhydrous and non-solvated nature of Form II of the present invention.

A representative TGA curve of the pralsetinib Form SDMSO is displayed in Figure 6 hereinafter and shows a distinct step which goes along with a mass loss of about 11.9 w-% and is due to a desolvation event, in which about 0.9 mol equivalents of DMSO are released. Hence, pralsetinib Form SDMSO can be assigned as DMSO /w/wsolvate.

Example 9: Gravimetric moisture sorption

Moisture sorption isotherms were recorded with an SPSx-lp moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient RH of 30%. RH was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0% RH. Afterwards RH was increased from 0% to 90% in a sorption cycle and decreased to 0 % in a desorption cycle in 5% steps. Finally the RH was increased to a relative humidity of 20% in 5% steps.

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.

As can be seen from Figure 7 herein, pralsetinib Form II of the present invention practically shows no mass increase in the sorption cycle from 0 to 70% RH, and only an increase of about 0.4 w-% from 0 to 80% RH and of about 1.2% from 0 to 90%. Hence, pralsetinib Form II of the present invention can be assigned as being slightly hygroscopic. The PXRD of the sample after the GMS experiment corresponds to the PXRD of the initial sample, confirming that no structural changes occured during the experiment.

Comparative Example 1: Mass loss during TGA

The TGA data of pralsetinib Form II of the present invention were compared with those of Form CM-I, CM-II and CM-III disclosed in CN 111777595 A and a summary is provided in Table 4.

Table 4: TGA data of various pralsetinib forms

The significant mass losses observed for Form CM-I, CM-II and CM-III during TGA experiments, point towards thermal instability which might be due to chemical degradation and/or desolvation events due to loss of organic solvent(s) and/or water. In contrast, no significant mass loss was observed for Form II during the TGA experiment up to about 150°C and even up to 200°C a mass loss of only about 0.4 w-% observed, indicating excellent physical and chemical stability upon temperature stress and the prescence of an anhydrous and nonsolvated crystalline form.

Comparative Example 2: Hygroscopicity

The GMS data of Form II of the present invention were compared with those disclosed in CN 111777595 A and a summary is provided in Table 5.

Table 5: Hygroscopicity of various pralsetinib forms

While Forms CM-II and CM-III are hygroscopic, Form CM-I and Form II are only slightly hygroscopic.

Claims

1) A crystalline form of pralsetinib (Form II) according to the chemical structure as depicted in Formula (A)

Formula (A), characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (5.5 ± 0.2)°, (9.6 ± 0.2)° and (11.6 ± 0.2)°, 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.

2) The crystalline form of claim 1 characterized by having a powder X-ray diffractogram comprising additional reflections at 2-Theta angles of (13.4 ± 0.2)° and/or (17.5 ± 0.2)°, 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.

3) The crystalline form of claim 1 or 2 characterized by having a powder X-ray diffractogram comprising no reflections at 2-Theta angles of (4.9 ± 0.2)° and (12.7 ± 0.2)°, 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. 4) The crystalline form according to any one of the preceding claims characterized by having a differential scanning calorimetry curve comprising an endothermic peak having a peak onset at a temperature of (205 ± 5)°C, when measured at a heating rate of lO K/min.

5) The crystalline form according to any one of the preceding claims characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 0.5 w- %, 0.4 w-%, 0.3 w-%, 0.2 w-% or 0.1 w-% based on the weight of the crystalline form, when heated from 25 to 150°C at a rate of 10 K/min.

6) The crystalline form according to any one of the preceding claims characterized in being anhydrous.

7) The crystalline form according to any one of the preceding claims characterized in being non-solvated.

8) A composition comprising the crystalline form as defined in any one of the preceding claims and at most 20 w-%, 10 w-%, 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid-state form of pralsetinib, based on the weight of the composition.

9) The composition according to claim 8, wherein the other solid-state form of pralsetinib is Form CM-I characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (4.9 ± 0.2)°, (12.7 ± 0.2)° and (14.8 ± 0.2)°, 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.

10) The composition as defined in claim 8 or 9, characterized by having a PXRD comprising no reflections at 2-Theta angles of (4.9 ± 0.2)° and (12.7 ± 0.2)°, 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.

1 l)Use of the crystalline form as defined in any one of claims 1 to 7 or the composition as defined in any one of claims 8 to 10 for the preparation of a pharmaceutical composition.

12) A pharmaceutical composition comprising the crystalline form as defined in any one of claims 1 to 7 or the composition as defined in any one of claims 8 to 10 and at least one pharmaceutically acceptable excipient.

13) The pharmaceutical composition of claim 12, which is an oral solid dosage form.

14) The crystalline form as defined in any one of claims 1 to 7, the composition as defined in any one of claims 8 to 10 or the pharmaceutical composition as defined in any one of claims 12 to 14 for use in the treatment of AEZ-associated cancer. ) The crystalline form as defined in any one of claims 1 to 7, the composition as defined in any one of claims 8 to 10 or the pharmaceutical composition as defined in any one of claims 12 to 14 for use in the treatment of advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), V/T-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer.