Method for preparing crystalline form A of the RET inhibitor selpercatinib

Abstract

Provided herein is a method for preparing crystalline selpercatinib Form A, which has little or no content of the more thermodynamically stable crystalline selpercatinib Form B. Selpercatinib is useful for the treatment and prevention of diseases treatable with RET kinase inhibitors, including RET-related diseases and disorders.

Description

[Technical Field]

[0001] Background technology Selpercatinib (LOXO-292 or RETEVMO™) is a RET inhibitor approved in the United States for use in treating patients with metastatic RET fusion-positive NSCLC, RET-mutated medullary thyroid cancer, and RET fusion-positive thyroid cancer. Selpercatinib, or 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[1,5-a]pyridine-3-carbonitrile, has the following chemical structure:

[0002] [ka]

[0003] Although several crystalline forms of selpercatinib are known and have been disclosed (see, e.g., U.S. Pat. No. 10,584,124), various crystalline polymorphic forms, when isolated, may contain some amount of one or more other crystalline forms as polymorphic impurities. For example, "Form A" is the crystalline form disclosed in U.S. Pat. No. 10,584,124, and typically contains at least some of the more thermodynamically stable crystalline "Form B." The Form A material disclosed in the 10,584,124 patent contained some Form B material. WO 2021 / 211380 discloses a method for selectively forming selpercatinib Form B. Disclosed herein is a method for selectively forming selpercatinib Form A that contains little, if any, Form B. Summary of the Invention

[0004] Disclosed herein are methods for preparing selpercatinib in its kinetically stable crystalline form, "Form A." In embodiments of these methods, the disclosure relates to converting a solubilized and / or solvated form of selpercatinib to selpercatinib Form A. In other embodiments of these methods, the disclosure relates to converting selpercatinib as a mixture of polymorphic forms to selpercatinib Form A. In yet other embodiments, the methods comprise converting a mixture containing selpercatinib Form B to Form A.

[0005] These crystalline forms can be incorporated into formulations such as tablets, capsules, and suspensions to provide patient benefit. It would also be advantageous to be able to provide selpercatinib in one of its crystalline forms (e.g., kinetically stable Form A) that can be mixed with one or more other crystalline forms and / or provided as a single crystalline form (i.e., as a pure or substantially pure crystalline form).

[0006] As described in more detail below, the compound of Formula I (selpercatinib) may be provided in polymorphic forms (Form A and Form B), and surprisingly, certain processes and methods are effective for providing selpercatinib in its kinetically stable polymorphic Form A. As described below and illustrated by the illustrative working examples, processes and methods for producing and preparing selpercatinib in certain polymorphic forms may involve converting (i.e., reacting, contacting, and / or treating) a compound of Formula I provided in one or more polymorphic forms under crystallization conditions effective to produce or convert other polymorphs (i.e., Form B) or amorphous selpercatinib to Form A. In other embodiments, processes and methods for producing selpercatinib Form A may include a synthetic route (i.e., a direct synthetic route) comprising reacting one or more intermediate or precursor compounds under conditions effective to produce selpercatinib Form A.

[0007] In some embodiments of these aspects, Form A prepared by a method according to the present disclosure may be converted to selpercatinib Form B using one or more of the methods described herein.

[0008] Form B has (a) an x-ray powder diffraction (XRPD) pattern containing a peak at 21.1° and one or more peaks at 7.5, 10.9, 12.0, 17.1, 17.7, and 19.8° ± 0.2° 2θ, when measured using an x-ray wavelength of 1.5418 Å, or (b) peaks referenced to the upfield resonance of adamantane (δ = 29.5 ppm) at 28.0, 48.0, 80.4, 106.8, 130.2, and 134.9 ppm (each ± ​​0.2 ppm). 13 C solid-state NMR spectrum. Typically, these signature spectra are unique to crystalline form B.

[0009] Similarly, Form A can be identified based on (a) XRPD peaks at 4.9, 9.7, and 15.5°, ±0.2° 2θ, which are not observable in Form B, and / or (b) an NMR spectrum containing a peak at 30.9 ppm (referenced to the upfield resonance of adamantane (δ=29.5 ppm)), which is not observable in Form B.

[0010] Disclosed herein are methods for converting selpercatinib to selpercatinib Form A. Preferably, the selpercatinib contains at least about 92% by weight of Form A. More preferably, the selpercatinib contains at least about 94% to about 98% by weight of Form A. The selpercatinib may be amorphous Form B (the more thermodynamically stable polymorph), a selpercatinib solvate, or a mixture of two or more thereof.

[0011] Also provided is a method for converting selpercatinib to selpercatinib Form A, the method comprising: a. dissolving selpercatinib in a solvent comprising DMSO, thereby forming a selpercatinib DMSO solution; b. adding water to the selpercatinib DMSO solution to form a slurry; and c. isolating crystallized selpercatinib Form A from the slurry, wherein Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

[0012] Further provided is a method for converting selpercatinib to selpercatinib Form A, the method comprising: a. dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; b. adding heptane to the solution under conditions effective to form a slurry; c. isolating selpercatinib form A from the slurry, wherein form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

[0013] Surprisingly, it has been discovered that when selpercatinib form A is prepared using the methods described herein, incorrect washing and drying protocols can result in form A containing up to about 20% by weight of form B. Accordingly, disclosed herein are methods for washing and drying selpercatinib form A that minimize or prevent the formation of form B. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is an overlay of XRPD data for Form A and Form B up to about 26 degrees two-theta (2θ). [Figure 2] 1 is a representative HPLC chromatogram used for crystallization development with assignment of impurities of interest. [Figure 3] Includes 13C solid state NMR data for Form A, Form B, and an overlay of Form A compared to Form B at approximately 25-60 ppm. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them unless specified otherwise:

[0016] As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties as a result of molecular ordering within the crystal lattice. Different polymorphs of a single compound (i.e., a compound of Formula I) have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form composed of one polymorph discolors more quickly than one composed of another), or mechanical changes (e.g., crystalline changes upon storage, such that a kinetically desirable polymorph transforms into a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. In addition, the physical properties of the crystals may be important in processing; for example, a polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (i.e., particle size and particle size distribution may differ between one polymorph and another). As used herein, "polymorph" does not include amorphous forms of the compound. In some specific embodiments, the polymorphs of the compound of Formula I (i.e., one or both of selpercatinib Form A and / or selpercatinib Form B) comprise the characteristics described herein.

[0017] As used herein, "amorphous" refers to a form of a compound that lacks crystalline order. For example, "amorphous" refers to a compound (e.g., a solid form of a compound) that does not have a regular repeating arrangement of molecules or external planes, and is typically characterized by the absence of sharp diffraction peaks in its powder x-ray diffraction pattern.

[0018] The term "anhydrous," as used herein, refers to a crystalline form of the compound of Formula (I) that does not contain a stoichiometric amount of water associated with the crystal lattice. Typically, anhydrous Form A and anhydrous Form B have 1% or less water by weight. For example, 0.5% or less, 0.25% or less, or 0.1% or less water by weight.

[0019] The term "solvate" as used herein refers to a crystalline form of a compound of formula (I) in which the crystal lattice contains one or more solvents.

[0020] The term "hydrate" or "hydrate polymorphic form" refers to a crystalline form of a compound of Formula (I), such as a polymorphic form of a compound in which the crystal lattice contains water. Unless otherwise specified, the term "hydrate" as used herein refers to a "stoichiometric hydrate." Stoichiometric hydrates contain water molecules as an integral part of the crystal lattice. In contrast, non-stoichiometric hydrates contain water, but changes in water content do not cause significant changes in the crystal structure. During drying of non-stoichiometric hydrates, a significant proportion of the water can be removed without significantly disrupting the crystalline network, and the crystals can then rehydrate to yield the original non-stoichiometric hydrate crystal form. Unlike stoichiometric hydrates, the dehydration and rehydration of non-stoichiometric hydrates does not involve a phase transition, so all hydration states of non-stoichiometric hydrates represent the same crystalline form.

[0021] "Purity," when used in reference to a composition comprising a polymorph of the compound of Formula (I), refers to the percentage of one particular polymorphic form relative to another polymorphic form or amorphous form of the compound of Formula (I) in the referenced composition. For example, a composition comprising polymorphic Form A having a purity of 90% contains 90 parts by weight of Form A and 10 parts by weight of other polymorphic and / or amorphous forms of the compound of Formula (I).

[0022] As used herein, a compound or composition is "substantially free" of one or more other components if the compound or composition does not contain significant amounts of such other components. For example, a composition may contain less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of other components. Such components may include starting materials, residual solvents, or other impurities that may result from the preparation and / or isolation of the compounds and compositions provided herein. In some embodiments, a polymorphic form provided herein is substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of Formula (I) is "substantially free" of other polymorphs if it constitutes at least about 95% by weight of the compound of Formula (I) in which the particular polymorph exists. In some embodiments, a particular polymorph of a compound of Formula (I) is "substantially free" of other polymorphs if it constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of Formula (I) in which the particular polymorph exists. In certain embodiments, a particular polymorph of the compound of Formula (I) is "substantially free" of water if the amount of water constitutes no more than about 2%, about 1%, or about 0.5% by weight of the polymorph.

[0023] As used herein, "substantially pure," when used in reference to a polymorphic form of the compound of Formula (I), refers to a sample of the polymorphic form of the compound having a purity greater than 90%, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% of the compound, and even equal to about 100%, based on the weight of the compound. The remaining material contains other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a polymorphic form of the compound of Formula (I) may be considered substantially pure in that the purity of the polymorphic form of the compound of Formula (I) is greater than 90%, and the remaining less than 10% of the material contains other forms of the compound of Formula (I) and / or reaction and / or processing impurities, as measured by means currently known and generally accepted in the art. The presence of reaction and / or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, or infrared spectroscopy.

[0024] For ease of description, some of the quantitative expressions herein are recited as ranges from about X to about Y. When a range is recited, it is understood that the range is not limited to the recited upper and lower limits, but rather includes the entire range from about X to about Y, or any range therein.

[0025] "Room temperature" or "RT" refers to the ambient temperature in a typical laboratory, which is typically about 20-25°C.

[0026] As used herein, the term "excipient" refers to any substance necessary to formulate a composition into a desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating or adhesive agents, disintegrants, lubricants, anti-adherents, glidants, dispersing or wetting agents, dissolution retarders or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners.

[0027] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients may also be incorporated into the formulation. In addition, various excipients commonly used in the art may be included. These and other such compounds are described in the literature, for example, in The Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.), 2010, Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0028] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0029] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About includes the exact amount. Thus, "about 5 grams" also means "about 5 grams" and "5 grams." Ranges expressed herein are understood to include integers and fractions thereof within the range. For example, the range of 5 to 20 grams includes integer values ​​such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams, as well as fractions within the range, including, but not limited to, 5.25, 6.5, 8.75, and 11.95 grams. The term "about" preceding values ​​for DSC, TGA, or TG are reported as degrees Celsius and have an allowable variation of + / - 5°C.

[0030] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs as well as examples when it does not occur. For example, a reaction mixture "optionally containing a catalyst" means that the reaction mixture either contains a catalyst or does not contain a catalyst.

[0031] As used herein, the term "diluent" when used in reference to an acidic solution refers to a solution having an acid concentration of less than about 0.1N.

[0032] The terms "hydrogen" and "H" are used interchangeably herein.

[0033] A salt can be formed from a compound in any manner familiar to one of ordinary skill in the art, and thus the statement "forming a compound or a salt thereof" includes embodiments in which a compound is formed and the salt is subsequently formed from the compound in a manner familiar to one of ordinary skill in the art.

[0034] As used herein, the patient is a patient in which a RET fusion or RET mutation has been determined. Thus, the term "determining a RET fusion or RET mutation" means determining whether a RET fusion or RET mutation exists. Methods for determining whether a RET fusion or RET mutation exists are known to those skilled in the art, see, for example, Wang, Yucong et al., Medicine 2019;98(3):e14120. In an embodiment, the term "patient" refers to a human.

[0035] A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for delivery of a biologically active agent to a mammal, eg, a human.

[0036] The terms "treatment," "treat," "treating," and the like are meant to include slowing, halting, or reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated, and even if the progression of the disorder or condition itself is not slowed, halted, or reversed.

[0037] "Effective amount" refers to the amount of a crystalline form of selpercatinib that elicits a biological or medical response or desired therapeutic effect in a patient according to the treating clinician. In one example, a crystalline form of selpercatinib inhibits native RET signaling in an in vitro or ex vivo RET enzyme assay. In another example, a crystalline form of selpercatinib inhibits native RET signaling in whole mouse blood from animals treated with different doses of the compound.

[0038] The effective amount can be readily determined by the attending diagnostician, such as one skilled in the art, by using known techniques and by observing results obtained under similar circumstances. In determining the effective amount for a patient, the attending physician will consider several factors, including, but not limited to, the patient's species; its size, age, and general health; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosage regimen; the use of concomitant medications; and other relevant circumstances.

[0039] Selpercatinib, either Form B or Form A, or a mixture thereof, is preferably formulated as a pharmaceutical composition to be administered by any route that makes the compound bioavailable, including oral, intravenous, and transdermal routes. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for their preparation are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (DB Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).)

[0040] As used herein, "granular composition" refers to a composition in granular form, which is a precursor to a pharmaceutical composition in a pharmaceutical manufacturing process.

[0041] As used herein, "manufacturing vessel" refers to a vessel used in the manufacture of pharmaceutical products, but not in a medicinal chemistry laboratory. Examples of manufacturing vessels include, but are not limited to, hopper collectors, beds, dryer beds, granulator beds, dryer trays, granulator buckets, and mixing bowls.

[0042] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0043] All combinations of embodiments with respect to aspects described herein, to the extent that such combinations encompass aspects that are possible, are specifically encompassed by the present disclosure as if each and every combination were individually expressly recited. In addition, all subcombinations of embodiments within aspects described herein, and all subcombinations of embodiments within all other aspects described herein, are also specifically encompassed by the present disclosure as if each and every subcombination of all embodiments were expressly recited herein.

[0044] Methods for Providing Crystalline Forms of Selpercatinib Some non-limiting methods of the present disclosure are described below. In some embodiments, the present disclosure provides methods and processes effective in converting Form A to Form B. Still other embodiments of the present disclosure provide methods and processes effective for preparing Form A and / or converting other forms of selpercatinib (e.g., Form B) to Form A.

[0045] Form A has unique XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ, while Form B has unique XRPD peaks at about 7.5, 10.9, and 12.0 degrees 2θ. The 2θ values ​​and / or peak intensities of other peaks also differ between the two forms, as can be seen in Table 1 below. For clarity, all XRPD peaks disclosed herein are ±0.2 degrees 2θ unless expressly specified otherwise.

[0046] [Table 1]

[0047] XRPD data were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKα source (λ = 1.54180 Å) and a Vantec detector, operating at 35 kV and 50 mA. Samples were scanned from 4 to 40° 2θ using a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detection slit, at a step size of 0.008° 2θ and a scan rate of 0.5 s / step. Dry powder was loaded into a quartz sample holder, and a smooth surface was obtained using a glass slide. Crystalline morphology diffraction patterns were collected at ambient temperature and relative humidity. Crystalline peak positions were determined with MDI-Jade after global pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774° 2θ. It is well known in the field of crystallography that for any given crystalline form, the relative intensities of diffraction peaks can vary due to preferred orientation resulting from factors such as crystalline form and crystal habit. When the effect of preferred orientation is present, peak intensities change, but the characteristic peak positions of a polymorph remain unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. It is also well known in the field of crystallography that for any given crystalline form, angular peak positions can vary slightly. For example, peak positions may shift due to variations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variation of ±0.2 2θ° is estimated to account for these potential variations without precluding unambiguous identification of the indicated crystalline form. Confirmation of a crystalline form can be based on any unique combination of characteristic peaks.

[0048] DSC-TGA analysis of anhydrous crystalline Form A showed an onset of melting at about 207°C and two endotherms, the first corresponding to the melting of Form A, followed by the exothermic recrystallization of Form B, and then the melting of Form B. DSC-TGA analysis of anhydrous crystalline Form B showed a single endotherm with an onset of melting at about 213°C.

[0049] Forms A and B are anhydrous polymorphs, however, Form A is slightly more hygroscopic than Form B and, as discussed herein, is thermodynamically less stable than Form B. Further, as discussed herein, some embodiments provide selpercatinib in the form of a solvate that can be isolated. In some embodiments, removal of solvent molecules from a solvated form of selpercatinib can provide selpercatinib Form A.

[0050] Forms A and B have similar solubilities. Both have low solubility at 25°C in many organic solvents, including methyl ethyl ketone (MEK), acetone, and many alcoholic solvents, while they have moderate solubility (3-30 mg / ml) in dichloromethane (DCM), dimethylsulfoxide (DMSO), and THF. Form B is practically insoluble in anisole.

[0051] Form A and Form B 13 The C solid-state NMR spectra are shown in Figure 3. Figure 3 also includes an overlay of portions of the spectra, showing that Form A has a peak at 30.9 ppm that is not observable in Form B, and Form B has a peak at approximately 48.0 ppm that is not observable in Form A. Both spectra were referenced to the upfield resonance of adamantane (δ=29.5 ppm).

[0052] A Bruker Avance III HD 400 MHz wide-bore NMR spectrometer, operating at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz and equipped with a Bruker 4 mm double resonance probe, was used to measure the NMR spectra of the NMR spectra referenced above. 13C cross-polarization / magic-angle spinning NMR (solid-state NMR or ssNMR) spectra were obtained. TOSS sideband suppression was used with SPINAL64 decoupling and cross-polarization using RAMP100 H-nucleus CP pulses. Acquisition parameters were as follows: 4.0 μs proton pulse, 1.5 ms contact time, 5 kHz MAS frequency, 30.2 kHz spectral width, and 34 ms acquisition time. A 3 s recycle delay was used, with 2655 scans. Chemical shifts were referenced to adamantane (δ=29.5 ppm) in a separate experiment. Representative values ​​for Form B were obtained. 13 C ssNMR resonances include peaks at about 26.44, 27.37, 28.00, 41.98, 43.43, 43.91, 48.04, 53.92, 56.31, 58.32, 69.48, 77.90, 80.38, 102.32, 106.77, 113.58, 115.24, 118.23, 120.76, 125.23, 130.23, 134.86, 136.93, 140.59, 148.42, 149.50, 151.20, 152.45, 158.22, and 163.52 ppm. As shown, Form A has a peak at about 30.9 ppm that is not observable in Form B.

[0053] The above data establish that Forms B and A 1) have several distinct properties, 2) can be readily identified and distinguished from one another based on such properties, 3) Form A can be prepared by the methods described herein, and, as discussed in the aspects and embodiments below, 5) Form A can be prepared from and / or converted from other forms of selpercatinib, including solvates and / or Form B.

[0054] Given the similar solubility between selpercatinib Form A and Form B, several suitable solvents may be used in accordance with aspects and embodiments of the present disclosure. In some embodiments, solvents and / or process conditions may be used and adjusted such that the resulting crystalline form may be predominantly Form A (e.g., pure or substantially pure Form A).

[0055] As noted above, selpercatinib may form solvates and metastable solid forms, both of which are generally not stable upon drying. Observed solvates include acetone solvates, chloroform solvates, 1,4-dioxane solvates, methyl ethyl ketone (MEK) solvates, dichloromethane (DCM) solvates, 2-butanol solvates, 1-butanol solvates, ethanol solvates, dimethyl sulfoxide (DMSO)-water solvates, DMSO solvates, isopropyl alcohol (IPA) solvates, and tetrahydrofuran (THF) solvates. Solvates and metastable forms typically revert to Form A upon isolation and / or drying, although films or amorphous material may form. The chloroform and 1,4-dioxane solvates were stable upon isolation / drying. Therefore, one strategy for preparing selpercatinib Form A is to convert amorphous selpercatinib and / or selpercatinib Form B into a solvate and then desolvate the solvate to obtain Form A.

[0056] In embodiments of the methods described herein for preparing Form A, the selpercatinib may include an amount of Form B and / or an amount of Form A.

[0057] In one aspect, described herein is selpercatinib Form A. This crystalline form of selpercatinib can be used to treat disorders associated with aberrant RET activity, such as IBS or cancer, particularly cancers resulting from excessive RET signaling (i.e., RET-associated cancers). More specifically, this crystalline form of selpercatinib may be used to treat RET-associated cancers such as lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiolopulmonary carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, breast tumor, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer.

[0058] Form A can be used in a method for treating cancer, comprising administering an effective amount of Form A to a patient in need thereof. Cancer types that can be treated using the methods described herein include hematological cancers or solid tumor cancers. Examples of cancer types that can be treated using Form B include lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. Specifically, the cancer type can be lung cancer or thyroid cancer. More specifically, the cancer can be non-small cell lung cancer or medullary thyroid cancer.

[0059] Form A for use in therapy is also described herein.

[0060] Form A can be used in the manufacture of a medicament for the treatment of a RET-related disease or disorder, such as IBS or cancer. Cancers that can be treated using such a medicament are described herein above. The use of Form A in the manufacture of a medicament can also include performing an in vitro assay using a biological sample from a patient to determine the presence of dysregulated expression, activity, or levels of the RET gene, RET kinase, or any of them, and administering a therapeutically effective amount of Form A to the patient if dysregulated expression, activity, or levels of the RET gene, RET kinase, or any of them is present. In these applications, the biological sample can be a tumor sample, and the tumor sample can be analyzed using methods known to those skilled in the art, such as genomic / DNA sequencing. Additionally, in these applications, a sample can be obtained from the patient before the first administration of Form A. In these applications of Form A, as described herein, therapy can be based on the patient being selected for treatment due to having at least one of dysregulated expression, activity, or levels of the RET gene, RET kinase, or any of them. Also, in these uses, Form A may be administered to the patient at a dosage of about 1 mg / kg to 200 mg / kg (subranges of effective dosages are provided herein above).

[0061] Selpercatinib Form A—Compositions, Compounds, and Processes As described herein, selpercatinib Form A may contain a certain amount of a thermodynamically stable polymorph, selpercatinib Form B. While both polymorphic forms are crystalline, high-melting, anhydrous, stable, and do not readily interconvert under typical storage or preparation conditions, these polymorphs have different properties and characteristics that allow them to distinguish Form A from Form B. Given the favorable differences in thermodynamic stability between selpercatinib Forms A and B, it is necessary to understand how either form can be converted to or produced from the other (e.g., from Form B to Form A, as described below).

[0062] Crystallization Methods Providing Form A In one aspect, the present disclosure provides methods for preparing selpercatinib Form A, including methods for converting amorphous selpercatinib and / or other polymorphic forms of selpercatinib, including from a mixture of forms (e.g., including selpercatinib Form B) to selpercatinib Form A. While selpercatinib Form A can be prepared or converted from other selpercatinib forms using a variety of different methods, disclosed herein are crystallization-based methods for preparing or converting other crystalline forms of selpercatinib (e.g., including selpercatinib Form B) to selpercatinib Form A.

[0063] Suitable methods for preparing Form A include, but are not limited to, cooling crystallization, evaporative crystallization, vapor diffusion, crystallization using one or more antisolvents (including forward antisolvent or reverse antisolvent addition, simultaneous addition, or sequential crystallization), and slurry crystallization. Suitable methods also include using washing and drying methods to help minimize or prevent the formation of Form B material. These methods are discussed herein.

[0064] In one aspect, disclosed herein is a method for converting a mixture of selpercatinib containing Form B to selpercatinib Form A.

[0065] In one aspect, disclosed herein is a method for converting amorphous selpercatinib to selpercatinib Form A.

[0066] In another aspect, disclosed herein is a method for converting another form or mixture of other forms of selpercatinib (e.g., including Form B) to selpercatinib Form A, the method comprising combining selpercatinib including Form B with DMSO and water to form a slurry, and isolating selpercatinib Form A from the slurry.

[0067] In yet another embodiment, there is provided a method for converting selpercatinib (e.g., Form B) to selpercatinib Form A, the method comprising: a. dissolving selpercatinib in a solvent comprising DMSO to form a solution; b. adding water to the solution, thereby forming a slurry containing selpercatinib A; c. isolating selpercatinib form A.

[0068] In one embodiment, about 1 gram of selpercatinib is dissolved in about 10-15 mL of DMSO. In another embodiment, forming the solution in step a comprises heating a solvent comprising selpercatinib and DMSO to about 50°C to about 70°C. In one embodiment, after heating the solution to about 50°C to about 70°C, the solution is cooled to a temperature below about 70°C and above about 20°C. In one embodiment, the solution is cooled to about 40°C. In another embodiment, step b comprises adding about 0.1 to about 1 mL / g of water to the solution, or step b comprises adding about 0.2 mL / g or less of water to the solution. In some embodiments, step b further comprises adding about 1 to about 15 wt% Form A seed crystals or about 1 wt% Form A seed crystals. In one embodiment, the slurry is cooled to about 0°C. In one embodiment, adding water to form the slurry in step b comprises adding two separate volumes of water to achieve a total DMSO:water ratio of 80:20 or less. In one embodiment, step c comprises filtration. The selpercatinib form A isolated from step c is washed with a solvent comprising MTBE and / or water.

[0069] In yet another embodiment, there is provided a method for converting selpercatinib (e.g., Form B) to selpercatinib Form A, the method comprising: a. dissolving selpercatinib in a solvent comprising DMSO to form a solution; b. adding the selpercatinib / DMSO solution to a water or DMSO / water solution, thereby forming a slurry containing selpercatinib Form A; c. isolating selpercatinib form A.

[0070] In one embodiment, about 1 gram of selpercatinib is dissolved in about 10 to 15 mL of DMSO. In another embodiment, forming the solution of step a comprises heating a solvent comprising selpercatinib and DMSO to about 50°C to about 70°C. In one embodiment, after heating the solution to about 50°C to about 70°C, the solution is cooled to a temperature below about 70°C and above about 20°C. In one embodiment, the solution is cooled to about 40°C. In another embodiment, step b comprises adding the solution of step a to at least 1 volume of water or DMSO / water. In some embodiments, step b further comprises adding about 1 to about 15 wt% Form A seed crystals or about 1 wt% Form A seed crystals. In one embodiment, the slurry is cooled to about 0°C. In one embodiment, at the end of step b, the ratio of DMSO:water is about 80:20. In one embodiment, step c comprises filtration. The selpercatinib form A isolated from step c is washed with a solvent comprising MTBE and / or water.

[0071] In another embodiment, there is provided a method for converting selpercatinib (e.g., Form B) to selpercatinib Form A, the method comprising: a. Dissolving selpercatinib in a solvent comprising DMSO to form a solution (Supply 1); b. Preparing a water or DMSO / water solution (Supply 2); c. adding the selpercatinib / DMSO solution (Feed 1) simultaneously with Feed 2 to the water or DMSO / water solution, thereby forming a slurry containing selpercatinib Form A; d. isolating selpercatinib form A.

[0072] In another aspect, disclosed herein is a method for converting selpercatinib (e.g., selpercatinib including Form B) to Form A, the method comprising combining selpercatinib and dichloromethane to form a solution, adding heptane to the solution under conditions to form a slurry, optionally stirring the slurry under conditions effective to form selpercatinib Form A, and isolating selpercatinib Form A. In one embodiment, about 1 gram of selpercatinib is dissolved in about 25 to 35 mL of dichloromethane. In one embodiment, forming the solution of step a comprises heating a solvent comprising selpercatinib and dichloromethane to about 30° C. to about 40° C. In a further embodiment, step b comprises adding a first batch of heptane and a second batch of heptane. In some embodiments, adding heptane comprises adding a first volume of heptane in an amount of about 8-12 mL / g of selpercatinib and a second volume of heptane in an amount of about 8-12 mL / g. In one embodiment, the solution of step b is cooled to a temperature below about 30° C. and above about 20° C., more preferably, the solution is cooled to a temperature of about 25° C. Step b may comprise stirring for at least about 8 hours.

[0073] A variety of different solvents can be used to prepare Form A and / or convert a different form of selpercatinib (e.g., Form B) to Form A. In some forms and embodiments, a solvent may be combined with selpercatinib to form a solvate. Solvents that can be used to prepare Form A and / or convert other selpercatinib forms (e.g., Form B) to Form A include, but are not limited to, C1-C6 alcohols (e.g., methanol or ethanol), water, acetonitrile (ACN), methyl tert-butyl ether (MTBE), dichloromethane (DCM), heptane, n-butyl acetate (n-BuOAC), 81% ACN-MeOH (81 mL of ACN combined with 19 mL of MeOH), wet ethyl acetate, cyclopentyl methyl ether (CPME), 1,2-dimethoxyethane, ethyl acetate, ethyl formate, methyl isobutyl ketone (MIBK), nitromethane, n-propyl acetate (NPA), 1-pentanol, toluene, 1:1 MeOH:water, 1:1 Examples include EtOH:water, ACN:water, DCM / heptane mixtures, DMSO / heptane mixtures, or DMSO / water mixtures. Using C1-C6 alcohols such as methanol and / or ethanol will convert Form B to Form A, but can also result in the formation of Form B. As detailed below, washing Form A with a C1-C6 alcohol can result in the formation of Form B. When washing Form A with a C1-C6 alcohol, it is preferred to use cold C1-C6.

[0074] It has been surprisingly and unexpectedly discovered that Form B material can form during washing and drying of Form A material. The following washing and drying protocol has been developed to reduce, if not prevent, the formation of Form B material. After the solvate is formed, a solvent such as heptane or MTBE is used to wash the solvate, and the resulting cake is then dried at about 40 to about 60°C. In one embodiment, the cake is dried under high vacuum. Drying under high vacuum allows for the use of lower drying temperatures. For example, when drying a cake of Form A under high vacuum, a temperature of about 40 to 45°C may be used. Heptane and MTBE may be used individually or sequentially. Excessive temperature and / or excessive drying time may allow the conversion of Form A, a kinetic product, to Form B, a thermodynamic product.

[0075] The inventors have discovered that drying Form A wet cake at 45°C and ambient pressure for several days results in slow conversion of Form A to Form B. Drying under high vacuum and / or using MTBE as a final wash shortens the drying time and reduces, if not prevents, the formation of Form B material. In a preferred embodiment, Form A material is washed with MTBE or heptane and then dried under high vacuum at a temperature of about 40 to about 45°C.

[0076] Additionally, the inventors have discovered that washing the Form A cake with water, MeOH, and finally MTBE, and then drying the resulting cake under high vacuum, can yield up to about 20% by weight of Form B material. Without wishing to be bound by theory, it is believed that washing with MeOH accelerates the formation of Form B material.

[0077] In some embodiments, methods and processes for preparing Form A may include solvents including, but not limited to, C1-C4 alcohols, water, DCM, DMSO, MTBE, ACN, and mixtures of two or more thereof. In still other embodiments of such methods, the solvent includes methanol, ethanol, water, DMSO, MTBE, ACN, or mixtures of two or more thereof. In yet further embodiments of such methods, the solvent includes DCM, heptane, DMSO, water, MTBE, or mixtures of two or more thereof.

[0078] In various embodiments, the method includes combining selpercatinib (e.g., selpercatinib containing a quantity of Form B) with a solvent and, optionally, heating the resulting mixture while stirring or mixing until the selpercatinib containing Form B is dissolved in the solvent. Once a solution is formed, the mixture may be filtered if any insoluble impurities are to be removed, or may be cooled, for example, to a temperature slightly above room temperature or to room temperature (e.g., about 25-40°C, depending on the solvent used). Additional solvent may be added during or after cooling.

[0079] In some embodiments of these aspects, the solvent comprises DMSO, and water is added to the solution during or after the cooling step. Once a certain amount of water has been added to the cooled solution, seed crystals comprising selpercatinib may be added in dry form or as a slurry in a minimal volume of liquid and incubated for a period of time. After the incubation period (e.g., about 40°C), additional water is slowly added. After the water addition, the mixture is gradually cooled to a target temperature of about 0°C. Once the target temperature is reached, the slurry or mixture is incubated for a period of time to promote the formation of additional solid product. After the incubation period, the resulting selpercatinib Form A material is isolated and, optionally, washed to remove residual water and DNSM content. Examples of washing solvents include, but are not limited to, heptane and MTBE. After washing, the Form A material may be dried at a temperature of about 40 to about 60°C at a pressure up to and including atmospheric pressure and below atmospheric pressure. In a preferred embodiment, the pressure is below atmospheric pressure.

[0080] In some alternative aspects of these aspects, the solvent comprises a solvent that forms a solvate of selpercatinib Form A. In some embodiments, the solvent comprises dichloromethane, and heptane is added to the solution, and once the heptane is added, the mixture is cooled (e.g., to about room temperature / 25°C). After the initial cooling, additional heptane is added, and the resulting mixture is stirred at room temperature / 25°C for a period of time (e.g., at least 8 hours). After stirring, the resulting selpercatinib Form A material is isolated and, optionally, washed to remove residual dichloromethane.

[0081] solvent A variety of different solvents may be used in the processes provided by these aspects and embodiments of the present disclosure. The solvent, or solvent system, may solubilize selpercatinib and / or form a solvated form of selpercatinib to obtain the desired Form A. Examples of suitable solvents include, but are not limited to, DMSO, C1-C6 alcohols, ACN, MTBE, dichloromethane, water, or combinations of two or more thereof. Non-limiting examples of C1-C6 alcohols include methanol, ethanol, propanol, and isopropanol. In some embodiments, DMSO is the solvent. In some embodiments, the solvent comprises an amount of DMSO and water, for example, about 2% or about 4% to about 20% (by volume) of water.

[0082] The amount of solvent used depends on the solvent used. Typically, 1 g of selpercatinib (e.g., containing a certain amount of Form B) is dissolved in about 8 to 20 mL, about 10 to 15 mL, about 11 to 14 mL, or about 12 to 13 mL of the solvent used (e.g., about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 volumes of solvent based on the weight of selpercatinib). In some embodiments, 1 gram of selpercatinib may be dissolved in 8 to 15 mL / g of DMSO, 1 gram of selpercatinib may be dissolved in about 11 to 13 mL / g of DMSO, or 1 gram of selpercatinib may be dissolved in about 10 to 15 mL / g of DMSO.

[0083] temperature Temperature can affect the rate at which initial selpercatinib (including, for example, Form B) is converted to Form A. In some embodiments, a mixture containing selpercatinib and a solvent is heated in an initial step to a temperature of at least about 70°C and up to the boiling point of the solvent. In some embodiments, the mixture is heated to a temperature of about 50-110°C, or about 50°C to about 70°C. In some embodiments, the mixture may be heated to about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, or about 110°C. After the mixture is heated to the desired temperature to dissolve the starting selpercatinib (including Form B) material, the temperature of the solution is reduced to about 15-40°C (e.g., before the addition of the first portion of water, discussed below). The temperature may be reduced by about 15°C, about 20°C, about 25°C, about 30°C, or about 35°C. In one embodiment, the solution is cooled to a temperature below about 70° C. and above about 20° C., and in some embodiments, to less than 50° C. (e.g., about 45° C., 44° C., 43° C., 42° C., 41° C., 40° C., 39° C., 38° C., or about 37° C.). In some embodiments, cooling is carried out at a rate of about 5° C. / h, 10° C. / h, 15° C. / h, 20° C. / h, 25° C. / h, or about 30° C. / h over a set period of time (i.e., controlled cooling).

[0084] In some embodiments, the solvent comprises DMSO and the selpercatinib / DMSO mixture is heated to about 60° C. to about 70° C. In further embodiments, the DMSO is then cooled to about 35° C. to about 45° C., or to about 40° C.

[0085] In some alternative embodiments, the solvent need not be heated to the high temperatures indicated above; i.e., selpercatinib is mixed with a solvent (e.g., dichloromethane) and stirred at a temperature slightly above ambient temperature (e.g., about 35°C, about 40-50°C) but effective to solubilize selpercatinib. In some embodiments, the temperature is selected so that a kinetically stable form of selpercatinib (Form A) is desired and reduces the likelihood of kinetic turnover. In such embodiments, the temperature may be selected toward the lower end of the temperature range identified above (e.g., about 40°C).

[0086] Antisolvent for the first part In some embodiments, the method includes the addition of an anti-solvent, such as water. In such embodiments, the addition of the anti-solvent (e.g., heptane or water, depending on the initial solvent used) may include multiple additions (e.g., added in portions) of separate volumes of anti-solvent. In embodiments including the addition of water, when the first portion of water is added to the solution, about 0.1 to 1.0 mL / g, or about 0.2 to 0.6 mL / g, or about 0.3 mL / g, or about 0.4 mL / g, or about 0.5 mL / g, or about 0.6 mL / g of water is added to Form A (mL of water per g of selpercatinib (e.g., Form B)). Stated another way, the first addition of water may include about 0.1 to about 1.0 volumes of water (i.e., relative to the weight of selpercatinib). In some embodiments, the first portion of water is added in an amount of about 0.3 mL / g, about 0.4 mL / g, about 0.5 mL / g, or about 0.6 mL / g.

[0087] The first portion of water is added over a period of about 30 seconds to about 15 minutes, or about 1 to 10 minutes, or 4 to 6 minutes, or about 5 minutes. Longer periods may be utilized if desired. The addition of the first portion of water is carried out under conditions effective to avoid any self-seeding of the solution, typically resulting in a final solvent to water ratio of about 93:7 to about 99:1 (e.g., 99:1, 98:2, 97:3, 96:4, 95:5, 94:6, or 93:7).

[0088] In other embodiments involving an anti-solvent other than water (e.g., heptane), the first portion added is typically in a larger volume, typically about 30-60% of the total volume of the initial solvent used to form the selpercatinib solution.

[0089] seed crystal Form A seed crystals may be added to the mixture when the target temperature is equilibrated in the solution, typically in an amount of about 0.1 to 15% by weight, or about 1 to about 10% by weight, or about 1 to about 5% by weight, or about 1%, 2%, 3%, or about 4% by weight relative to the initial amount of selpercatinib. In some embodiments, about 0.1%, 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5% by weight of seed crystals are added.

[0090] In some embodiments, the seeding temperature is selected to favor a kinetically stable form of selpercatinib (Form A) and reduce the likelihood of kinetic turnover. In such embodiments, the temperature may be selected toward the lower end of the above-specified temperature range (e.g., about 40°C).

[0091] Seed crystals can be prepared using methods known in the art, such as those described in A. Cote, E. Sirota, A. Moment, "The Pursuit of a Robust Approach for Growing Crystals Directly to Target Size," American Pharmaceutical Review - The Review of American Pharmaceutical Business & Technology, 2010, and DJ Lamberto et al., "Crystallization Process Development for the Final Step of the Biocatalytic Synthesis of Islatravir: Comprehensive Crystal Engineering for a Low-Dose Drug," Organic Process Research & Development 2021 25(2), 308-317. For example, seed crystals can be prepared, obtained, and / or isolated from a source of purified material, including, for example, optically or polymorphically pure material, including, for example, pure selpercatinib form A. In some embodiments, seed crystals can be obtained or provided from a previous source of seed crystals. In yet some other embodiments, seed crystals can be processed, for example, to provide homogeneous seed crystal material (e.g., to obtain a desired D 50 , D 90 In some embodiments, the seed crystals are jet milled to a crystal size of about 1 um to about 10 um (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 um). 90 may also include:

[0092] Seed crystal incubation time After initial heating and cooling of the mixture containing starting selpercatinib (e.g., Form A) and addition of seed crystals, if present, the solution is incubated for about 30 to 300 minutes, or about 30 to 180 minutes, or about 30 to 120 minutes, or about 30 to 60 minutes. In some embodiments, the mixture is incubated for about 30 minutes or less.

[0093] Antisolvent for the second part In some embodiments, after an incubation period of about 30 minutes or more, the mixture is heated to a target incubation temperature of about 35° C. to about 50° C., or about 35° C. to about 45° C., or about 40° C. Once equilibrated to the target incubation temperature, the second portion of water is slowly added. The amount of water in the second portion is about 0.1-3 mL / g, or about 1.0-2.5 mL / g, or about 1.1 mL / g, about 1.2 mL / g, 1.3 mL / g, about 1.4 mL / g, 1.5 mL / g, about 1.6 mL / g, 1.7 mL / g, about 1.8 mL / g, 1.9 mL / g, about 2.0 mL / g, about 2.1 mL / g, about 2.2 mL / g, 2.3 mL / g, about 2.4 mL / g, 2.5 mL / g, about 2.6 mL / g, 2.7 mL / g, about 2.8 mL / g, 2.9 mL / g, or about 3.0 mL / g of water relative to the amount of initial selpercatinib material added (mL of water per g of selpercatinib (e.g., Form B)). Alternatively stated, the second addition of water may comprise about 0.1 to about 3.0 volumes of water (i.e., relative to the weight of selpercatinib). In some embodiments, the first portion of water is added in an amount of about 2.0 mL / g, 2.1 mL / g, 2.2 mL / g, 2.3 mL / g, 2.4 mL / g, 2.5 mL / g, or about 2.6 mL / g. In some embodiments, the second portion of water is added in 2.5 volumes. The resulting amount of water in the resulting solution after the addition of the second portion of water is complete is about 80:20 (solvent:water, by volume).

[0094] The second portion of water is added at a slow rate over a period of time, typically about 10 minutes to about 5 hours, or about 4 hours, about 3 hours, about 2 hours, about 30-90 minutes, about 45-60 minutes, or about 60 minutes. Longer periods may be used if desired. As indicated above, the addition of the second portion of water is typically effective to provide a final solvent to water ratio (by volume) of about 90:10 to about 75:25 (e.g., 90:10, 85:15, 80:20, 75:25).

[0095] In some other embodiments, the method does not include the addition of seed crystals, and the addition of an anti-solvent is effective to form product selpercatinib form A. In some of these other embodiments, after the addition of the first portion of the anti-solvent, the mixture may be cooled to a target temperature (e.g., to ambient temperature), and once the target temperature is reached, a second portion of the anti-solvent is added in an amount effective to form selpercatinib form A (e.g., in a volume approximately equal to the first portion of the anti-solvent). In such embodiments, after the addition of the second portion of the anti-solvent, the mixture may be incubated with stirring for a period of time to provide crystallized selpercatinib form A.

[0096] cooling In some embodiments, after adding the second portion of water, the mixture is cooled to a temperature of about 0° C. over a period of time to form a slurry. In some embodiments, the mixture is cooled to 0° C. and maintained at that target temperature for at least about 60 minutes (e.g., about 60, 70, 80, 90, 100, 110, or about 120 minutes).

[0097] After adding the second portion of water, the mixture is cooled at a rate of about 1-30°C / hour (e.g., about 10-30°C / hour, e.g., or about 20°C / hour) until the desired temperature is reached. In one embodiment, the cooling rate is about 10°C / hour, about 11°C / hour, about 12°C / hour, about 13°C / hour, about 14°C / hour, about 15°C / hour, about 16°C / hour, about 17°C / hour, about 18°C / hour, about 19°C / hour, or about 20°C / hour.

[0098] Isolating Form A Form A material may be isolated using any method known in the art. In one embodiment, separation involves gravity filtration. In another embodiment, separation involves high vacuum filtration. In yet another embodiment, separation involves the use of centrifugation.

[0099] Fresh solvent, such as ethanol, methanol, ACN, MTBE, water, or a combination of two or more thereof, may be used to wash the Form A material. As previously mentioned, when ethanol and / or methanol are used to wash the Form A material, they should be at low temperatures, e.g., about 0°C. In some embodiments, DMSO, methanol, ACN, MTBE, water, or a combination of two or more thereof, is used to wash the Form A material. In still further embodiments, a solvent comprising DMSO / water (80:20 DMSO:water) is used. In some further embodiments, MTBE may be used to wash any residual solvent (e.g., DMSO / water) to obtain the final Form A material. In these embodiments, the fresh solvent may be cooled to a temperature of about 0°C to less than about 20°C before using it to wash the Form A material. In these embodiments, the final wash solvent may be a volatile solvent (e.g., MTBE), which helps reduce solvent retention in the cake after filtration and shorten the required drying time. The use of a volatile solvent also allows for the use of lower temperatures, which helps reduce, if not prevent, the formation of Form B material. Excessive drying time and / or temperature may cause Form B to form.

[0100] The isolated selpercatinib Form A may be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and / or using subatmospheric pressure. In one embodiment, drying under subatmospheric pressure is preferred.

[0101] In embodiments where the solvent comprises DMSO and / or DMSO / water, the isolated selpercatinib form A may be washed with MTBE until the isolated selpercatinib form A contains less than 0.5% by weight of DMSO (or DMSO / water).

[0102] The selpercatinib starting material used in accordance with any of the aspects and embodiments described herein can be purchased from commercial sources, prepared by known synthetic methods, and / or converted from a source of selpercatinib (i.e., amorphous selpercatinib, selpercatinib API, or another polymorphic form of selpercatinib, e.g., one of Form A, Form B, or a mixture thereof).

[0103] In embodiments relating to Form A, selpercatinib provided by the present disclosure may exhibit greater kinetic stability compared to other polymorphic and / or amorphous forms of selpercatinib (e.g., Form B).

[0104] In any of the aspects and embodiments provided herein, the selpercatinib provided by the present disclosure may be prepared as a free amine. When the methods described herein are used to prepare a particular crystalline form of selpercatinib (e.g., selpercatinib Form A), whether such a form is obtained by a direct synthesis method or conversion from selpercatinib according to aspects and embodiments of the present disclosure (i.e., amorphous selpercatinib or another polymorphic form of selpercatinib), it may further be provided as a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Thus, depending on the particular form, such compounds, salts, and compositions may include crystalline selpercatinib that may exhibit greater thermodynamic stability than other polymorphic and / or amorphous forms of selpercatinib, or may exhibit greater kinetic stability than other polymorphic and / or amorphous forms of selpercatinib. Selpercatinib in either Form A or Form B retains its activity as a RET inhibitor, and activity can be evaluated and assessed by any assay known in the art, including, for example, the assays described in PCT Publication No. WO 2018 / 071447 and U.S. Patent Application Publication No. 2018 / 0134702, each of which is incorporated by reference in its entirety. In one embodiment, selpercatinib Form A is a tosylate or besylate salt. More preferably, when the Form A material is a salt, the salt is a tosylate salt.

[0105] Also disclosed herein is a pharmaceutical composition comprising selpercatinib Form A produced by any of the methods disclosed herein. The pharmaceutical compound may further comprise at least one pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition contains less than about 20% by weight of other crystalline forms of selpercatinib, or less than about 10% by weight of other crystalline forms of selpercatinib, or less than about 5% by weight of other crystalline forms of selpercatinib. The pharmaceutical composition contains about 40 mg or about 80 mg of selpercatinib Form A. Other pharmaceutical compositions contain about 120 mg or about 160 mg of selpercatinib Form A. The pharmaceutical formulation may be a tablet. Alternatively, the pharmaceutical formulation may be a capsule.

[0106] Further disclosed herein is a method of treating cancer in a patient, comprising administering to a patient in need of such treatment an effective amount of selpercatinib Form A made according to any of the methods disclosed herein, or a pharmaceutical composition described herein. In a preferred embodiment, the cancer is a RET-associated cancer. A RET-associated cancer is a cancer that responds to inhibition of RET.

[0107] In one embodiment, the cancer that can be treated using Form A and compositions described herein is selected from the group consisting of solid tumors, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. In one embodiment, the cancer is medullary thyroid cancer. In another embodiment, the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma, RET fusion lung cancer, or lung adenocarcinoma. In another preferred embodiment, the cancer is a solid tumor. In some embodiments, the solid tumor is a locally advanced or metastatic solid tumor. In a further embodiment, the solid tumor is a locally advanced or metastatic solid tumor with a RET gene fusion that has progressed on or following prior systemic therapy or has no satisfactory alternative treatment options. In another embodiment, the cancer is locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearrangement during transfection (RET) gene fusion as detected by an FDA-approved test. In yet another embodiment, the cancer is advanced or metastatic thyroid cancer with a RET gene fusion as detected by an FDA-approved test that requires systemic therapy and is radioiodine-refractory (if radioiodine is appropriate).

[0108] The following examples are provided solely to illustrate and describe certain embodiments within the scope of the methods described and claimed herein. [Example]

[0109] The selpercatinib (6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-5 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile) used in the crystallization procedures described herein was prepared using the techniques and methods described in U.S. Pat. No. 10,112,942.

[0110] Example 1: Gram-scale cooling crystallization process to produce Form A Using a chemical synthesis reactor (Easymax, Mettler Toledo), approximately 5 g of selpercatinib is added to the reactor along with (11 volumes) of DMSO and heated at 70°C until the selpercatinib dissolves and the system reaches the target temperature of 70°C. The solution is optionally polish filtered before being transferred to the crystallizer through a heated transfer line. The reactor and transfer line are rinsed with (1 volume) of DMSO, which is then added to the crystallizer and combined with the selpercatinib solution. The resulting solution is cooled to 40°C over 1.5 hours. Once the target temperature of 40°C is reached, approximately 0.5 volumes of water are slowly added (above the surface) to the crystallizer over 5 minutes to avoid self-seeding, providing a solvent ratio of approximately 96:4 DMSO:water (by volume). The solution is seeded by adding 1 wt% selpercatinib Form A seed crystals (D90 approximately 7 um). The seed crystals may be added as dry seeds or as a slurry in a minimum volume of 80:20 DMSO:water (by volume). The seeded solution is incubated for approximately 30 minutes. After the 30-minute incubation, 2.5 volumes of room temperature water are added over 1 hour. Upon completion of the water addition, the composition has a solvent ratio of approximately 80:20 DMSO:water (by volume).

[0111] Immediately after adding 2.5 volumes of water, the reactor is cooled to 0°C over a 2-hour period (at a rate of 20°C / hour). Once at 0°C, the slurry temperature is maintained at 0°C for 1 hour. The solids are isolated by filtration, optionally at a cool temperature, at a rate that maintains a wet filter cake. The filtered solids are washed with a first wash solution of 8 volumes of DMSO / water (80 / 20, by volume), and the cake is filtered and dried. The dried cake is washed with a second wash solution of 8 volumes of water, filtered, and dried. An additional 8 volumes of water are added to the dried cake with stirring (e.g., for 30-60 seconds) to resuspend the solid cake material. The water washes are continued until the amount of residual DMSO detected in the sample is 0.5% or less. Once the residual DMSO threshold is reached, the filter cake is washed with 8 volumes of MTBE to displace the water. An optional additional displacement wash using MTBE (8 volumes) may be performed to further reduce the residual water content in the solid material. The resulting solid selpercatinib Form A is dried under high vacuum with a slight stream of nitrogen gas through an oven at 45° C. The resulting selpercatinib contains about 94 to about 98% by weight of Form A.

[0112] Example 2 - Gram-scale cooling crystallization process at elevated drying temperatures to produce Form A Using a chemical synthesis reactor (Easymax, Mettler Toledo), approximately 6 g of selpercatinib was added to the reactor along with (11 volumes) of degassed DMSO and heated at 70°C under N2 until the selpercatinib dissolved and the system reached the target temperature of 70°C. An additional DMSO (1 volume) was added to the reactor. The resulting solution was cooled to 40°C over 1.5 hours. Once the target temperature of 40°C was reached, 0.5 volumes of water was slowly added (above the surface) to the crystallizer over 5 minutes to avoid self-seeding, providing a solvent ratio of approximately 96:4 DMSO:water (by volume). The solution was seeded by adding 1% by weight of selpercatinib Form A seed crystals. The seeded solution was incubated for approximately 30 minutes. After the 30-minute incubation, 2.5 volumes of room temperature water was added over 1 hour. Immediately after adding 2.5 volumes of water, the reactor is cooled to 0°C over a period of 2 hours. Once at 0°C, the temperature of the slurry is maintained at 0°C for 1 hour. The slurry is transferred from the vessel to a 10 micron disposable filter and completely drained. The filtered solids are pumped under high vacuum (e.g., for 20 minutes). The filtered solids are then washed with a first wash solution of 8 volumes of DMSO / water (80 / 20, by volume), and the cake is filtered and dried. The dried cake is then washed with a second wash solution of 8 volumes of water, and the cake is filtered and dried. Eight volumes of water are added to the dried cake with stirring (e.g., for 10-30 seconds) to resuspend the solid cake material. The solids are isolated by filtration. Eight volumes of MTBE are added to the dried cake with stirring (e.g., for 30 seconds), and the solid cake material is resuspended. The solids are isolated by filtration. An optional additional displacement wash using MTBE may be performed to further reduce the residual water content in the solid material. The resulting solid selpercatinib Form A is dried at 60° C. under high vacuum with a slight nitrogen gas flow through an oven.

[0113] Using the methodology described above, a series of seven experiments were performed, all under baseline conditions, and are summarized in Table 2 to identify any baseline process variability. Two of the experiments were from batch seeding experiments (032 and 033), which utilized different starting material qualities, amounts / qualities, and overall magnitudes of Form B in the seed crystals. The values ​​in italics represent HPLC integrals of several known impurities that were present in the starting material used in each experiment. The first set of impurity integrals for each line represents the impurity profile of the starting material, and the second set is the impurity profile of the isolated solid after crystallization.

[0114] [Table 2] 1 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carboxamide. 2 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. 3 4-[6-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. (a) The seed was a single lot containing 1.6% Form B and having a d90 of 6um. (b) The seed was a single lot containing 3.3% form B and having a d90 of 29 um. (b1) Seed was a single lot containing form B of ND but with a d90 of 67um. A. The starting material was a relatively clean batch. B. The starting material was an impure batch to test for impurity rejection. C. The starting material was a second, relatively clean batch. The HPLC method used to analyze the final solid is shown in Table 3, and an example chromatogram is shown in Figure 1. COM-1074 is 6-methoxynicotinaldehyde.

[0115] [Table 3]

[0116] Seed crystals of selpercatinib Form A of sufficient quality can enhance growth and secondary nucleation of the desired form, reducing variability from unseeded processes that rely on, for example, primary nucleation. Seed crystal specifications can be used to control the amount of Form B content that is acceptable within the seed.

[0117] Example 3: Reverse Addition Process for Direct Isolation of Form A DMSO was saturated with excess Form B at room temperature. A liquid was obtained from this slurry by filtration. 25 mL of the saturated DMSO solution was taken in a syringe and added at 1 mL / min to a pot containing 15 mL of water (approximately 63 / 37 DMSO / HO) at 20°C. Immediate crystallization was observed throughout the addition. Upon completion of the addition, a sample of the solid was taken and XRPD analysis found that no Form B was detectable. Alternative DMSO and water volumes (and therefore DMSO / HO ratios) are expected to have similar control over Form B due to the higher driving force. Ratios ranging from 90 / 10 to 20 / 80 are expected to give similar performance.

[0118] Example 4: Simultaneous Addition Process for Direct Isolation of Form A Experiments demonstrated simultaneous addition designed to maintain either an 80 / 20 or 90 / 10 vol% DMSO / water solvent composition in the crystallization mixture by using a pure selpercatinib / DMSO feed stream and a water feed stream that were simultaneously added to a pot containing a seed bed in the corresponding DMSO / water solvent system. An exemplary process description of the 80 / 20 process is provided below.

[0119] Prepare the water (antisolvent) feed by drawing up 3 volumes into a syringe.

[0120] The API feed was prepared by dissolving 1 equivalent basis of API (which could be Form A or Form B) in 12 volumes of DMSO, which was heated to 65°C to obtain a solution. This solution was collected in a dispensing syringe. The feed should be kept at an elevated temperature to prevent crystallization, but can be cooled to room temperature on a short timescale of hours without crystallization.

[0121] Prepare a crystallizer pot by charging 3.2 volumes DMSO, 0.8 volumes water (targeting 4 volumes for an 80 / 20 ratio, volume suitable for stirring) and equilibrate to 20° C. Charge 1 wt % (optional) Form A seeds and begin stirring.

[0122] Simultaneous addition is then initiated by feeding both feeds over a 4 hour period, with volumetric flow rates and volumes designed to maintain a constant 80 / 20 DMSO / water ratio.

[0123] After the simultaneous addition, the slurry can be isolated immediately or after an extended hold.

[0124] Using the methodology described above, a series of eight experiments was performed and summarized in Table 4 to identify significant factors for form purity. Some of the experiments utilized mixtures of Form A and Form B species to test the robustness of the conditions.

[0125] [Table 4] c: Form A and Form B in a ratio of 90 / 10 were used. d: Form A and Form B were used in a 90 / 10 ratio, but a different lot of Form B was used compared to (c). e: Single lot of Form A containing 1.6% Form B. f: Form A and Form B in a ratio of 95 / 5 were used using the same lot as in (d). 1 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carboxamide. 2 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. 3 4-[6-(6-ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile. A. The starting material was a relatively clean batch. B. The starting material was an impure batch to test for impurity rejection.

[0126] The results showed that the 80 / 20 condition provided better Form A control than the 90 / 10 condition due to the higher supersaturation level. Therefore, higher water / DMSO ratios, such as 50 / 50 or 20 / 80, can also be used to ensure high Form A purity. The simultaneous addition conditions shown are also representative of a continuous crystallization process, where continuous feeding and removal of the slurry can be performed.

[0127] Example 5: Solvate preparation and conversion process Selpercatinib can form solvates with solvent molecules, most of which are not stable when dry. In this example, Form A of selpercatinib is prepared from a dichloromethane (DCM) solvate.

[0128] In a reaction vessel, selpercatinib (0.8751 g, API) and water-saturated DCM (29.55 volumes) are mixed and heated (35°C) to dissolve. Alternatively, the same volume of DCM without water saturation can be used as the solvent to achieve similar results. Once selpercatinib is dissolved, heptane (10 volumes) is added over 30 minutes. After the heptane addition is complete, the mixture is cooled to a target temperature of 25°C over 30 minutes. Once the target temperature is reached, a second portion of heptane (10 volumes) is added to the mixture over 30 minutes. After the addition of the second portion of heptane is complete, the mixture is stirred at ambient temperature (25°C) for at least 8 hours. The resulting solid is isolated, washed (one wash with 4 volumes of heptane, a second wash with 4 volumes of MTBE), and dried at 45°C.

[0129] The resulting solid produced by this process is characterized as a DCM solvate, which forms at the end of crystallization and converts to Form A upon drying. The formation of the solvate appears to eliminate any dependence on or influence from seed crystal form.

[0130] Disclosed herein is a compound of Formula I, wherein the compound of Formula I contains at least about 90% by weight of Form A, and the compound of Formula I is obtained by adding selpercatinib to DMSO to form a mixture, heating the mixture to about 50-70°C to dissolve selpercatinib, thereby forming a solution, cooling the solution to about 40°C, and then adding a first batch and a second batch of water. The first batch of water can be, for example, about 0.5 volumes of water. Optionally, the selpercatinib / DMSO / water mixture is seeded with seed crystals, a second batch of water, about 2.5 volumes of water, is added, and the mixture is then cooled to about 0°C to isolate selpercatinib Form A. After adding the first batch of water, the ratio of DMSO:water is about 96:4. After adding the second batch of water, for example, 2.5 volumes of water, the ratio of DMSO:water is about 80:20. The isolated Form A is washed with about 8 volumes of DMSO:water (80:20), filtered and dried, and then washed with another 8 volumes of DMSO:water (80:20), filtered and dried again. The cake is then suspended in about 8 volumes of water and filtered. This process is repeated until the amount of residual DMSO detected in the sample is 0.5% or less. The filter cake is then washed at least once with about 8 volumes of MTBE. Selpercatinib Form A is then dried under high vacuum at a temperature of about 45°C.

[0131] Embodiment Embodiment 1. A method for converting selpercatinib to selpercatinib Form A, comprising: a) dissolving selpercatinib in a solvent comprising DMSO, thereby forming a selpercatinib DMSO solution; b) adding water to the selpercatinib DMSO solution to form a slurry; c) isolating crystallized selpercatinib Form A from the slurry, wherein Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ; or d) dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; e) adding heptane to the solution under conditions effective to form a slurry; f) isolating selpercatinib Form A from the slurry, wherein Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

[0132] Embodiment 2. A method for converting selpercatinib to selpercatinib Form A, the method comprising: a) dissolving selpercatinib in a solvent comprising DMSO, thereby forming a selpercatinib DMSO solution; b) adding water to the selpercatinib DMSO solution to form a slurry; c) isolating crystallized selpercatinib Form A from the slurry, wherein Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

[0133] Embodiment 3. The method of embodiment 2, wherein about 1 gram of selpercatinib is dissolved in about 10-15 mL of DMSO.

[0134] Embodiment 4. The method of embodiment 2 or 3, wherein step a comprises heating the DMSO and selpercatinib to a temperature of about 50-70°C.

[0135] Embodiment 5. The method of any one of embodiments 2-4, wherein step b comprises adding a first batch of water and a second batch of water.

[0136] Embodiment 6. The method of embodiment 5, wherein after the first batch of water has been added, the ratio of DMSO to water is about 96:4 by volume.

[0137] Embodiment 7. The method of any one of embodiments 5-6, comprising cooling the DMSO and selpercatinib to about 40° C. before the first batch of water is added.

[0138] Embodiment 8. The method of any one of embodiments 5-7, wherein after the second batch of water is added, the ratio of DMSO:water is about 80:20.

[0139] Embodiment 9. The method of any one of embodiments 5-8, comprising adding a second batch of water and cooling the DMSO:water to about 0°C, thereby forming a slurry.

[0140] Embodiment 10. The method of any one of embodiments 2 to 9, wherein step b comprises adding about 0.1 to about 1 mL / g of water to the solution.

[0141] Embodiment 11. The method of any one of embodiments 2 to 10, wherein step b comprises adding no more than about 0.2 mL / g of water to the solution.

[0142] Embodiment 12. The method of any one of embodiments 2 to 11, further comprising adding selpercatinib seed crystals to DMSO:water.

[0143] Embodiment 13. The method of embodiment 12, wherein about 1-15% by weight of selpercatinib Form A seed crystals are added to DMSO:water.

[0144] Embodiment 14 The method of embodiment 12 or 13, wherein about 1% by weight of selpercatinib Form A seed crystals are added to DMSO:water.

[0145] Embodiment 15. The method of any one of embodiments 12-14, comprising adding selpercatinib seed crystals before adding the second batch of water.

[0146] Embodiment 16. The method of any one of embodiments 2 to 15, wherein step c comprises high vacuum filtration.

[0147] Embodiment 17. The method of any one of embodiments 2 to 15, wherein step c comprises centrifugation.

[0148] Embodiment 18. The method of any one of embodiments 2 to 17, comprising washing the selpercatinib form A isolated from step c with a solvent comprising MTBE and / or water.

[0149] Embodiment 19. The method of any one of embodiments 2 to 18, further comprising drying selpercatinib Form A.

[0150] Embodiment 20. A method for converting selpercatinib to selpercatinib form A, the method comprising: a. dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; b. adding heptane to the solution under conditions effective to form a slurry; c. isolating selpercatinib form A from the slurry, wherein form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

[0151] Embodiment 21. The method of embodiment 20, wherein about 1 gram of selpercatinib is dissolved in about 25 to 35 mL of dichloromethane.

[0152] Embodiment 22. The method of any one of embodiments 20-21, wherein step a comprises heating a solvent comprising selpercatinib and dichloromethane to about 30-40°C.

[0153] Embodiment 23. The method of any one of embodiments 20-22, wherein step b comprises adding a first batch of heptane and a second batch of heptane.

[0154] Embodiment 24. The method of embodiment 23, wherein the first batch of heptane comprises about 8-12 mL of heptane per 1 g of selpercatinib.

[0155] Embodiment 25. The method of embodiment 23 or 24, wherein the second batch of heptane comprises about 8 to 12 mL of heptane per 1 g of selpercatinib.

[0156] Embodiment 26. The method of any one of embodiments 20-25, wherein step b comprises cooling to a temperature below about 30°C and above about 20°C.

[0157] Embodiment 27. The method of embodiment 26, wherein step b comprises cooling to a temperature of about 25°C.

[0158] Embodiment 28. The method of any one of embodiments 20-27, wherein step b comprises stirring for at least about 8 hours.

[0159] Embodiment 29. A pharmaceutical composition comprising selpercatinib Form A made according to any of Embodiments 1 to 28.

[0160] Embodiment 30. The composition of embodiment 29, further comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0161] Embodiment 31. The pharmaceutical composition of embodiment 29 or 30, wherein the composition contains less than about 20% by weight of other crystalline forms of selpercatinib.

[0162] Embodiment 32. The pharmaceutical composition of embodiment 29 or 30, wherein the composition contains less than about 10% by weight of other crystalline forms of selpercatinib.

[0163] Embodiment 33. The pharmaceutical composition of embodiment 29 or 30, wherein the composition contains less than about 5% by weight of other crystalline forms of selpercatinib.

[0164] Embodiment 34. The pharmaceutical composition of embodiment 29 or 30, wherein the composition comprising selpercatinib form A is substantially pure.

[0165] Embodiment 35. A method of treating cancer in a patient, comprising administering to a patient in need of such treatment an effective amount of selpercatinib Form A made according to any of embodiments 1 to 28, or a pharmaceutical composition described in any of embodiments 29 to 34.

[0166] Embodiment 36 The method of embodiment 35, wherein the cancer is a RET-associated cancer.

[0167] Embodiment 37. The method of embodiment 35 or 36, wherein the cancer is selected from the group consisting of solid tumors, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer.

[0168] Embodiment 38. The method of embodiment 37, wherein the cancer is medullary thyroid cancer.

[0169] Embodiment 39. The method of embodiment 37, wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

[0170] Embodiment 40. The method of embodiment 37, wherein the cancer is a solid tumor.

[0171] Embodiment 41. The method of embodiment 37 or 40, wherein the solid tumor is a locally advanced or metastatic solid tumor.

[0172] Embodiment 42. The method of embodiment 41, wherein the solid tumor is a locally advanced or metastatic solid tumor with a RET gene fusion that has progressed on or following previous systemic therapy or has no satisfactory alternative treatment options.

[0173] Embodiment 43. The method of embodiment 35 or 36, wherein the cancer is locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearrangement during transfection (RET) gene fusion, as detected by an FDA-approved test.

[0174] Embodiment 44. The method of embodiment 35 or 36, wherein the cancer is advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, that requires systemic therapy and is radioactive iodine-refractory (if radioactive iodine is appropriate).

[0175] Embodiment 45. The method of any one of embodiments 35 to 44, wherein the pharmaceutical composition contains about 40 mg of selpercatinib Form A.

[0176] Embodiment 46. The method of any one of embodiments 35 to 44, wherein the pharmaceutical composition contains about 80 mg of selpercatinib Form A.

[0177] Embodiment 47. The method of any one of embodiments 35 to 44, wherein the pharmaceutical composition contains about 120 mg of selpercatinib Form A.

[0178] Embodiment 48. The method of any one of embodiments 35 to 44, wherein the pharmaceutical composition contains about 160 mg of selpercatinib Form A.

[0179] Embodiment 49. The method of any one of embodiments 35 to 48, wherein the pharmaceutical composition is provided in a tablet.

[0180] Embodiment 50. The method of any one of embodiments 35 to 48, wherein the pharmaceutical composition is provided in a capsule.

[0181] Embodiment 51. A pharmaceutical composition comprising at least about 80% by weight of selpercatinib form A, or a pharmaceutically acceptable salt thereof, for use in therapy, wherein the pharmaceutical composition comprises selpercatinib form A made according to any one of embodiments 1 to 50.

[0182] Embodiment 52. A pharmaceutical composition comprising at least about 80% by weight of selpercatinib Form A, or a pharmaceutically acceptable salt thereof, for use according to embodiment 51, further comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0183] Embodiment 53. A pharmaceutical composition for use according to embodiment 51 or 52, wherein the pharmaceutical composition contains less than about 20% by weight of other forms of selpercatinib.

[0184] Embodiment 54. A pharmaceutical composition for use according to embodiment 51 or 52, wherein the composition contains less than about 10% by weight of other forms of selpercatinib.

[0185] Embodiment 55. A pharmaceutical composition for use according to embodiment 51 or 52, wherein the composition contains less than about 5% by weight of other forms of selpercatinib.

[0186] Embodiment 56. A pharmaceutical composition for use according to embodiment 51 or 52, wherein the composition comprising selpercatinib form A is substantially pure.

[0187] Embodiment 57. A pharmaceutical composition comprising at least about 80% by weight of selpercatinib form A, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

[0188] Embodiment 58. A pharmaceutical composition comprising at least about 80% by weight of selpercatinib form A, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the pharmaceutical composition comprises selpercatinib form A made according to any one of embodiments 1 to 50.

[0189] Embodiment 59. A pharmaceutical composition for use according to embodiment 57 or 58, wherein the pharmaceutical composition contains less than about 20% by weight of other forms of selpercatinib.

[0190] Embodiment 60. A pharmaceutical composition for use according to embodiment 57 or 58, wherein the composition contains less than about 10% by weight of other forms of selpercatinib.

[0191] Embodiment 61. A pharmaceutical composition for use according to embodiment 57 or 58, wherein the composition contains less than about 5% by weight of other forms of selpercatinib.

[0192] Embodiment 62. The pharmaceutical composition for use according to any one of embodiments 57 to 61, wherein the cancer is a RET-associated cancer.

[0193] Embodiment 63. The pharmaceutical composition for use of any one of embodiments 57 to 61, wherein the cancer is selected from the group consisting of solid tumors, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer.

[0194] Embodiment 64. The pharmaceutical composition for use according to embodiment 63, wherein the cancer is medullary thyroid cancer.

[0195] Embodiment 65. The pharmaceutical composition for use according to embodiment 63, wherein the cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

[0196] Embodiment 66. A pharmaceutical composition for use according to embodiment 62 or 63, wherein the cancer is a RET fusion lung cancer.

[0197] Embodiment 67. The pharmaceutical composition for use according to embodiment 63, wherein the cancer is a solid tumor.

[0198] Embodiment 68. A pharmaceutical composition for use according to embodiment 63 or 67, wherein the solid tumor is a locally advanced or metastatic solid tumor.

[0199] Embodiment 69. A pharmaceutical composition for use according to embodiment 63, 67, or 68, wherein the solid tumor is a locally advanced or metastatic solid tumor with a RET gene fusion that has progressed during or following previous systemic therapy or has no satisfactory alternative treatment options.

[0200] Embodiment 70. The pharmaceutical composition for use according to embodiment 63, wherein the cancer is locally advanced or metastatic non-small cell lung cancer (NSCLC) with rearrangement during transfection (RET) gene fusion as detected by an FDA approved test.

[0201] Embodiment 71. A pharmaceutical composition for use according to embodiment 63, wherein the cancer is advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, that requires systemic therapy and is radioiodine-refractory (if radioiodine is appropriate).

[0202] Embodiment 72. A pharmaceutical composition for use according to any one of embodiments 51 to 71, wherein the pharmaceutical composition contains about 40 mg of selpercatinib form A.

[0203] Embodiment 73. A pharmaceutical composition for use according to any one of embodiments 51 to 71, wherein the pharmaceutical composition contains about 80 mg of selpercatinib form A.

[0204] Embodiment 74. A pharmaceutical composition for use according to any one of embodiments 51 to 71, wherein the pharmaceutical composition contains about 120 mg of selpercatinib form A.

[0205] Embodiment 75. A pharmaceutical composition for use according to any one of embodiments 51 to 71, wherein the pharmaceutical composition contains about 160 mg of selpercatinib form A.

[0206] Embodiment 76. A pharmaceutical composition for use according to any one of embodiments 51 to 75, wherein the pharmaceutical composition is provided in a tablet form.

[0207] Embodiment 77. A pharmaceutical composition for use according to any one of embodiments 51 to 75, wherein the pharmaceutical composition is provided in a capsule. The present invention includes the following aspects. <1> 1. A method for converting selpercatinib to selpercatinib Form A, said method comprising: a. dissolving selpercatinib in a solvent comprising DMSO, thereby forming a selpercatinib DMSO solution; b. adding water to the selpercatinib DMSO solution to form a slurry; c. isolating crystallized selpercatinib Form A from said slurry; and Including, wherein said Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ. <2> Dissolve approximately 1 gram of selpercatinib in approximately 10-15 mL of DMSO. <1> The method described below. <3> Step a comprises heating the DMSO and selpercatinib to a temperature of about 50 to 70°C. <1> or <2> The method described below. <4> Step b comprises adding a first batch of water and a second batch of water; <1> ~ <3> A method according to any one of the preceding claims. <5> After the first batch of water is added, the ratio of DMSO to water is about 96:4 by volume. <4> The method described below. <6> cooling the DMSO and selpercatinib to about 40° C. before the first batch of water is added. <4> or <5> The method described below. <7> After the second batch of water is added, the ratio of DMSO:water is about 80:20. <4> ~ <6> A method according to any one of the preceding claims. <8> adding the second batch of water and cooling the DMSO:water to about 0°C, thereby forming a slurry. <4> ~ <7> A method according to any one of the preceding claims. <9> Step b comprises adding about 0.1 to about 1 mL / g of water to the solution; <1> ~ <8> A method according to any one of the preceding claims. <10> Step b comprises adding about 0.2 mL / g or less of water to the solution; <1> ~ <9> A method according to any one of the preceding claims. <11> further comprising adding selpercatinib seed crystals to the DMSO:water. <1> ~ <10> A method according to any one of the preceding claims. <12> adding about 1-15% by weight of selpercatinib Form A seed crystals to the DMSO:water; <11> The method described below. <13> adding about 1% by weight of selpercatinib Form A seed crystals to the DMSO:water; <11> or <12> The method described below. <14> adding the selpercatinib seed crystals before adding the second batch of water. <11> ~ <13> A method according to any one of the preceding claims. <15> Step c comprises high vacuum filtration; <1> ~ <14> A method according to any one of the preceding claims. <16> Step c comprises centrifugation; <1> ~ <14> A method according to any one of the preceding claims. <17> washing the selpercatinib form A isolated from step c with a solvent comprising MTBE and / or water; <1> ~ <16> A method according to any one of the preceding claims. <18> further comprising drying the selpercatinib Form A. <1> ~ <17> A method according to any one of the preceding claims. <19> 1. A method for converting selpercatinib to selpercatinib Form A, said method comprising: a. dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; b. adding heptane to the solution under conditions effective to form a slurry; c. isolating said selpercatinib Form A from said slurry, wherein said Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ. <20> Dissolve approximately 1 gram of selpercatinib in approximately 25-35 mL of dichloromethane. <19> The method described below. <21> Step a comprises heating the solvent containing the selpercatinib and the dichloromethane to about 30 to 40°C. <19> or <20> The method described below. <22> Step b comprises adding a first batch of heptane and a second batch of heptane; <19> ~ <21> A method according to any one of the preceding claims. <23> the first batch of heptane comprises about 8 to 12 mL of heptane per gram of selpercatinib; <22> The method described below. <24> the second batch of heptane comprises about 8 to 12 mL of heptane per gram of selpercatinib; <22> or <23> The method described below. <25> Step b comprises cooling to a temperature below about 30°C and above about 20°C; <19> ~ <24> A method according to any one of the preceding claims. <26> Step b includes cooling to a temperature of about 25°C. <25> The method described below. <27> Step b comprises stirring for at least about 8 hours; <19> ~ <26> A method according to any one of the preceding claims. <28> <1> ~ <27> 10. A pharmaceutical composition comprising selpercatinib Form A made according to any one of the preceding claims. <29> further comprising at least one pharmaceutically acceptable carrier, diluent or excipient; <28> The composition described in <30> the composition contains less than about 20% by weight of other crystalline forms of selpercatinib. <28> or <29> The pharmaceutical composition described in <31> the composition contains less than about 10% by weight of other crystalline forms of selpercatinib. <28> or <29> The pharmaceutical composition described in <32> the composition contains less than about 5% by weight of other crystalline forms of selpercatinib. <28> or <29> The pharmaceutical composition described in <33> the composition comprising selpercatinib Form A is substantially pure; <28> or <29> The pharmaceutical composition described in <34> 1. A method of treating cancer in a patient, comprising administering to a patient in need of such treatment: <1> ~ <27> an effective amount of selpercatinib Form A made according to any of the preceding claims; or <28> ~ <33> A method comprising administering the pharmaceutical composition according to any one of the preceding claims. <35> the cancer is a RET-associated cancer; <34> The method described below. <36> the cancer is selected from the group consisting of solid tumors, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer; <34> or <35> The method described below. <37> the cancer is medullary thyroid cancer; <36> The method described below. <38> The cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary carcinoma, RET fusion lung cancer, or lung adenocarcinoma. <36> The method described below. <39> the cancer is a solid tumor; <36> The method described below. <40> the solid tumor is a locally advanced or metastatic solid tumor; <36> or <39> The method described below. <41> the solid tumor is a locally advanced or metastatic solid tumor with a RET gene fusion that has progressed on or following previous systemic therapy or has no satisfactory alternative treatment options; <40> The method described below. <42> the cancer is locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearrangement during transfection (RET) gene fusion as detected by an FDA-approved test; <34> or <35> The method described below. <43> the cancer is advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, that requires systemic therapy and is radioactive iodine-refractory (if radioactive iodine is appropriate); <34> or <35> The method described below.

Claims

1. 1. A method for converting selpercatinib to selpercatinib Form A, said method comprising: a. dissolving selpercatinib in a solvent comprising DMSO, thereby forming a selpercatinib DMSO solution; b. adding water to the selpercatinib DMSO solution to form a slurry, wherein after the addition of water, the selpercatinib DMSO solution is cooled to 0°C; c. isolating crystallized selpercatinib Form A from said slurry; Including, Form A has XRPD peaks at 4.9±0.2°, 9.7±0.2°, and 15.5±0.2° 2θ; The method comprises: washing the isolated selpercatinib form A from step c) with water to an amount of residual DMSO of 0.5% by weight or less, and further with a solvent comprising heptane and / or MTBE; and drying the solvent-washed selpercatinib Form A at 40-60°C.

2. 2. The method of claim 1, wherein 1 gram of selpercatinib is dissolved in 10 to 15 mL of DMSO.

3. 2. The method of claim 1, wherein step a comprises heating the DMSO and selpercatinib to a temperature of 50-70°C.

4. 10. The method of claim 1, wherein step b comprises adding a first batch of water and a second batch of water.

5. 5. The method of claim 4, wherein after the first batch of water has been added, the ratio of DMSO to water is 96:4 by volume.

6. 5. The method of claim 4, comprising cooling the DMSO and selpercatinib to 40° C. before the first batch of water is added.

7. 5. The method of claim 4, wherein after the second batch of water is added, the ratio of DMSO:water is 80:

20.

8. 5. The method of claim 4, comprising adding the second batch of water and cooling the DMSO:water to 0°C, thereby forming a slurry.

9. 10. The method of claim 1, wherein step b comprises adding 0.1 to 1 mL / g of water to the solution.

10. 10. The method of claim 1, wherein step b comprises adding no more than 0.2 mL / g of water to the solution.

11. 10. The method of claim 1, further comprising adding selpercatinib seed crystals to the DMSO:water.

12. adding 1-15 wt % of selpercatinib Form A seed crystals to the DMSO:water; 12. The method of claim 11, wherein the selpercatinib Form A seed crystals have XRPD peaks at 4.9±0.2°, 9.7±0.2°, and 15.5±0.2° 2θ.

13. adding 1 wt% of selpercatinib Form A seed crystals to the DMSO:water; 12. The method of claim 11, wherein the selpercatinib Form A seed crystals have XRPD peaks at 4.9±0.2°, 9.7±0.2°, and 15.5±0.2° 2θ.

14. step b comprises adding a first batch of water and a second batch of water; 12. The method of claim 11, comprising adding the selpercatinib seed crystals before adding the second batch of water.

15. 10. The method of claim 1, wherein step c comprises high vacuum filtration.

16. The method of claim 1 , wherein step c comprises centrifugation.

17. 1. A method for converting selpercatinib to selpercatinib Form A, said method comprising: a. dissolving selpercatinib in a solvent comprising dichloromethane to form a solution; b. adding heptane to the solution under conditions effective to form a slurry; and c. isolating the selpercatinib Form A from the slurry, wherein the Form A has XRPD peaks at 4.9±0.2°, 9.7±0.2°, and 15.5±0.2° 2θ; The method comprises: washing the isolated selpercatinib form A from step c with a solvent comprising heptane and / or MTBE; and drying the solvent-washed selpercatinib Form A at 40-60°C.

18. 18. The method of claim 17, wherein 1 gram of selpercatinib is dissolved in 25 to 35 mL of dichloromethane.

19. 18. The method of claim 17, wherein step a comprises heating the solvent containing the selpercatinib and the dichloromethane to 30-40°C.

20. 18. The method of claim 17, wherein step b comprises adding a first batch of heptane and a second batch of heptane.

21. 21. The method of claim 20, wherein the first batch of heptane comprises 8 to 12 mL of heptane per gram of selpercatinib.

22. 21. The method of claim 20, wherein the second batch of heptane comprises 8 to 12 mL of heptane per gram of selpercatinib.

23. 18. The method of claim 17, wherein step b comprises cooling to a temperature below 30°C and above 20°C.

24. 24. The method of claim 23, wherein step b comprises cooling to a temperature of 25°C.

25. 18. The method of claim 17, wherein step b comprises stirring for at least 8 hours.

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