FIELD OF THE INVENTION

The present invention relates to a crystalline form of selpercatinib and to a process for its preparation. Furthermore, the invention relates to a pharmaceutical composition comprising the crystalline form of selpercatinib 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 EET-associated cancers, such as non-small cell lune cancer and thyroid cancer.

BACKGROUND OF THE INVENTION

Selpercatinib is an oral kinase inhibitor indicated for the treatment of patients with advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), 7: /'-mutant medullary thyroid cancer (MTC) and RET fusion-positive thyroid cancer. The chemical name of selpercatinib is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-y l)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]p yridine-3-carbonitrile.

Selpercatinib can be represented by the following chemical structure according to Formula (A) Formula (A).

Selpercatinib and its preparation are disclosed in WO 2018/071447 Al e.g. in Example 163. The last step includes purification by silica chromatography. The application is silent about the obtained solid-state form though.

WO 2019/075108 Al describes various crystalline forms of selpercatinib including an anhydrous Form 1, hydrates Form 2 and Form 7, and an IPA solvate Form 8, which were the result of an extensive polymorph screening program. The application teaches that Form 1 of selpercatinib is the most stable form (e.g. WO 2019/075108 Al, page 334, paragraph [00841] and page 335, paragraph [00843]). Form 1 is also the form present in the marketed selpercatinib capsules RETEVMO™

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 forms. For example, 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 (e.g. via hydrolysis), trigger changes of the physical form (e.g. via hydrate formation), lead to changes in dissolution behavior and influence powder properties such as flowability, compactability, tableting and compression behavior etc.

Also, the sudden appearance or disappearance of a metastable polymorph can present a problem in pharmaceutical development. Similarly, serious pharmaceutical consequences may arise if transformation occurs in a dosage form, e.g. upon storage.

There is thus a need for the provision of crystalline forms of selpercatinib having improved physicochemical properties. In particular, there is a strong need for the provision of a solid form of selpercatinib which is non-hygroscopic and thermodynamically stable and does not undergo phase transformation during pharmaceutical processing or storage. There is also a strong need for the provision of a pharmaceutical composition comprising a solid form of selpercatinib, which is stable at the conditions typically encountered during pharmaceutical processing and storage.

SUMMARY OF THE INVENTION

The present invention provides a crystalline form of selpercatinib, which is hereinafter also designated as “Form A”. Form A of the present invention posesses one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.

In particular, the inventors of the present invention surprisingly found that selpercatinib Form A of the present invention shows practically no interaction with water vapor (see Example 7, Comparative Example 3 and Figure 5 hereinafter). Due to its non-hygroscopic behavior, the physicochemical properties of Form A of the present invention are preserved regardless of 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. In contrast Form 1 of WO 2019/075108 Al shows interaction with water vapour when exposed to moisture and takes up to 2.6% of water (see Figure 19D of WO 2019/075108 Al).

In addition, selpercatinib Form A of the present invention possesses a higher melting point and enthalpy of fusion compared to Form 1 of WO 2019/075108 Al, indicating that Form A is thermodynamically more stable than Form 1, irrespective of the temperature (see Example 5, Comparative Example 1 and Figure 3 hereinafter). Competitive slurry experiments conducted with Form A of the present invention and Form 1 of WO 2019/075108 Al confirmed that Form A is thermodynamically more stable than Form 1 (see Comparative Example 2 hereinafter). The usage of a thermodynamically stable form of a compound is of great importance since polymorphic conversions, which may occur during manufacturing process and/or storage of a drug substance or drug product containing the drug substance can be excluded, when a stable form is used. This ensures reliable bioavailability and therefore consistent efficacy and safety of a drug product.

Abbreviations

PXRD powder X-ray diffractogram

FTIR Fourier transform infrared

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption

CPME cyclopentylmethyl ether

RET rearranged during transfection w-% weight percent RH relative humidity

Definitions

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

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.

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

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 7.5° 2-Theta for example can appear between 7.3° and 7.7° 2-Theta, preferably between 7.4° and 7.6° 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.

The term “Form 1” as used herein, when talking about a solid-state form of selpercatinib refers to the crystalline form of selpercatinib which is disclosed in WO 2019/075108 Al. Form 1 of selpercatinib can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (5.0 ± 0.2)°, (8.2 ± 0.2)° and (9.8 ± 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.

Crystalline Form A of selpercatinib 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 reflection 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 form and the confirmation that two sets of graphical data relate to the same crystal form is well with in 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.

As used herein, the term “amorphous” refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.

The terms “anhydrous form” 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. Typically, an anhydrous form does not contain more than 2.0 w-%, preferably not more than 1.0 w-% and most preferably not more than 0.5 w-% of water, based on the weight of the crystalline form.

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. Typically, a nonsolvated form does not contain more than 1.0 w-%, preferably not more than 0.5 w-%, and most preferably not more than 0.1 w-% of organic solvents, based on the weight of the crystalline form.

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

The term “effective amount” as used herein with regard to selpercatinib Form A encompasses an amount of selpercatinib Form A which causes the desired therapeutic and/or prophylactic effect.

The term “non-hygroscopic” as used herein refers to a compound showing a water uptake of at most 2 w-% in the sorption cycle when measured with GMS at a relative humidity in the range of from 0 to 90% RH and a temperature of (25.0 ± 0.1) °C, based on the weight of the compound.

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.

As used herein, the term “substantially free of any other solid-state form” with reference to a composition comprising Form A of selpercatinib of the present invention means that the composition includes at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, even more preferably at most 2 w-% and most preferably at most 1 w-% of any other solid-state form than Form A of selpercatinib, based on the weight of the composition.

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 or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.

The terms “filler” or “diluent” as used herein refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizers.

As used herein the term “binder” refers to substances which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.

The terms “disintegrant” or “disintegrating agent” as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.

The term “lubricant” as used herein refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process. They aid the ejection of the tablet from the dies and can improve powder flow.

The term “glidant” as used herein refers to substances which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti -caking effect.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates a representative PXRD of selpercatinib Form A according to 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 comparison of representative PXRDs of selpercatinib Form A of the present invention (top) and Form 1 of WO 2019/075108 Al (bottom). The x-axis shows the scattering angle in °2-Theta. The powder X-ray diffractogram of Form A was shifted along the y-axis to separate the diffractograms for clarity.

Figure 3: illustrates a representative DSC curve of selpercatinib Form A according to 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 4: illustrates a representative TGA curve of selpercatinib Form A 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 5: illustrates representative GMS isotherms of selpercatinib Form A of the present invention in the range of from 0 to 90% RH. The x-axis displays the relative humidity 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a crystalline form of selpercatinib, herein also designated as “Form A”.

Crystalline Form A of selpercatinib of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, FTIR spectroscopy, DSC, TGA and GMS. Selpercatinib Form A 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 A of selpercatinib 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 A) of selpercatinib characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.5 ± 0.2)°, (11.0 ± 0.2)° and (12.1 ± 0.2)°; or

(7.5 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)° and (17.3 ± 0.2)°; or

(7.5 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (17.3 ± 0.2)° and (21.2 ± 0.2)°; or

(7.5 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (17.3 ± 0.2)° and (21.2 ± 0.2)°; or

(7.5 ± 0.2)°, (9.3 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (17.3 ± 0.2)° and (21.2 ±

0.2)°; or

(7.5 ± 0.2)°, (9.3± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (17.3 ± 0.2)°, (17.8 ± 0.2)° and (21.2 ± 0.2)°; or

(7.5 ± 0.2)°, (9.3 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (17.3 ± 0.2)°, (17.8 ± 0.2)°, (19.9 ± 0.2)° and (21.2 ± 0.2)°; or (7.5 ± 0.2)°, (9.3 ± 0.2)°, (11.0 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (16.3 ± 0.2)°, (17.3 ± 0.2)°, (17.8 ± 0.2)°, (19.9 ± 0.2)° and (21.2 ± 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 A) of selpercatinib characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.2)°, (12.1 ± 0.2)°, (13.3 ± 0.2)°, (17.3 ± 0.2)°, (17.8 ± 0.2)°, (18.3 ± 0.2)°, (19.7 ± 0.2)°, (19.9 ± 0.2)°, (21.2 ± 0.2)°, (22.8 ± 0.2)° and (25.1 ± 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 present invention relates to a crystalline form (Form A) of selpercatinib characterized by having a PXRD comprising reflections at 2-Theta angles of: (7.5 ± 0.1)°, (11.0 ± 0.1)° and (12.1 ± 0.1)°; or

(7.5 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)° and (17.3 ± 0.1)°; or

(7.5 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (17.3 ± 0.1)° and (21.2 ± 0.1)°; or

(7.5 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (17.3 ± 0.1)° and (21.2 ± 0.1)°; or

(7.5 ± 0.1)°, (9.3 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (17.3 ± 0.1)° and (21.2 ±

0.1)°; or

(7.5 ± 0.1)°, (9.3± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (17.3 ± 0.1)°, (17.8 ± 0.1)° and (21.2 ± 0.1)°; or

(7.5 ± 0.1)°, (9.3 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (17.3 ± 0.1)°, (17.8 ± 0.1)°, (19.9 ± 0.1)° and (21.2 ± 0.1)°; or

(7.5 ± 0.1)°, (9.3 ± 0.1)°, (11.0 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (16.3 ± 0.1)°, (17.3 ± 0.1)°, (17.8 ± 0.1)°, (19.9 ± 0.1)° and (21.2 ± 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 A) of selpercatinib characterized by having a PXRD comprising reflections at 2-Theta angles of (7.5 ± 0.1)°, (12.1 ± 0.1)°, (13.3 ± 0.1)°, (17.3 ± 0.1)°, (17.8 ± 0.1)°, (18.3 ± 0.1)°, (19.7 ± 0.1)°, (19.9 ± 0.1)°, (21.2 ± 0.1)°, (22.8 ± 0.1)° and (25.1 ± 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 Form A of the present invention can be readily distinguished from the PXRDs of selpercatinib Form 1, Form 2, Form 7 and Form 8 of WO 2019/075108 Al . Form A for example shows characteristic reflections at (7.5 ± 0.2)°, (11.0 ± 0.2)° and (12.1 ± 0.2)°, whereas none of the crystalline forms of selpercatinib disclosed in WO 2019/075108 Al shows reflections in the same ranges.

In another embodiment, the present invention relates to a crystalline form (Form A) of selpercatinib, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak onset at a temperature of (212 ± 2)°C, preferably of (212 ± 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 A) of selpercatinib, characterized by having a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak maximum at a temperature of (214 ± 2)°C, preferably of (214 ± 1)°C, when measured at a heating rate of 10 K/min.

In another embodiment, the present invention relates to a crystalline form (Form A) of selpercatinib, characterized by having a TGA curve showing a mass loss of not more than 0.5 w-%, preferably of not more than 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 200°C at a rate of 10 K/min.

In a further embodiment, the present invention relates to a crystalline form (Form A) of selpercatinib characterized by showing a mass change of not more than 2.0 w-%, preferably of not more than 1.0 w-%, most preferably of not more than 0.5 w-%, such as not more than 0.3 w-% based on the weight of the crystalline form, when measured with GMS at a relative humidity in the range of from 0 to 90% and a temperature of (25.0 ± 1.0)°C.

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

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

In further embodiment, the present invention relates to a crystalline form (Form A) of selpercatinib characterized in being non-hygroscopic. Compositions

In another aspect, the present invention relates to a composition comprising the crystalline form (Form A) of selpercatinib 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 selpercatinib. For example, a composition comprising the crystalline Form A of selpercatinib of the present invention comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% of any other solid-state form than Form A of selpercatinib, based on the weight of the composition. Preferably, the any other solid-state form is crystalline Form 1 of selpercatinib of WO 2019/075108 Al or amorphous selpercatinib.

Form 1 of selpercatinib exhibits a PXRD comprising amongst others characteristic reflections at 2-Theta angles of (5.0 ± 0.2)° and (9.8 ± 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. Therefore, the absence of reflections at 2-Theta angles of (5.0 ± 0.2)° and (9.8 ± 0.2)°, in the PXRD confirms the absence of Form 1 of selpercatinib in the composition of the present invention.

Hence, in a preferred embodiment, the present invention relates to a composition comprising the crystalline form (Form A) of selpercatinib 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 (5.0 ± 0.2)° and (9.8 ± 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.

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 A) of selpercatinib 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 selpercatinib, and/or reaction impurities and/or processing impurities arising from the preparation of the composition.

Pharmaceutical compositions and medical use

In a further aspect, the present invention relates to the use of the crystalline form of selpercatinib (Form A) of the present invention, or the composition comprising the crystalline form of selpercatinib (Form A) 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. Furthermore, the present invention relates to a pharmaceutical composition comprising the crystalline form of selpercatinib (Form A) of the present invention, or the composition comprising the crystalline form of selpercatinib (Form A) 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 of selpercatinib (Form A) of the present invention, or the composition comprising the crystalline form of selpercatinib (Form A) 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 10 to 200 mg, calculated as selpercatinib (water free). For example, the effective and/or predetermined amount is selected from the group consisting of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg and 200 mg calculated as selpercatinib (water free). Preferably, the effective and/or predetermined amount is 40 mg or 80 mg calculated as selpercatinib (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, lubricants, glidants and combinations thereof. Preferably, the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is selected from the group consisting of fillers, glidants and combinations thereof.

In a particular embodiment, the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments comprising the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, a filler and a glidant.

Preferably, the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments comprising 15 to 35 w-% of the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, 60 to 85 w-% filler and 0.1 to 5 w-% glidant, based on the total weight of the composition.

More preferably, the present invention relates to a pharmaceutical composition as defined in any one of the above described embodiments comprising 45 to 60 w-% of the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, 35 to 54 w-% filler and 0.1 to 5 w-% glidant, based on the total weight of the composition.

In one embodiment, the filler is selected from the group consisting of dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, glucose or other monosaccharides, dextrin or other polysaccharides, microcrystalline cellulose, powdered cellulose, cellulose derivatives, precipitated calcium carbonate, calcium sulfate, sorbitol, inositol and starch, and combinations thereof. Most preferably the filler is microcrystalline cellulose.

In one embodiment, the glidant is selected from the group consisting of coloidal silica, colloidal silicon dioxide, fumed silica, silicon dioxide, com starch, talc, calcium silicate, magnesium silicate, tribasic calcium phosphate, silicon hydrogel, and combinations thereof. Most preferably the glidant is silicon dioxide.

Hence in a particular preferred embodiment, the invention relates to a pharmaceutical composition comprising 15 to 35 w-% of the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, 60 to 85 w-% microcrystalline cellulose and 0.1 to 5 w-% silicon dioxide, based on the total weight of the composition.

In an even more preferred embodiment, the invention relates to a pharmaceutical composition comprising 45 to 60 w-% of the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, 35 to 54 w-% microcrystalline cellulose and 0.1 to 5 w-% silicon dioxide, based on the total weight of the composition. Preferably, the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a tablet or a capsule. In a particular preferred embodiment, the pharmaceutical composition of the present invention as described above is a capsule, preferably a hard gelatin 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 e.g. selected from the group consisting of micronization, blending, milling, granulation (wet or dry granulation), capsule filling, tabletting, film-coating and any combinations thereof.

In a particular aspect, the present invention relates to a process for the preparation of a pharmaceutical composition comprising the crystalline form of selpercatinib (Form A) of the present invention, as defined in any one of the above described embodiments, preferably a capsule such as a hard gelatin capsule, comprising the steps of:

(a) micronizing the crystalline form of selpercatinib (Form A) of the present invention or the composition comprising the crystalline form of selpercatinib (Form A) of the present invention;

(b) blending the micronized crystalline form of selpercatinib (Form A) or the micronized composition comprising the crystalline form of selpercatinib (Form A) of the present invention obtained in (a) with at least one filler and at least one glidant;

(c) milling and/or sieving the blend obtained in (b);

(d) optionally, blending the milled and/or sieved mixture obtained in (c); and

(e) filling the mixture obtained in either (c) or (d) into capsules;

In a further aspect, the present invention relates to the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A), or the pharmaceutical composition comprising the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) 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 of selpercatinib (Form A), or the composition comprising the crystalline form of selpercatinib (Form A), or the pharmaceutical composition comprising the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of /////'-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 of selpercatinib (Form A), or the composition comprising the crystalline form of selpercatinib (Form A), or the pharmaceutical composition comprising the crystalline form of selpercatinib (Form A) or the composition comprising the crystalline form of selpercatinib (Form A) 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 AET-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 embodiment, the EET-associated cancer is selected from the group consisting of advanced or metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic / //'-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 selpercatinib Form A

Selpercatinib (500 mg, e.g. prepared according to the procedure disclosed in WO 2018/071447 Al, Example 163) was dissolved in cyclopentylmethyl ether (45 mL) upon heating to reflux temperature. The resulting clear solution was cooled to 25°C within 6 hours, whereupon crystallization occured. The suspension was further stirred at 25°C for 24 hours. Subsequently, the solid was collected by filtration and dried for 17 hours at 40°C under vacuum (5 mb ar).

Yield: 245 mg (49% of theory) Example 2: Preparation of selpercatinib Form A

Selpercatinib (7.204 g, e.g. prepared according to the procedure disclosed in WO 2018/071447 Al, Example 163) was dissolved in ethanol (750 mL) upon heating to reflux temperature. The resulting clear solution was cooled to 20°C within 7 hours, whereat Form A seed crystals (about 30 mg, prepared according to the procedure disclosed in Example 1 hereinabove) were added to the solution at 74°C. During the cooling step a suspension formed, which was further stirred for 2 hours at 20°C. Finally, the crystals were collected by filtration and dried under vacuum (about 10 mbar) for 42 hours.

Yield: 6.141 g (85% of theory)

Example 3: Preparation of selpercatinib Form A

Selpercatinib (7.278 g, e.g. prepared according to the procedure disclosed in WO 2018/071447 Al, Example 163) was dissolved in /.wbutanol (290 mL) upon heating to reflux temperature. The resulting clear solution was cooled to 90°C at a cooling rate of -0.5 K/min, whereat Form A seed crystals (203 mg, prepared according to the procedure disclosed in Example 1 hereinabove) were added to the solution which became slightly turbid. Subsequently, the mixture was further cooled to 0 °C at a cooling rate of -0.1 K/min. The resulting suspension was further stirred for 7 hours at 0°C. Finally, the crystals were collected by filtration and dried at 40°C under vacuum (about 5 mbar) for 3 days.

Yield: 7.040 g (94% of theory)

Example 4: 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 selpercatinib Form A of the present invention is displayed in Figure 1 hereinafter. The corresponding reflection list of crystalline form A of selpercatinib of the present invention is provided in Table 1 below.

Table 1: Reflection positions of crystalline Form A of selpercatinib 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.

Figure 2 illustrates an overlay of the PXRDs of selpercatinib Form A of the present invention (top) and Form 1 of WO 2019/075108 Al (bottom). As can be seen both forms can be readily distinguished from each other by powder X-ray diffractometry. For example, the PXRD of selpercatinib Form A possesses reflections at (7.5 ± 0.2)°, (11.0 ± 0.2)° and (12.1 ± 0.2) °2- Theta, whereas no reflections are visible in the PXRD of selpercatinib Form 1 in these ranges. On the other hand, the PXRD of selpercatinib Form 1 displays i.a. reflections at (5.0 ± 0.2)° and (9.8 ± 0.2)° 2-Theta, whereas the PXRD of selpercatinib Form A shows no reflection in these ranges.

Example 5: Differential Scanning Calorimetry

DSC was performed on a Mettler Polymer DSC R instrument. The sample (5.20 mg Form A) 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 selpercatinib Form A is displayed in Figure 3 hereinafter and shows a single endotherm with an onset temperature of about 212.3°C and a peak maximum at a temperature of about 213 ,6°C, which is due to melting. The enthalpy of fusion was determined to be about 120.4 J/g.

Example 6: Thermogravimetric analysis

TGA was performed on a Mettler TGA/DSC 1 instrument. The sample (8.02 mg Form A) was heated in a 100 microliter aluminium pan closed with an aluminium lid from 25 to 250°C at a rate of 10 K/min. The lid was automatically pierced at the beginning of the measurement. Nitrogen (purge rate 50 mL/min) was used as purge gas.

A representative TGA curve of selpercatinib Form A of the present invention is displayed in Figure 4 hereinafter and shows no significant mass loss up to a temperature of about 200°C. Therefore, selpercatinib Form A of the present invention can be assigned an anhydrous and non-solvated crystal form.

Example 7: Gravimetric moisture sorption

Gravimetric moisture sorption was performed with an SPSx-lp moisture sorption analyzer (ProUmid, Ulm). The measurement cycle was started at ambient relative humidity (RH) of 35%. RH was then decreased to 5% in 5% steps, followed by a further decrease to 3% and to 0%. Afterwards RH was increased from 0% to 90% in a sorption cycle and subsequently decreased to 0 % in a desorption cycle each in 5% steps. Finally, RH was increased to ambient relative humidity of 35% 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.

The moisture sorption/desorption isotherms of selpercatinib Form A of the present invention in the range from 0-90% RH are displayed in Figure 5. The mass difference in the sorption cycle between 0 and 90% RH is only about 0.3 w-% indicating the non-hygroscopic behaviour of this crystalline form. The lacking hysteresis between the sorption and the desorption isotherms indicates that no structural changes appear during the experiment. This assumption is strengthened by the fact that the sample still shows the same PXRD after the experiment. Example 8: Powder blend in hard gelatin capsule

Powder blend formulations were prepared and encapsulated in a hard gelatin capsules in a 40 mg and 80 mg dosage form (see Tables 2 to 5). Thereby, selpercatinib Form A was milled and blended with silicon dioxide and sieved. Microcrystalline cellulose was added to the powder and blended a second time before it was filled by weight into hard gelatin capsules.

Table 2: 40 mg and 80 mg powder blend formulations

Table 3: 40 mg and 80 mg powder blend formulations

Table 4: 40 mg and 80 mg powder blend formulations

Table 5: 40 mg and 80 mg powder blend formulations Comparative Example 1: Differential Scanning Calorimetry

A comparison of the DSC data of selpercatinib Form A of the present invention and Form 1 of WO 2019/075108 shows that Form A possesses a higher melting point and fusion enthalpy indicating that Form A is the more stable form irrespective of temperature. In Figure 19B of WO 2019/075108 a small endothermic event before the melting endotherm is visible, indicating some thermal events before melting of the sample. In contrast, the DSC curve of Form A of the present invention only shows a single sharp melting endotherm (see Figure 3 hereinafter).

Table 6: DSC data of the melting events

Comparative Example 2: Competitive slurry experiments

Suspensions of selpercatinib Form A of the present invention (about 30 mg, e.g. prepared according to Example 2 of the present invention) and selpercatinib Form 1 of WO 2019/075108 Al (about 30 mg, prepared according to one of the methods provided in Example 5 of WO 2019/075108) in ^-heptane (2.5 mL) were magnetically stirred at 20°C, 40°C, 60°C and 80°C, respectively. Samples were taken after 1 hour, 2 hours, 1 day, 5 days and 7 days and subjected to PXRD measurement. The results provided in Table 7 show that Form 1 fully converted to Form A over time at all conditions. Table 7: Results from competitive slurry experiments with selpercatinib Form A of the present invention and selpercatinib Form 1 ofWO 2019/075108 Al

Comparative Example 3: Hygroscopicity

A comparison of the GMS data of selpercatinib Form A of the present invention and Form 1 of WO 2019/075108 shows that Form A shows almost no interaction with water vapour and can be assigned as being non-hygroscopic, whereas selpercatinib Form 1 of WO 2019/075108 Al is slightly hygroscopic and takes up well above 2 w-% of water upon contact with moisture.

Table 8: Summary of GMS data