WO2022020279A1 - Solid state forms of selpercatinib and process for preparation thereof - Google Patents

Abstract

The present disclosure encompasses solid state forms of Selpercatinib, in embodiments crystalline polymorphs of Selpercatinib, processes for preparation thereof, and pharmaceutical compositions thereof.

Description

SOLID STATE FORMS OF SELPERCATINIB AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE DISCLOSURE

[0001] The present disclosure encompasses solid state forms of Selpercatinib, in embodiments crystalline polymorphs of Selpercatinib, processes for preparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

[0002] Selpercatinib, 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3- yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carbonitrile, has the following chemical structure:

[0003] Selpercatinib is a kinase inhibitor, and it is approved for the treatment of adult patients with metastatic RET fusion -positive non-small cell lung cancer (NSCLC); adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). [0004] The compound is described in International Publication No. WO 2018/71447. International Publication No. WO 2019/75108 discloses crystalline forms of Selpercatinib.

[0005] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (¹³C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Selpercatinib.

SUMMARY OF THE DISCLOSURE

[0008] The present disclosure provides crystalline polymorphs of Selpercatinib, processes for preparation thereof, and pharmaceutical compositions thereof. These crystalline polymorphs can be used to prepare other solid state forms of Selpercatinib, Selpercatinib salts and their solid state forms.

[0009] In embodiments, the present disclosure provides Selpercatinib and crystalline forms thereof. In embodiments, the present disclosure provides crystalline form of Selpercatinib designated as Form SI, Form S2, Form S3, Form S4 and/or 1,4 Dioxane solvate (defined herein).

[0010] The present disclosure also provides uses of the said solid state forms of Selpercatinib in the preparation of other solid state forms of Selpercatinib or salts thereof.

[0011] The present disclosure provides crystalline polymorphs of Selpercatinib for use in medicine, including for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

[0012] The present disclosure also encompasses the use of crystalline polymorphs of Selpercatinib of the present disclosure for the preparation of pharmaceutical compositions and/or formulations.

[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising crystalline polymorphs of Selpercatinib according to the present disclosure.

[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Selpercatinib with at least one pharmaceutically acceptable excipient.

[0015] The crystalline polymorph of Selpercatinib as defined herein and the pharmaceutical compositions or formulations of the crystalline polymorph of Selpercatinib may be used as medicaments, such as for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

[0016] The present disclosure also provides methods of treating metastatic RET fusion positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer, by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Selpercatinib of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from metastatic RET fusion -positive non small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer, or otherwise in need of the treatment. [0017] The present disclosure also provides uses of crystalline polymorphs of Selpercatinib of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., metastatic RET fusion -positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Selpercatinib Form SI.

[0019] Figure 2 shows a characteristic X-ray powder diffraction pattern (XRPD) of Selpercatinib Form S2.

[0020] Figure 3 shows a characteristic X-ray powder diffraction pattern (XRPD) of Selpercatinib Form S3.

[0021] Figure 4 shows a characteristic X-ray powder diffraction pattern (XRPD) of Selpercatinib Form S4.

[0022] Figure 5 shows a characteristic X-ray powder diffraction pattern (XRPD) of Selpercatinib 1, 4-dioxane solvate.

[0023] Figure 6 shows a characteristic X-ray powder diffraction pattern (XRPD) of Amorphous Selpercatinib.

[0024] Figure 7a shows ¹³C solid state NMR spectrum of Form SI of Selpercatinib (full scan).

[0025] Figure 7b shows ¹³C solid state NMR spectrum of Form SI of Selpercatinib (at the range of 0-100 ppm).

[0026] Figure 7c shows ¹³C solid state NMR spectrum of Form SI of Selpercatinib (at the range of 100-210 ppm).

DETAILED DESCRIPTION OF THE DISCLOSURE

[0027] The present disclosure encompasses solid state forms of Selpercatinib, including crystalline polymorphs of Selpercatinib, processes for preparation thereof, and pharmaceutical compositions thereof.

[0028] In embodiments, the present disclosure provides Selpercatinib and crystalline forms thereof. In embodiments, the present disclosure provides crystalline form of Selpercatinib designated as Form SI, Form S2, Form S3, Form S4 and/or 1,4 Dioxane solvate (defined herein).

[0029] Solid state properties of Selpercatinib and crystalline polymorphs thereof can be influenced by controlling the conditions under which Selpercatinib and crystalline polymorphs thereof are obtained in solid form.

[0030] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. Thus, a crystalline polymorph of Selpercatinib described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Selpercatinib. In some embodiments of the disclosure, the described crystalline polymorph of Selpercatinib may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Selpercatinib.

[0031] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Selpercatinib of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0032] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Selpercatinib referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Selpercatinib characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0033] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Selpercatinib, relates to a crystalline form of Selpercatinib which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.

[0034] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0035] As used herein, the term "isolated" in reference to crystalline polymorph of Selpercatinib of the present disclosure corresponds to a crystalline polymorph of Selpercatinib that is physically separated from the reaction mixture in which it is formed.

[0036] As used herein, unless stated otherwise, the XRPD measurements are taken using copper Ka radiation wavelength 1.5418 A. XRPD peaks reported herein are measured using CuK a radiation, l = 1.5418 A, typically at a temperature of 25 ± 3°C.

[0037] As used herein, unless stated otherwise, ¹³C NMR reported herein are measured at 125 MHz at a magic angle spinning frequency w_G/2p = 11 kHz, preferably at a temperature of at 293 K ± 3°C. [0038] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature”, often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0039] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added. [0040] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.

[0041] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.

[0042] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.

[0043] The present disclosure includes a crystalline polymorph of Selpercatinib, designated S I .

[0044] According to one embodiment of the present disclosure crystalline Form SI of Selpercatinib may be characterized by an X-ray powder diffraction pattern having peaks at 7.3 and 11.9, degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form SI of Selpercatinib according to this embodiment may be further characterized by an X-ray powder diffraction pattern having any one, two, or three additional peaks at 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2- theta. Alternatively, crystalline Form SI of Selpercatinib according to this embodiment may be characterized by an X-ray powder diffraction pattern having peaks at 7.3 and 11.9, degrees 2- theta± 0.2 degrees 2-theta, and any one, two, or three additional peaks at 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and further having any one, two, three, or four additional peaks selected from 16.1, 17.5, 22.4 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0045] According to an alternative embodiment of this disclosure, crystalline Form SI of Selpercatinib may be characterized by an X-ray powder diffraction pattern having peaks at 7.3,

11.9 and 13.1 degrees 2-theta ± 0.2 degrees 2-theta. Crystalline Form SI of Selpercatinib according to this embodiment may be further characterized by an X-ray powder diffraction pattern having one or both additional peaks at 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2- theta. Alternatively, crystalline Form SI of Selpercatinib according to this embodiment may be characterized by an X-ray powder diffraction pattern having peaks at 7.3, 11.9, and 13.1 degrees 2-theta ± 0.2 degrees 2-theta, and having one or both additional peaks at 17.0 and 21.0 degrees 2- theta ± 0.2 degrees 2-theta, and further having any one, two, three, or four additional peaks selected from 16.1, 17.5, 22.4 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0046] In any of the above embodiments, crystalline Form SI of Selpercatinib may be further characterized by any of the characteristic XRPD peaks as discussed above, and additionally by a solid state ¹³C NMR spectrum having peaks at 47.7, 80.0, 106.4, 129.9, 134.5 and 152.0 ppm ± 0.2 ppm; and/or a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a reference peak at 163.1 ppm ± 2 ppm of 115.4, 83.1, 56.7, 33.2, 28.6 and 11.1 ppm ± 0.1 ppm; and/or a solid state ¹³C NMR spectrum substantially as depicted in Figures 7a,

7b or 7c; and combinations of these data.

[0047] The crystalline Form SI of Selpercatinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 7.3, 11.9, 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; a solid state ¹³C NMR spectrum having peaks at 47.7, 80.0,

106.4, 129.9, 134.5 and 152.0 ppm ± 0.2 ppm; a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 163.1 ppm ± 2 ppm of

115.4, 83.1, 56.7, 33.2, 28.6 and 11.1 ppm ± 0.1 ppm; a solid state ¹³C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c; and combinations of these data.

[0048] Crystalline Form SI of Selpercatinib may be further characterized by an X-ray powder diffraction pattern having peaks at 7.3, 11.9, 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 16.1, 17.5, 22.4 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0049] Crystalline Form SI of Selpercatinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.3, 11.9, 13.1, 16.1, 17.0, 17.5, 21.0, 22.4, and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0050] In any embodiment or aspect of the present disclosure, crystalline Form SI of Selpercatinib may be isolated.

[0051] Crystalline Form SI of Selpercatinib according to any aspect or embodiment of the disclosure may be anhydrous.

[0052] Crystalline Form SI of Selpercatinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.3, 11.9, 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.

[0053] The present disclosure further comprises processes for the preparation of Form SI of Selpercatinib according to any aspect or embodiment of the present disclosure.

[0054] In one embodiment, the process comprises:

(i) combining Selpercatinib with a solvent mixture comprising water and acetone;

(ii) heating the mixture;

(iii) subjecting the mixture to heating-cooling cycles for a sufficient period of time to prepare Form SI Selpercatinib;

(iv) isolating the solid; and

(v) optionally drying.

[0055] In any embodiment of the process, step (i) may be carried out at a temperature of about 18°C to about 40°C, or about 20°C to about 35°C, or about 25°C to about 30°C .

[0056] In any embodiment of the process, step (ii) may comprise heating the mixture to a temperature of about 50°C to about 55°C, or about 45°C to about 50°C, or about 40°C. Particularly, the heating may be carried out at the rate of about 0.05 °C/minute to about l°C/minute, about 0.07 °C/minute to about 0.5°C/minute, about 0.08 °C/minute to about 0.3°C/minute, about 0.09 °C/minute to about 0.2°C/minute, or about 0.1°C/minute.

[0057] In any embodiment of the process described herein, the water-acetone mixture may comprise water in an amount of: about 2% to about 20%, about 5% to about 15%, about 7% to about 12%, about 8% to about 11%, or about 10% (v/v). In any embodiment of this process, the water- acetone solvent mixture in step (i) may be typically used in an amount of about 5 ml to about 15 ml, about 8 ml to about 13 ml, or about 10 ml, per gram of Selpercatinib.

[0058] In any embodiment of this process, step (iii) may comprise keeping the reaction mixture for temperature cycling between temperature of about 50°C and about 15°C, or about 45°C and about 20°C, or about 40°C and about 25°C at the rate of 0.1°C/minute. Particularly, the temperature cycling may be carried out over a period of about 50 hours to 90 hours, or about 60 hours to 80 hours, or about 72 hours

[0059] In any embodiment of this process, step (iv) may comprise isolating the resulting solid by any suitable process, for example, by filtration or centrifuge. Particularly, step (iv) may be carried out by filtration. The isolation (preferably filtration) may be carried out at room temperature, preferably at 22-28°C or about 25°C.

[0060] In any embodiment of this process, the crystalline Form SI of Selpercatinib may be dried by any suitable process, e.g., in air, by suction filtration, or in a vacuum oven. The crystalline Form SI of Selpercatinib may be dried under vacuum, typically at a temperature of about 15°C to about 60°C, about 20°C to about 55°C, or about 25°C. The drying may be carried out for any suitable time to remove the solvent, typically about 5 minutes to about 2 hours, about 7 minutes to about 1 hours, or about 10 minutes to about 15 minutes.

[0061] Alternatively, form SI may be prepared by a process comprising:

(i) combining amorphous Selpercatinib in a suitable solvent, optionally wherein herein the solvent is acetonitrile, or a Ci-₄ alcohol;

(ii) optionally heating the reaction mixture;

(iii) isolating the solid; and

(iv) optionally drying.

[0062] In any embodiment of the process, the solvent in step (i) may be methanol, ethanol or acetonitrile.

[0063] In any embodiment of the process, step (i) comprises adding the solvent to the Selpercatinib. Particularly, the solvent in step (i) may be optionally added at a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C.

[0064] In any embodiment of the process, the reaction mixture in step (ii) may be heated to a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C and the reaction mixture in step (ii) may be maintained to a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C for period of about 15 hours to about 48 hours, about 20 hours to about 30 hours, or about 24 hours.

[0065] In any embodiment of this process, step (iii) may comprise isolating the resulting solid by any suitable process, for example, by filtration or centrifuge. In any embodiment of the process, step (iii) may comprise filtering the solid. The isolation (preferably filtration) may be carried out at room temperature, preferably at 22-28°C or about 25 °C.

[0066] In any embodiment of this process, the solvent in step (i) may typically be used in an amount of about 10 ml to about 30 ml, about 15 ml to about 25 ml, or about 20 ml per gram of Selpercatinib.

[0067] In any embodiment of this process, the crystalline Form SI of Selpercatinib may be dried. The drying may be by any suitable process, e.g., in air, by suction filtration, or in a vacuum. Optionally, the crystalline Form SI of Selpercatinib may be dried under vacuum, typically at a temperature of about 20°C to about 60°C, about 22°C to about 55°C, about 23°C to about 40°C, or about 25°C. The drying may be carried out for any suitable time to remove the solvent, typically about 1 to about 2 hours, about 0.5 hours to about 1 hours, or about 5 minutes to about 10 minutes.

[0068] Alternatively, form SI of Selpercatinib may be prepared by crystallisation from a mixture of N,N-dimethylformamide and ethanol. The process may comprise:

(i) preparing a solution of Selpercatinib in N,N-Dimethylformamide (DMF);

(ii) adding ethanol

(iii) optionally adding seeds of Form SI

(iv) optionally adding N,N-Dimethylformamide (DMF)

(v) isolating the solid; and

(vi) optionally drying.

[0069] In any embodiment of the process, step (i) may comprise dissolving N,N- Dimethylformamide (DMF). Particularly the DMF may be heated to a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C.

[0070] Optionally the solution in step (i) may be filtered, particularly to remove undissolved particles. In any embodiment of the process, step (ii) comprises adding ethanol to the hot solution in step (i). Optionally, according to step (iii), Form SI seeds of Selpercatinib may be added to the mixture. In any embodiment of the process, DMF may be added according to step

(iv). The DMF added may be optionally heated, preferably at a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C.

[0071] In any embodiment of the process, the reaction mixture in step (iv) may be maintained to a temperature of about 40°C to about 80°C, or about 50°C to about 70°C, or about 60°C for period of about 15 hours to about 48 hours, about 20 hours to about 30 hours, or about 24 hours.

[0072] In any embodiment of this process, step (v) may comprise isolating the solid by any suitable process, for example, by filtration or centrifuge. In any embodiment of the process, step

(v) may comprise filtering the solid.

[0073] In any embodiment of this process, N,N-Dimethylformamide (DMF) in step (i) may be typically used in an amount of about 10 ml to about 20 ml, about 12 ml to about 18 ml, or about 15 ml per gram of Selpercatinib.

[0074] In any embodiment of this process, N,N-Dimethylformamide (DMF) in step (iv) is typically used in an amount of about 10 ml to about 20 ml, about 12 ml to about 18 ml, or about 15 ml per gram of Selpercatinib.

[0075] In any embodiment of this process, ethanol in step (ii) is typically used in an amount of about 50 ml to about 150 ml, about 70 ml to about 120 ml, or about 75 ml per gram of Selpercatinib.

[0076] In any embodiment of this process, the crystalline Form SI of Selpercatinib may be dried. The drying may be by any suitable process, e.g., in air, by suction filtration, or in a vacuum. Optionally, the crystalline Form SI of Selpercatinib may be dried under vacuum, typically at a temperature of about 20°C to about 60°C, about 22°C to about 55°C, about 23°C to about 40°C, or about 25°C. The drying may be carried out for any suitable time to remove the solvent, typically about 1 to about 2 hours, about 0.5 hours to about 1 hours, or about 10 minutes to about 15 minutes.

[0077] In any embodiment of the processes disclosed herein, there is provided a further step of combining the crystalline form S 1 with at least one pharmaceutically acceptable excipient to prepare a pharmaceutical composition or dosage form.

[0078] The present disclosure includes a crystalline polymorph of Selpercatinib, designated S2. The crystalline Form S2 of Selpercatinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 8.6, 10.0, 15.4, 18.3 and 23.2 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0079] Crystalline Form S2 of Selpercatinib may be further characterized by an X-ray powder diffraction pattern having peaks at 8.6, 10.0, 15.4, 18.3 and 23.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 4.8, 22.2 and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0080] Crystalline Form S2 of Selpercatinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.8, 8.6, 10.0, 15.4, 18.3, 22.2, 23.2, and 25.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0081] In one embodiment of the present disclosure, crystalline Form S2 of Selpercatinib is isolated.

[0082] Crystalline Form S2 of Selpercatinib may be an isopropyl alcohol-water mixture solvate.

[0083] Crystalline Form S2 of Selpercatinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.6, 10.0, 15.4, 18.3 and 23.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.

[0084] The present disclosure includes a crystalline polymorph of Selpercatinib, designated S3. The crystalline Form S3 of Selpercatinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 4.6, 10.2, 14.8, 17.9 and 21.6 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0085] Crystalline Form S3 of Selpercatinib may be further characterized by an X-ray powder diffraction pattern having peaks at 4.6, 10.2, 14.8, 17.9 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, or four additional peaks selected from 16.6, 17.9, 23.4 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0086] Crystalline Form S3 of Selpercatinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.6, 10.2, 14.8, 17.9, and 21.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 16.6, 23.4 and 26.9 degrees 2-theta ± 0.2 degrees 2-theta. [0087] Crystalline Form S3 of Selpercatinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 4.6, 10.2, 14.8, 16.6, 17.9, 21.6, 23.4, and 26.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0088] In one embodiment of the present disclosure, crystalline Form S3 of Selpercatinib is isolated.

[0089] Crystalline Form S3 of Selpercatinib may be a hydrate, and more preferably monohydrate.

[0090] Crystalline Form S3 of Selpercatinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 4.6, 10.2, 14.8, 17.9 and 21.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.

[0091] The present disclosure includes a crystalline polymorph of Selpercatinib, designated S4. The crystalline Form S4 of Selpercatinib may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at 9.5, 14.6, 18.2, 26.9 and 28.9 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.

[0092] Crystalline Form S4 of Selpercatinib may be further characterized by an X-ray powder diffraction pattern having peaks at 9.5, 14.6, 18.2, 26.9 and 28.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, or three additional peaks selected from 16.8, 19.2, and 23.2 degrees 2-theta ± 0.2 degrees 2-theta.

[0093] Crystalline Form S4 of Selpercatinib may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 9.5, 14.6, 16.8, 18.2, 19.2, 23.2, 26.9, and 28.9 degrees 2-theta ± 0.2 degrees 2-theta.

[0094] In one embodiment of the present disclosure, crystalline Form S4 of Selpercatinib is isolated.

[0095] Crystalline Form S4 of Selpercatinib may be tert-butyl alcohol solvate

[0096] Crystalline Form S4 of Selpercatinib may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.5, 14.6, 18.2, 26.9 and 28.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof. [0097] The above crystalline polymorphs can be used to prepare other crystalline polymorphs of Selpercatinib, and their solid state forms.

[0098] The present disclosure encompasses a process for preparing other solid state forms of Selpercatinib, or a Selpercatinib salt or a solid state form thereof. The process includes preparing any one of the crystalline polymorph of Selpercatinib by the processes of the present disclosure and converting it to another solid state form of Selpercatinib or Selpercatinib salt or a solid state form thereof.

[0099] In any aspect or embodiment of the present disclosure, any of the solid state forms of Selpercatinib described herein may be polymorphically pure or may be substantially free of any other solid state forms of Selpercatinib. In any aspect or embodiment of the present disclosure, any of the solid state forms of Selpercatinib may contain: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0%, of any other solid state forms of the subject compound, preferably as measured by XRPD. Thus, any of the disclosed crystalline forms of Selpercatinib described herein may be substantially free of any other solid state forms of Selpercatinib, and may contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject solid state form of Selpercatinib.

[00100] The present disclosure provides the above described crystalline polymorphs of Selpercatinib for use in the preparation of pharmaceutical compositions comprising Selpercatinib and/or crystalline polymorphs thereof.

[00101] The present disclosure also encompasses the use of crystalline polymorphs of Selpercatinib of the present disclosure for the preparation of pharmaceutical compositions of crystalline Selpercatinib and/or crystalline polymorphs thereof.

[00102] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes includes combining any one or a combination of the crystalline polymorphs of Selpercatinib of the present disclosure with at least one pharmaceutically acceptable excipient.

[00103] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the solid state forms of Selpercatinib of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes. [00104] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[00105] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), hydroxypropyl methyl cellulose (e.g., Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch. [00106] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.

[00107] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[00108] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00109] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00110] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00111] In liquid pharmaceutical compositions of the present invention, Selpercatinib and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[00112] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[00113] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.

[00114] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste. [00115] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[00116] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[00117] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[00118] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00119] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.

[00120] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00121] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00122] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00123] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00124] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00125] A pharmaceutical formulation of Selpercatinib can be administered. Selpercatinib may be formulated for administration to a mammal, in embodiments to a human, by injection. Selpercatinib can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00126] The crystalline polymorphs of Selpercatinib and the pharmaceutical compositions and/or formulations of Selpercatinib of the present disclosure can be used as medicaments, in embodiments in the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

[00127] The present disclosure also provides methods of treating metastatic RET fusion positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer by administering a therapeutically effective amount of any one or a combination of the crystalline polymorphs of Selpercatinib of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.

[00128] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.

Powder X-ray Diffraction method

[00129] X-ray diffraction was performed on X-Ray powder diffractometer:

Bruker D8 Advance; CuKa radiation (l = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring with silicon low background holder. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring with silicon low background holder.

All X-Ray Powder Diffraction peak values are calibrated with regard to standard silicon spiking in the sample.

Solid state ¹³C-NMR method:

[00130] Solid-state NMR spectra were measured at 11.7 T using a Bruker Avance III HD 500 US/WB NMR spectrometer (Karlsruhe, Germany, 2013) with 3.2 mm probehead. The ¹³C CP/MAS NMR spectra employing cross-polarization were acquired using the standard pulse scheme at spinning frequency of 15 kHz and a room temperature (300 K). The recycle delay was 8 s and the cross-polarization contact time was 2 ms. The ¹³C scale was referenced to a- glycine (176.03 ppm for ¹³C). Frictional heating of the spinning samples was offset by active cooling, and the temperature calibration was performed with Pb(N0₃)_2.The NMR spectrometer was completely calibrated and all experimental parameters were carefully optimized prior the investigation. Magic angle was set using KBr during standard optimization procedure and homogeneity of magnetic field was optimized using adamantane sample (resulting line-width at half-height Du1/2 was less than 3.5 Hz at 250 ms of acquisition time).

EXAMPLES

Preparation of starting materials

[00131] Selpercatinib can be prepared according to methods known from the literature, for example U.S. Patent No. 10,112,942 and U.S. Patent Publication No. 2019/0106438.

Example 1 : Preparation of Selpercatinib Form SI

[00132] Selpercatinib (0.1 grams) was taken in a 10 ml reaction-tube and 10% water- acetone solvent mixture (1ml) was added at temperature of about 25°C to about 30°C. The reaction mixture was heated to 40°C at the rate of 0. l°C/minute and clear solution was observed in heating. The reaction mixture was kept for temperature cycling between temperature of about 40°C and temperature of about 25°C at the rate of 0.1°C/minute. The heat-cool cycles were carried out for period of about 72 hours. After 72 hours, the reaction mass was filtered under vacuum and suck dried for period of about 10 minutes to about 15 minutes at temperature of about 25°C. Crystalline Selpercatinib was obtained. A sample was analyzed by XRPD. Form SI was obtained. An XRPD pattern is shown in Figure 1.

Example 2: Preparation of Selpercatinib Form S2

[00133] Selpercatinib (0.1 grams) was taken in a 10 ml reaction-tube and 10% water- isopropyl alcohol solvent mixture (1ml) was added at temperature of about 25°C to about 30°C. The reaction mixture was heated to 40°C at the rate of 0. l°C/minute and clear solution was observed in heating. The reaction mixture was kept for temperature cycling between temperature of about 40°C and temperature of about 25°C at the rate of 0. l°C/minute. The heat-cool cycles were carried out for period of about 72 hours. After 72 hours, the reaction mass was filtered under vacuum and suck dried at temperature of about 25°C for period of about 10 minutes to about 15 minutes. Crystalline Selpercatinib was obtained. A sample was analyzed by XRPD. Form S2 was obtained. An XRPD pattern is shown in Figure 2. Example 3: Preparation of Selpercatinib Form S3

[00134] Selpercatinib (0.1 grams) was taken in a 10 ml reaction-tube and added 10% water- Butanol solvent mixture (1ml) at temperature of about 25°C to about 30°C. The reaction mixture was heated to 40°C at the rate of 0. l°C/minute and clear solution was observed in heating. The reaction mixture was kept for temperature cycling between temperature of about 40°C and temperature of about 25°C at the rate of 0.1°C/minute. The heat-cool cycles were carried out for period of about 72 hours. After 72 hours, the reaction mass was filtered under vacuum and suck dried at temperature of about 25°C for period of about 10 minutes to about 15 minutes. Crystalline Selpercatinib was obtained. A sample was analyzed by XRPD. Form S3 was obtained. An XRPD pattern is shown in Figure 3.

Example 4: Preparation of Selpercatinib 1,4 Dioxane solvate

[00135] Selpercatinib (3.0g) was dissolved in 75mL 1,4 Dioxane solvent at temperature of about 60°C and filtered to remove any undissolved particulates. The clear solution was maintained under stirring at temperature of about 60°C for period of about 1 hour. This clear solution was cooled to temperature of about 10°C and maintained for period of about 2 hours to about 3 hours. The reaction mass was filtered under vacuum for period of about 10 minutes to about 15 minutes at 25°C. The obtained solid was analyzed by XRPD. Selpercatinib 1,4 Dioxane solvate was obtained. An XRPD pattern is shown in Figure 5.

Example 5: Preparation of Selpercatinib Form S4

[00136] Selpercatinib (1,4 Dioxane solvate) (25 mg) was taken in a 10 ml reaction-tube and added 5% water- tert-butyl alcohol solvent mixture (1ml) at temperature of about 25°C to about 30°C. The slurry mass was kept under magnetic stirring at temperature of about 25°C for period of about 3 days. After 3 days, the reaction mass was filtered under vacuum for period of about 5 minutes to about 10 minutes at temperature of about 25°C. The obtained solid was analyzed by XRPD. Form S4 was obtained. An XRPD pattern is shown in Figure 4.

Example 6: Preparation of Selpercatinib Form SI

[00137] Selpercatinib (Amorphous) (0.05 grams) was taken in a 10 ml test-tube and methanol (lml) was added and the test tube was crimped with silicon septum. The reaction mixture was heated up to temperature of about 60°C and maintained under stirring at temperature of about 60°C for period of about 24 hours After 24 hours, the reaction mass was filtered under vacuum and suck dried for period of about 5 minutes to about 10 minutes at temperature of about 25°C. The obtained solid was analyzed by XRPD. Form SI was obtained.

Example 7: Preparation of Selpercatinib Form SI

[00138] Selpercatinib (Amorphous) (0.05 grams) was taken in a 10 ml test-tube and ethanol (lml) was added at temperature of about 60°C. The reaction mixture was maintained under stirring at temperature of about 60°C for period of about 24 hours. After 24 hours, the reaction mass was filtered under vacuum and suck dried for period of about 5 minutes to about 10 minutes at temperature of about 25°C. The obtained solid was analyzed by XRPD. Form SI was obtained.

Example 8: Preparation of Selpercatinib Form SI

[00139] Selpercatinib (Amorphous) (0.05 grams) was taken in a 10 ml test-tube and acetonitrile (lml) was added at temperature of about 60°C. The reaction mixture was maintained under stirring at 60°C for period of about 24 hours. After 24 hours, the reaction mass was filtered under vacuum and suck dried for period of about 5 minutes to about 10 minutes at temperature of about 25°C. The obtained solid was analyzed by XRPD. Form SI was obtained.

Example 9: Preparation of Selpercatinib Form SI

[00140] Selpercatinib (l.Og) was dissolved in N,N-Dimethylformamide (DMF) (15mL ) at temperature of about 60°C. The solution was filtered to remove any undissolved particles. In another 250mL round bottom flask charged Ethanol (75 mL) and seeds of Form SI (20 mg) were added and hot DMF solution (15ml) was added to it at temperature of about 60°C under stirring. The reaction mixture was maintained under stirring at temperature of about 60°C for 24 hours. After 24 hours, the reaction mass was filtered under vacuum and suck dried for period of about 10-15 minutes at 25°C. The obtained solid was analyzed by XRPD. Form SI was obtained.

Example 10: Preparation of Amorphous Selpercatinib

[00141] Selpercatinib (1.0 gram) was taken in a 600 mL lyophilization flask and dissolved in acetic acid (5ml) at temperature of about 25 °C and then water (95 mL) was added. The clear solution was frozen under liquid nitrogen for period of about 5 minutes to 10 minutes. The frozen solid material was subjected to lyophilization under reduced pressure (200 mTorr) at condenser temperature of about -80°C and isolated solid after about 24 hours. The obtained solid was immediately dissolved in dichloromethane (20-25 mL). The clear solution was subjected to distillation under reduced pressure on Rotary evaporator at temperature of about 60°C for period of about 1 hour. The obtained solid was analyzed by XRPD. Amorphous Selpercatinib was obtained. An XRPD pattern is shown in Figure 6.

Example 11: Preparation of Amorphous Selpercatinib

[00142] Selpercatinib (2.0 grams) was taken in a 600 mL lyophilization flask and dissolved in formic acid (5ml) at 25 °C and then water (45 mL) was added. The clear solution was frozen under liquid nitrogen for period of about 5 minutes to 10 minutes. . The frozen solid material was subjected to lyophilization under reduced pressure (200 mTorr) at condenser temperature of about -80°C and isolated solid after about 12 hours. The obtained solid was immediately dissolved in dichloromethane (60 mL). The clear solution was subjected to distillation under reduced pressure on Rotary evaporator at temperature of about 35°C for period of about 2 hours. The obtained solid was analyzed by XRPD. Amorphous Selpercatinib was obtained.

Claims

Claims:

1. Crystalline Form SI of Selpercatinib characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 7.3, 11.9, 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta; b. an XRPD pattern as depicted in Figure 1; c. a solid state ¹³C NMR spectrum having peaks at 47.7, 80.0, 106.4, 129.9, 134.5 and 152.0 ppm ± 0.2 ppm; d. a solid state ¹³C NMR spectrum having the following chemical shift absolute differences from a reference peak at 163.1 ppm ± 2 ppm of 115.4, 83.1, 56.7,

33.2, 28.6 and 11.1 ppm ± 0.1 ppm; e. a solid-state ¹³C NMR spectrum substantially as depicted in Figures 7a, 7b or 7c; and f. combinations of two or more of: a, b, c, d, and e.

2. Crystalline Form SI of Selpercatinib according to Claim 1, which is characterized by an XRPD pattern having peaks at 7.3, 11.9, 13.1, 17.0 and 21.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, or four additional peaks selected from 16.1, 17.5, 22.4 and 29.9 degrees two theta ± 0.2 degrees two theta.

3. Crystalline Form SI of Selpercatinib according to any of Claims 1, or 2, which is characterized by an XRPD pattern having peaks at: 7.3, 11.9, 13.1, 16.1, 17.0, 17.5, 21.0, 22.4 and 29.9 degrees 2-theta ± 0.2 degrees 2-theta.

4. Crystalline Form SI of Selpercatinib according to any of Claims 1 to 3, which is an anhydrous form.

5. Crystalline Form SI of Selpercatinib according to any of Claims 1 to 4, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of any other crystalline forms of Selpercatinib.

6. Crystalline Form SI of Selpercatinib according to any of Claims 1 to 5, which contains: no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% or about 0% of amorphous Selpercatinib.

7. A pharmaceutical composition comprising crystalline Form SI of Selpercatinib according to any of Claims 1 to 6.

8. Use of crystalline Form SI of Selpercatinib according to any of Claims 1 to 6 for the preparation of a pharmaceutical composition and/or pharmaceutical formulation, preferably wherein the pharmaceutical formulation is oral formulation.

9. A pharmaceutical formulation comprising crystalline Form SI of Selpercatinib according to any of Claims 1 to 6, or a pharmaceutical composition of Claim 7, with at least one pharmaceutically acceptable excipient.

10. A process for preparing a pharmaceutical formulation according to Claim 9, comprising combining crystalline Form SI of Selpercatinib according to any of Claims 1 to 6 or a pharmaceutical composition of Claim 7, with at least one pharmaceutically acceptable excipient.

11. Crystalline Form SI of Selpercatinib, according to any one of Claims 1 to 6, a pharmaceutical composition according to Claim 7, or a pharmaceutical formulation according to Claim 9, for use as a medicament.

12. Crystalline Form SI of Selpercatinib, according to any one of Claims 1 to 6, a pharmaceutical composition according to Claim 7, or a pharmaceutical formulation according to Claim 9, for use in the treatment of: metastatic RET fusion -positive non small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

13. A method of treating metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer, comprising administering a therapeutically effective amount of crystalline Form SI of Selpercatinib according to any one of Claims 1 to 6, a pharmaceutical composition according to Claim 7, or a pharmaceutical formulation according to Claim 9, to a subject in need of the treatment.

14. Crystalline Form SI of Selpercatinib, according to any one of Claims 1 to 6, a pharmaceutical composition according to Claim 7, or a pharmaceutical formulation according to Claim 9, for the manufacture of a medicament for metastatic RET fusion- positive non-small cell lung cancer (NSCLC), advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and advanced or metastatic RET fusion-positive thyroid cancer.

15. Else of crystalline Form SI of Selpercatinib according to any one of Claims 1 to 6, in the preparation of another solid state form of Selpercatinib, or Selpercatinib salt or solid state form thereof.

16. A process for preparing another solid state form of Selpercatinib or Selpercatinib salt or a solid state form thereof comprising preparing crystalline Form SI of Selpercatinib according to any one of Claims 1 to 6, and converting it to another solid state form of Selpercatinib or Selpercatinib salt or a solid state form thereof.