Method for preparing crystalline form A of the RET inhibitor selpercatinib

Abstract

A method for preparing crystalline selpercatinib Form A, which is substantially free of or completely free of the more thermodynamically stable crystalline selpercatinib Form B, is provided. 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. 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 treatment for metastatic RET with fusion-positive NSCLC, RET-mutated medullary thyroid cancer, and RET-fusion-positive thyroid cancer Selpercatinib is a RET inhibitor approved in the US for use in treating patients with HER2. , or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-meth (3-xypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane- 3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile has the following chemical structure

[0002] [ka]

[0003] Several crystalline forms of selpercatinib are known and have been disclosed (e.g., US (See US Patent No. 10,584,124), however, various crystalline polymorphic forms may be isolated. When a compound is used, it may contain a certain 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 is typically contains at least some of the thermodynamically more stable crystalline "Form B." The Form A material disclosed in the '124 patent contained some Form B material. Publication No. 2021 / 211380 describes a method for selectively forming selpercatinib form B. The present disclosure discloses a method containing little, if any, Form B. A method for selectively forming selpercatinib form A is disclosed. Summary of the Invention

[0004] Selpercatinib is described herein in its kinetically stable crystalline form, "Form A." In embodiments of these methods, the present disclosure provides a solubilized form and and / or a solvated form of selpercatinib to selpercatinib form A. In other embodiments of these methods, the present disclosure provides for the preparation of Serperca as a mixture of polymorphic forms. In yet another embodiment, the method comprises converting selpercatinib to selpercatinib Form A. The method comprises 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; It can be mixed with one or more other crystalline forms and can provide benefits to patients. and / or as a single crystalline form (i.e., as a pure or substantially pure crystalline form). and one of its crystalline forms (e.g., kinetically stable form A), which can be used in It would also be advantageous to be able to provide selpercatinib as a therapeutically effective treatment.

[0006] As described in more detail below, the compound of formula I (selpercatinib) may exist in polymorphic forms. (Form A and Form B), and surprisingly, the specific process and The method is effective to provide selpercatinib in its kinetically stable polymorphic form A. As described below and illustrated by the illustrative working examples, selpercatinib has been identified. The processes and methods for producing and preparing polymorphic forms of the compound provided in one or more polymorphic forms are The compound of formula I provided may be used in combination with other polymorphs (i.e., Form B) or amorphous selpercatinib. converting (i.e., reacting) under crystallization conditions effective to produce or convert to Form A; In another embodiment, the method may include contacting and / or treating the cell permeable membrane. Processes and methods for producing selpercatinib form A produce selpercatinib form A a synthetic route comprising reacting one or more intermediate or precursor compounds under conditions effective to (i.e., a direct synthetic route).

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

[0008] Form B (a) is at 21.1° when measured using an x-ray wavelength of 1.5418 Å Peaks at 7.5, 10.9, 12.0°, 17.1°, 17.7°, and 19. X-ray powder diffraction with one or more peaks at 8°±0.2° 2θ fraction, XRPD) pattern, or (b) 28.0, 48.0, 80.4, 106.8 Adamantane at 130.2, 130.2, and 134.9 ppm (each ±0.2 ppm) Contains a peak based on the high-field resonance (δ=29.5 ppm) of 13 C solid-state NMR Typically, these signatures are characterized by at least one of the following: The chromatographic spectrum is unique to crystalline form B.

[0009] Similarly, Form A exhibits 4.9, 9.7, and 15.5 which cannot be observed in Form B. , ±0.2° 2θ, and / or (b) XRPD peaks at 0.2° 2θ observed in Form B. The high-field resonance of adamantane (δ = 29.5 ppm) at 30.9 ppm cannot be observed. The identification can be based on the NMR spectrum containing peaks based on m).

[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, Preferably, selpercatinib contains at least about 94% to about 98% by weight of Form A. Selpercatinib is available in amorphous form B (the thermodynamically more stable polymorph); It may be a tinib solvate, or a mixture of two or more thereof.

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

[0012] Further, there is provided a method for converting selpercatinib to selpercatinib form A, comprising the steps of: The method is 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 is in an amount of about 4 A method is disclosed in which the compound has XRPD peaks at 0.9, 9.7, and 15.5 degrees 2θ.

[0013] Surprisingly, selpercatinib form A can be prepared using the methods described herein. However, if incorrect washing and drying protocols are used, it may contain up to about 20% by weight of Form B. It has been discovered that Form A is obtained, which results in Form B. Therefore, it is important to minimize or eliminate the formation of Form B. Disclosed herein are methods for washing and drying selpercatinib form A, which will be done. [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 are intended to be used in conjunction with the present invention. As used herein, the terms "antibody" and "antibody" have the meaning commonly understood by those skilled in the art to which they pertain. When used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0016] As used herein, the term "polymorphism" refers to the result of molecular ordering within a crystal lattice. refers to crystals of the same compound having different physical properties as a single compound (i.e., a single compound of Formula I) Different polymorphs of a compound (compound) have one or more different chemical, physical, mechanical, electrical, The differences in physical properties exhibited by polymorphs are , storage stability, compressibility, density (important in the formulation and manufacturing of the product), dissolution rate (bio (important factors determining availability), solubility, melting point, chemical stability, physical stability , can affect pharmaceutical parameters such as powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability can be attributed to changes in chemical reactivity (e.g., the ability of a compound to be composed of one polymorph to be composed of another polymorph). (differential oxidation) or mechanical modification, such that the dosage form discolors more quickly than if it were composed of Conversion (e.g., protection such that a kinetically favored polymorph is converted to a thermodynamically more stable polymorph) crystal changes during storage), or both (e.g., one polymorph is more hygroscopic than another) As a result of differences in solubility / dissolution, some transitions may result in differences in potency and / or toxicity. In addition, the physical properties of the crystals can be important in processing, e.g. Certain polymorphs may be more likely to form solvates or may be insoluble after filtration and washing. It can be difficult to keep the particles free (i.e., particle size and size distribution may vary). (The amount of a compound may vary between one polymorph and another). " does not include amorphous forms of the compound. In some particular embodiments, the compound of Formula I Polymorphism (i.e., one of selpercatinib form A and / or selpercatinib form B) Either or both of the above may include the features 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 that does not have a regular repeating arrangement of molecules or external planes (e.g. , refers to the solid form of a compound, and typically has sharp diffraction peaks in its powder X-ray diffraction pattern. is characterized by the absence of

[0018] The term "anhydrous" as used herein refers to an anhydrous substance that is free from stoichiometric amounts of water associated with the crystal lattice. Refers to a crystalline form of the compound of formula (I) that does not contain water. Typically, anhydrous form A and anhydrous form B are Phase B has 1% by weight or less of water, for example, 0.5% by weight or less, 0.25% by weight or less, or has 0.1% by weight or less of water.

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

[0020] The term "hydrate" or "hydrate polymorph" refers to a polymorphic form of a compound whose crystal lattice contains water. Unless otherwise specified, as used herein, the term "crystalline form" refers to a crystalline form of a compound of formula (I), such as The term "hydrate" used herein refers to a "stoichiometric hydrate." A stoichiometric hydrate is a crystalline structure. Contains water molecules as an integral part of the molecule. In contrast, non-stoichiometric hydrates contain water However, changes in water content do not cause significant changes in the crystal structure. During drying, a significant proportion of the water can be removed without significantly disrupting the crystalline network. , the crystals can then be rehydrated to give the original non-stoichiometric hydrated crystal form. Unlike stoichiometric hydrates, the dehydration and rehydration of nonstoichiometric hydrates does not involve a phase transformation. Therefore, all hydration states of non-stoichiometric hydrates represent the same crystalline form.

[0021] "Purity" when used in reference to a composition containing a polymorph of the compound of formula (I) refers to The present invention relates to the identification of one particular polymorphic form of the compound of formula (I) relative to another polymorphic or amorphous form in a composition comprising the compound of formula (I). For example, a composition containing polymorph Form A with a purity of 90% comprises 90 parts by weight of Form A and 10 parts by weight of other polymorphs and / or amorphous forms of the compound of formula (I). The form includes.

[0022] As used herein, a compound or composition does not contain significant amounts of other components. In some cases, a compound or composition is "substantially free" of one or more such other components. For example, , the composition may contain less than 5 wt.%, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, or less than 1 wt.% Such components may include starting materials, residual solvents, or other components not listed herein. Other impurities that may arise from the preparation and / or isolation of the provided compounds and compositions are In some embodiments, the polymorphic forms provided herein may be present in combination with other polymorphic forms. In some embodiments, a particular polymorph of the compound of Formula (I) is substantially free of a particular When the polymorph of formula (I) exists, and comprises at least about 95% by weight of the compound of formula (I), other polymorphs In some embodiments, a particular polymorph of the compound of formula (I) is At least about 97%, about 98%, about 9% by weight of a compound of formula (I) in which a particular polymorph exists. 9%, or about 99.5% by weight of other polymorphs. In certain embodiments, the particular polymorph of the compound of Formula (I) has an amount of water that is about 2% by weight of the polymorph, about 1% by weight of the polymorph, %, or about 0.5% by weight or less, of water is "substantially free" of water.

[0023] As used herein, "substantially pure" refers to polymorphic forms of the compound of formula (I). When used as a sachet, 90%, 91%, 92%, 93%, or 100% of the compound, based on the weight of the compound. %, 94%, 95%, 96%, 97%, 98%, and more than 99%, as well as about 10 means a sample of a polymorphic form of a compound with a purity greater than 90%, including those with a purity equal to 0%. The remaining material may be other forms of the compound and / or reaction impurities arising from its preparation. For example, polymorphic forms of the compound of formula (I) are known in the art and / or contain processing impurities. When measured by known and generally accepted means at the The purity of the polymorphic form of the compound of formula (I) is greater than 90%, and the remaining material is less than 10% of the compound of formula (I). substantially pure in that it contains other forms of and / or reaction and / or processing impurities. The presence of reaction and / or processing impurities is considered to be undesirable in the art. Analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or This can be determined by infrared spectroscopy or the like.

[0024] For the sake of brevity, some of the quantitative expressions herein are expressed as about X to about The amount Y is recited as a range. When a range is recited, the range is limited to the recited upper and lower limits. It is not limited to a lower limit, but rather includes the entire range of about X to about Y, or any range therein. It is understood that:

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

[0026] As used herein, the term "excipient" refers to an agent that formulates a composition into a desired form. For example, suitable excipients include diluents or fillers, binders, or a granulating or adhesive agent, a disintegrant, a lubricant, an anti-adherent, a glidant, a dispersing or wetting agent; Dissolution retarders or enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, and sweeteners These include, but are not limited to, flavorings.

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

[0028] As used herein, the singular forms "a," "an," and "the" are used interchangeably, particularly where the context requires. Thus, unless expressly indicated otherwise, it includes multiple referents.

[0029] As used herein, ranges and amounts may be expressed as "about" a particular value or range. About includes exact amounts. Therefore, "about 5 grams" can be used to mean "about 5 grams" and "5 Also means "grams." Ranges expressed herein include whole numbers and fractions thereof within that range. For example, the range of 5 to 20 grams includes 5, 6, 7, 8, 9, 10, 1 Integer values ​​such as 1, 12, 13, 14, 15, 16, 17, 18, 19, and 20 grams and 5.25, 6.5, 8.75, and 11.95 grams The values ​​for DSC, TGA, or TG may be preceded by "about." The term is reported as a temperature in degrees Celsius with an allowable variation of + / - 5°C.

[0030] As used herein, "optional" or "optionally" means The events or circumstances described may or may not occur, and the statements made may not be accurate or implied. This is meant to include examples of when this happens and examples of when it does not happen. The term "catalyzed" refers to a reaction mixture that either contains a catalyst or does not contain a catalyst. means.

[0031] As used herein, the term "diluent" when used in reference to an acidic solution In this case, it 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] Salts can be formed from compounds in any manner well known to those skilled in the art. Thus, the phrase "form a compound or a salt thereof" means that a compound is formed and the salt is Included are embodiments that are subsequently formed from compounds in a manner well known to those skilled in the art.

[0034] As used herein, a patient is one in which a RET fusion or RET mutation has been determined. Thus, the term "determining a RET fusion or RET mutation" refers to determining a RET fusion or RET mutation. This means determining whether a RET fusion or RET mutation is present. Methods for determining whether a protein is present are known to those skilled in the art and are described, for example, in Wang, Yuc, See ong et al., Medicine 2019;98(3):e14120 In embodiments, the term "patient" refers to a human.

[0035] A "pharmaceutically acceptable carrier, diluent, or excipient" is a substance that is administered to a mammal, e.g., a human, or other organism. These are vehicles generally accepted in the art for the delivery of biologically active agents.

[0036] The terms "treatment," "treat," "treating," and similar terms refer to the treatment of a disorder, including the slowing of progression of the disorder. These terms also include: Even if the disability or condition is not actually eliminated, and the progression of the disability or condition itself is delayed or stopped, or, if not reversed, alleviating or ameliorating one or more symptoms of the disorder or condition; This includes weakening, eliminating, or reducing.

[0037] An "effective amount" is defined as the biological or medical response of a patient or the amount of a substance that a patient experiences, as determined by the treating clinician. In one example, the amount of crystalline form of selpercatinib that induces the desired therapeutic effect on The crystalline form of selpercatinib exhibits a cytotoxic effect in in vitro or ex vivo RET enzyme assays. In another example, a crystalline form of selpercatinib is Inhibition of native RET signaling in mouse whole blood from animals treated with different doses of the compound To harm.

[0038] An effective amount can be determined by the attending diagnostician, such as one skilled in the art, using known techniques and under similar circumstances. The effective amount for a patient can be readily determined by observing the results obtained under the conditions. In making this determination, the attending physician will take into account, but not be limited to, the patient's species; its size, age, and overall general health status; any specific associated disease or disorder; the extent or involvement or severity of the disease or disorder; individual patient response; the particular compound administered; the mode of administration; the biological availability of the administered preparation the efficacy characteristics; the selected dosing regimen; the use of concomitant medications; and other relevant circumstances. Several factors are taken into consideration.

[0039] Selpercatinib is available as either Form B or Form A, or a mixture thereof. Preferably, the compound is administered via a route that is bioavailable, including oral, intravenous, and transdermal routes. The compound is formulated as a pharmaceutical composition to be administered by any route that will Such compositions are for oral administration. Processes for this purpose are well known in the art (see, e.g., Remington: he Science and Practice of Pharmacy(DB Troy, Editor, 21st Edition, Lippincott, Will (See Iams & Wilkins, 2006.)

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

[0041] As used herein, a "manufacturing vessel" refers to a vessel used in the manufacture of a pharmaceutical product, but not in the pharmaceutical formulation. This refers to a container that is not used in a scientific laboratory. Examples of production containers include hopper collectors. , bed, dryer bed, granulator bed, dryer tray, granulator bucket, and mixer These include, but are not limited to, bowls.

[0042] Certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be used interchangeably. It is understood that they may be provided in combination in one embodiment. Various features of the disclosure that are described in the context of a single embodiment may also be used separately or in any suitable manner. It may be provided as a subcombination.

[0043] All combinations of embodiments relating to aspects described herein are to be construed as being within the scope of the present invention. To the extent that it encompasses all possible aspects, it is as if every possible combination were individually and explicitly enumerated. In addition, the aspects described herein are specifically encompassed by the present disclosure as if fully set forth herein. All subcombinations of the embodiments included in this application, and all other aspects described herein. All subcombinations of the included embodiments are also included as if each and every embodiment were included. Such subcombinations are considered to be within the scope of the present invention as if they were expressly recited herein. Specifically included.

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

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

[0046] [Table 1]

[0047] XRPD data were obtained using a CuKα source (λ = 1.54180 Å) and a Vantec detector. The Bruker D4 Endeavor is installed and operates at 35kV and 50mA. The samples were obtained on an X-ray powder diffractometer with a step size of 0.008° 2θ and a time of 0.5 seconds. 1.0mm divergence slit, 6.6mm fixed anti-scatter slit, with a scanning speed of / step The dry powder was scanned from 4 to 40° 2θ using a 11.3 mm detector slit. The sample is packed into a quartz sample holder and a smooth surface is obtained using a glass slide. Crystalline form diffraction patterns are collected at ambient temperature and relative humidity. Crystalline peak positions are Based on an internal NIST 675 standard with peaks at 0.853 and 26.774 2θ° After the overall pattern shift, it is determined by MDI-Jade. For a given crystalline form, the preferred orientation resulting from factors such as crystalline form and habit It is well known that the relative intensities of the diffraction peaks can change as a result of the orientation of the crystal. In this case, the peak intensities change, but the characteristic peak positions of the polymorphs remain unchanged. e United States Pharmacopeia #23,Nationa See Formulary #18, pages 1843-1844, 1995 Furthermore, for any given crystalline form, the angular peak positions may vary slightly. For example, peak positions are related to the temperature at which the sample is analyzed. This may shift due to variations, sample displacement, or the presence or absence of an internal standard. In this case, peak position variations of ±0.2 2θ° do not prevent unambiguous identification of the crystalline form shown. It is assumed that these potential variations are taken into account without considering the crystal morphology. This can be done based on any unique combination of peaks.

[0048] DSC-TGA analysis of anhydrous crystalline Form A showed a melting onset at approximately 207°C with two endotherms. The first endotherm is the melting of Form A, followed by the exothermic recrystallization of Form B, and then Form B DSC-TGA analysis of anhydrous crystalline form B shows a melting onset of approximately 213°C. The reaction mixture showed a single endotherm accompanied by

[0049] Forms A and B are anhydrous polymorphs, but Form A is slightly more hygroscopic than Form B. As discussed herein, it is thermodynamically less stable than Form B. Furthermore, as discussed herein, As can be seen, some embodiments provide serpercatini in the form of a solvate that can be isolated. In some embodiments, the solvated form of selpercatinib is provided by removing solvent molecules. Removal can provide selpercatinib Form A.

[0050] Forms A and B have similar solubilities. Both are soluble in methyl ethyl ketone (methyl ethyl ketone). Many organic solvents, including methyl ketone (MEK), acetone, and many alcoholic solvents Its solubility at 25°C is low, but it is easily dissolved in dichloromethane (DCM), Moderate solubility in dimethylsulfoxide (DMSO) and THF ( Form B is practically insoluble in anisole.

[0051] Form A and Form B 13 The C solid-state NMR spectrum is shown in Figure 3. It includes a partial overlay of the kutol, and Form A cannot be observed in Form B30. Form B has a peak at about 48.0 ppm that is not observed in Form A. Both spectra show a high field peak at 100 ppm for adamantane. The resonance (δ=29.5 ppm) was used as the reference.

[0052] It operates at a carbon frequency of 100.62 MHz and a proton frequency of 400.13 MHz. Bruker Avance III equipped with a Bruker 4mm dual resonance probe Using a HD 400 MHz wide-bore NMR spectrometer, 13 C Cross Polarization / Ma G-angle spinning NMR (solid-state NMR or ssNMR) spectra were obtained. The band suppression was achieved by SPINAL64 decoupling and RAMP100-type H-nucleus CP pulses. The acquisition parameters were: 4.0 μs proton pulse, 1.5 ms contact time, 5 kHz MAS frequency, 30.2 kHz A spectral width and acquisition time of 34 ms were used. A recycle delay of 3 seconds was used, and the number of scans was 2. The chemical shift was determined in a separate experiment from that of adamantane (δ = 29.5 ppm). ) is the standard. 13 The C ssNMR resonance is at approximately 26.44, 27.37, 28.00, 41.98, 43.43, 43.91, 48.04, 53.9 2, 56.31, 58.32, 69.48, 77.90, 80.38, 102.32, 1 06.77, 113.58, 115.24, 118.23, 120.76, 125.23 , 130.23, 134.86, 136.93, 140.59, 148.42, 149. Pi at 50, 151.20, 152.45, 158.22, and 163.52 ppm As shown, Form A contains approximately 30% cleavage peaks that cannot be observed in Form B. It has a peak at 9 ppm.

[0053] The above data demonstrate that Forms B and A 1) have several different properties, and 2) have such properties. 3) Form A is readily identifiable and distinguishable from one another based on their sex; and and as discussed in the following aspects and embodiments. 5) Form A is prepared from other forms of selpercatinib, including solvates and / or Form B. and / or establish that it can be converted.

[0054] Given the similar solubility between selpercatinib Form A and Form B, several preferred A variety of solvents may be used in accordance with aspects and embodiments of the present disclosure. In some embodiments, The solvent and / or process conditions may be such that the resulting crystalline form is predominantly Form A (e.g., pure or practical). It can be used and prepared in such a way that it can be in qualitatively pure form A).

[0055] As mentioned above, selpercatinib may form solvates and metastable solid forms. may form, both of which are generally not stable when dried. Solvates include acetone solvate, chloroform solvate, 1,4-dioxane solvate, Methyl ethyl ketone (MEK) solvate, dichloromethane (DCM) solvate, 2-butadiene 1-butanol solvate, 1-butanol solvate, ethanol solvate, dimethyl sulfoxide (DMSO)-water solvate, DMSO solvate, isopropyl alcohol This includes tetrahydrofuran (THF) solvates, tetrahydrofuran (IPA) solvates, and tetrahydrofuran (THF) solvates. Solvates and metastable forms usually revert to Form A during isolation and / or drying, but films or non-solvents Crystalline material may be formed. Chloroform and 1,4-dioxane solvates are It was stable upon isolation / drying. Therefore, it was one of the methods for preparing selpercatinib form A. The strategy converts amorphous selpercatinib and / or selpercatinib Form B into a solvate. and then desolvating the solvate to obtain Form A.

[0056] In an embodiment of the method described herein for preparing Form A, selpercatinib may contain an amount of Form B and / or an amount of Form A.

[0057] In one aspect, selpercatinib Form A is described herein. The crystalline form of is useful in the treatment of disorders associated with abnormal RET activity, such as IBS or cancer, particularly hyperactivity. It is used to treat cancers caused by abnormal RET signaling (i.e., RET-associated cancers). More specifically, this crystalline form of selpercatinib may be used to treat lung cancer (e.g., small cell lung cancer). 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 tumors, lung adenocarcinoma, bronchiolopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (or MEN2A or MEN2B, respectively, pheochromocytoma, parathyroid hyperplasia, breast cancer cer, breast cancer, mammary carcinoma, breast tumor, colorectal Cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, inflammation It is used to treat RET-related cancers such as myofibroblastic tumors or cervical cancer. obtain.

[0058] Form A is a compound that can be used to treat cancer, comprising administering an effective amount of Form A to a patient in need thereof. can be used in methods for treating, The types of cancer that can be treated using Form B include blood cancers or solid tumor cancers. Examples of types of cancer 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 (or MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, and colorectal cancer These include cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. Specifically, the type of cancer may be lung cancer or thyroid cancer. More specifically, the cancer may be non- It may be small cell lung cancer or medullary thyroid cancer.

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

[0060] Form A is useful 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 medicaments are described herein as The use of Form A in the manufacture of a medicament also involves the preparation of a biological sample from a patient. Perform an in vitro assay using the materials to detect the RET gene, RET kinase, or their determining the presence of dysregulation of the expression or activity or level of any of the RET gene , RET kinase, or dysregulation of the expression or activity or levels of any of them These may include administering to the patient a therapeutically effective amount of Form A when In use, the biological sample can be a tumor sample, and the tumor sample can be used for genome / DNA sequencing or other similar purposes. The assay can be performed using any method known to those skilled in the art. A sample can be obtained from the patient prior to the first administration of Form A. In this regard, as described herein, the therapy may be performed by determining whether the patient has a gene encoding the RET gene, RET kinase, or at least one of the dysregulation of expression, activity or level of any of them These uses may also be based on the selection for treatment by the presence of one or more of the following: In the present invention, Form A may be administered to a patient at a dose 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 contains an amount of thermodynamically stable The compound may contain the polymorphic selpercatinib form B. Both polymorphic forms are crystalline and highly melting point, anhydrous, stable, and readily compatible under typical storage or preparation conditions. Although not interconvertible, these polymorphs have different structures that allow Form A to be distinguished from Form B. The favorable thermodynamic stability difference between selpercatinib Form A and Form B Considering the above, from either form to the other (e.g., form B, as described below), It is necessary to understand how the two are transformed and produced (from Form A to Form B).

[0062] Crystallization Methods Providing Form A In one aspect, the present disclosure provides a method for producing selpercatinib from a mixture of forms (e.g., including selpercatinib form B). The composition of amorphous selpercatinib and / or other polymorphic forms thereof, including selpercatinib Form A, A method for preparing lupercatinib Form A is provided, which includes a method for converting lupercatinib. Selpercatinib Form A may be synthesized from other selpercatinib forms using a variety of different methods. Although other crystalline forms of serpercatini may be prepared or converted from these forms, the present disclosure does not include the use of other crystalline forms of serpercatini. Preparing or converting selpercatinib (e.g., including selpercatinib form B) to selpercatinib form A A crystallization-based method is disclosed.

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

[0064] In one embodiment, a mixture of selpercatinib containing Form B is converted to selpercatinib Form A. Disclosed herein are methods for:

[0065] In one embodiment, the method for converting amorphous selpercatinib to selpercatinib Form A comprises the steps of: Disclosed in the specification.

[0066] In another embodiment, selpercatinib in another form or mixture of other forms (e.g., Form B) may be administered. a method for converting selpercatinib Form A from a cell containing Form B, Combining percatinib with DMSO and water to form a slurry and extracting the slurry from the cells. and isolating percatinib form A.

[0067] In yet another embodiment, selpercatinib (e.g., Form B) is converted to selpercatinib Form A. 1. A method for converting, 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; And, c. isolating selpercatinib form A.

[0068] 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 selpercatinib, and The method includes heating a solvent containing DMSO to about 50°C to about 70°C. After heating the solution to about 50°C to about 70°C, the solution is cooled to a temperature lower than about 70°C and lower than about 20°C. In one embodiment, the solution is cooled to about 40° C. In another embodiment, or step b includes adding about 0.1 to about 1 mL / g of water to the solution; or Step b includes adding about 0.2 mL / g or less of water to the solution. Step b comprises 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 this embodiment, the addition of water to form the slurry in step b may involve adding two separate volumes of water: In one embodiment, the total DMSO:water ratio is 80:20 or less. Step c comprises filtration. The selpercatinib form A isolated from step c is filtered using MTB. Wash with a solvent containing E and / or water.

[0069] In yet another embodiment, selpercatinib (e.g., Form B) is converted to selpercatinib Form A. 1. A method for converting, the method comprising: a. dissolving selpercatinib in a solvent comprising DMSO to form a solution; b. Add the selpercatinib / DMSO solution to a water or DMSO / water solution, Thus, forming a slurry comprising 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 selpercatinib, and The method includes heating a solvent containing DMSO to about 50°C to about 70°C. After heating the solution to about 50°C to about 70°C, the solution is cooled to a temperature lower than about 70°C and lower than about 20°C. In one embodiment, the solution is cooled to about 40° C. In another embodiment, Step b: Add the solution from step a to at least 1 volume of water or DMSO / water. In some embodiments, step b comprises adding about 1 to about 15% by weight of Form A. In one embodiment, the slurry further comprises adding seed crystals or about 1% by weight of Form A seed crystals. The solution is cooled to about 0° C. In one embodiment, at the end of step b, the ratio of DMSO:water is is about 80:20. In one embodiment, step c includes filtration. The isolated selpercatinib form A is washed with a solvent comprising MTBE and / or water.

[0071] In another embodiment, selpercatinib (e.g., Form B) is converted to selpercatinib Form A. 1. A method for producing a medicament for use in a method for producing a medicament for a patient, the method comprising: a. Dissolving selpercatinib in a solvent containing DMSO to form a solution (Supply 1) And, b. Preparing a water or DMSO / water solution (Supply 2); c. The selpercatinib / DMSO solution (Feed 1) was added simultaneously with Feed 2 in water or DMSO. SO / water solution, thereby forming a slurry containing selpercatinib Form A. To do, d. isolating selpercatinib form A.

[0072] In another embodiment, selpercatinib (e.g., selpercatinib comprising Form B) is converted to Form A. 1. A process for converting selpercatinib into and adding heptane to the solution under conditions to form a slurry. and optionally, subjecting the slurry to conditions effective to form selpercatinib Form A. and isolating selpercatinib form A. In one embodiment, about 1 gram of selpercatinib is added to about 25 to 35 mL of In one embodiment, forming the solution of step a comprises dissolving the solution in dichloromethane. Heat the solvent containing percatinib and dichloromethane to about 30°C to about 40°C. In a further embodiment, step b comprises: In some embodiments, the addition of heptane comprises adding 1 g of heptane. a first volume of heptane in an amount of about 8-12 mL per selpercatinib, and about 8-12 m In one embodiment, step b comprises adding a second volume of heptane in an amount of 1 L / g. the solution 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 is stirred for at least about 8 hours. may also include:

[0073] A variety of different solvents may be used to prepare Form A and / or different compositions of selpercatinib. A form (e.g., form B) can be converted to form A. Some forms and embodiments In the method, a solvent may be combined with selpercatinib to form a solvate. Form A is prepared by: and / or used to convert other selpercatinib forms (e.g., Form B) to Form A. Examples of solvents that can be used include, but are not limited to, C1 to C6 alcohols (e.g., meth alcohol or ethanol), water, acetonitrile (ACN), methyl t methyl tert-butyl ether (MTBE), dichloromethane (D CM), heptane, n-butyl acetate (n-BuOAC), 81% A CN-MeOH (81 mL ACN combined with 19 mL MeOH), wet ethyl acetate Cyclopentyl methyl ether (CPME), 1,2- Dimethoxyethane, ethyl acetate, ethyl formate, methyl isobutyl ketone (MIBK), Tromethane, n-propyl acetate (NPA), 1-pentanol, toluene Ene, 1:1 MeOH:water, 1:1 EtOH:water, ACN:water, DCM / heptane mixture DMSO / heptane mixture, or DMSO / water mixture. When C1-C6 alcohols such as ethanol are used, Form B is converted to Form A. However, this can also result in the formation of Form B. As shown in more detail below, C1-C6 Washing Form A with alcohol can lead to the formation of Form B. 6 When using alcohol to wash Form A, it is preferable to use cold C1 to C6.

[0074] Surprisingly and unexpectedly, Form B material was found to be soluble during washing and drying of Form A material. It has been found that Form B material can be formed. The following washing and drying protocol was developed: After solvation, heptane or MT The solvate is washed using a solvent such as BE, and then the resulting cake is In one embodiment, the cake is dried under high vacuum. For example, drying the Form A cake under high vacuum may allow for the use of lower drying temperatures. In this case, a temperature of about 40-45°C may be used. Heptane and MTBE may be added individually or May be used sequentially. Excessive temperature and / or excessive drying time are kinetic products. This allows for the conversion of Form A, which is a thermodynamic product, to Form B.

[0075] The inventors have found that Form A wet cake can be dried at 45° C. and ambient pressure for several days. It has been found that Form A slowly converts to Form B. Drying under high vacuum and / or The use of MTBE as a final wash reduces drying time and reduces, if not prevents, morphology. In one preferred embodiment, Form A material is dissolved in MTBE or heptane. and then dried under high vacuum at a temperature of about 40 to about 45°C.

[0076] Additionally, we have demonstrated that Form A cake can be prepared using water, MeOH, and finally MTBE. The resulting cake is then dried under high vacuum to remove up to about 20% by weight of Form B material. Without wishing to be bound by theory, it was found that MeOH Washing with HCl is believed to accelerate the formation of Form B material.

[0077] In some embodiments, the methods and processes for preparing Form A include C1-C4 alkyl acrylates. Alcohol, water, DCM, DMSO, MTBE, ACN, and mixtures of two or more of these In yet another embodiment of such a method, the solvent may include, but is not limited to, a solvent. is methanol, ethanol, water, DMSO, MTBE, ACN, or two or more of these In yet a further embodiment of such a method, the solvent comprises a mixture of DCM, heptane , DMSO, water, MTBE, or a mixture of two or more thereof.

[0078] In various embodiments, the methods include administering selpercatinib (e.g., selpercatinib) containing an amount of Form B. selpercatinib) and a solvent, and optionally, obtaining Form B containing selpercatinib. and heating the resulting mixture while stirring or mixing until dissolved in the solvent. Once a solution is formed, the mixture may be filtered if any insoluble impurities are to be removed. Often, the reaction is carried out at a temperature slightly above room temperature or at room temperature (e.g., depending on the solvent used). The mixture may be cooled to about 25-40°C. Additional solvent may be added during or after cooling. stomach.

[0079] In some embodiments of these aspects, the solvent comprises DMSO, and during the cooling step or After the cooling step, water is added to the solution. A certain amount of water is added to the cooled solution. and seed crystals containing selpercatinib, either in dry form or as a slurry in a minimal volume of liquid. The incubation period (e.g., After the water is added, the mixture is cooled to about 0°C. Once the target temperature is reached, the slurry or mixture is left to cool for a certain period of time. After the incubation period, the resulting solid product is The resulting selpercatinib Form A material is isolated and, optionally, washed to remove residual water and DNS. The contents of M are removed. Examples of washing solvents include, but are not limited to, heptane and MTBE. After washing, the Form A material is heated at a temperature of about 40 to about 60°C, at a pressure of up to atmospheric pressure. The drying may be carried out at sub-atmospheric pressures, including atmospheric pressures. In a preferred embodiment, the pressure is is less than.

[0080] In some alternative embodiments of these embodiments, the solvent is a solvent for selpercatinib Form A. In some embodiments, the solvent comprises dichloromethane; Heptane is added to the solution, and once the heptane is added, the mixture is cooled (e.g., to about room temperature / After the initial cooling, additional heptane was added and the resulting mixture was allowed to cool to room temperature / 25°C. Stir at 0°C for a certain period of time (for example, at least 8 hours). The Form A material is isolated and optionally washed to remove residual dichloromethane.

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

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

[0083] temperature The temperature affects the rate at which initial selpercatinib (e.g., containing Form B) is converted to Form A. In some embodiments, a mixture comprising selpercatinib and a solvent may affect 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 about 50 to 110°C, or about 50 to about 70°C. In some embodiments, the mixture is heated to a temperature of about 50° C., about 60° C., about 70° C. The mixture may be heated to about 80°C, about 90°C, about 100°C, or about 110°C. Heat to the desired temperature to dissolve the starting selpercatinib (including Form B) material, and then add the solution. The temperature 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 embodiments, the solution is cooled to a temperature below about 70° C. and above about 20° C. In some embodiments, the temperature is 50°C (e.g., about 45°C, 44°C, 43°C, 42°C, 41°C, 4 In some embodiments, the solution is cooled to below 0°C, 39°C, 38°C, or about 37°C. Cooling is at about 5°C / h, 10°C / h, 15°C / h, 20°C / h, 25°C / h, or about 30°C / h. h for a set period of time (i.e., controlled cooling).

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

[0085] In some alternative embodiments, the solvent does not need to be heated to the high temperatures indicated above. Alternatively, selpercatinib may be mixed with a solvent (e.g., dichloromethane) and heated at ambient temperature. The temperature is slightly higher than the normal temperature (e.g., about 35°C, about 40-50°C), but the cell permeability is In some embodiments, the temperature is The kinetically stable form of selpercatinib (Form A) is preferred, as it exhibits a high kinetic turnover rate. In such an embodiment, the temperature is selected to reduce the likelihood of The temperature may be selected towards the lower end of the specified temperature range (eg, 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 this embodiment, the addition of an anti-solvent (e.g., heptane or water, depending on the initial solvent used) It may involve multiple additions (e.g., added in portions) of separate volumes of anti-solvent. In embodiments involving the addition of about 0.1 to 1.0 m of water, when the first portion of water is added to the solution, L / g, or about 0.2-0.6 mL / g, or about 0.3 mL / g, or about 0.4 mL / g Add about 0.5 mL / g, or about 0.6 mL / g of water to Form A (Celpercati (The number of grams of nib (e.g., Form B) per mL of water). In other words, the first The addition is about 0.1 to about 1.0 volumes of water (i.e., based on the weight of selpercatinib). In some embodiments, the first portion of water may comprise about 0.3 mL / g, about Add in an amount of 0.4 mL / g, about 0.5 mL / g or about 0.6 mL / g.

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

[0088] In other embodiments involving an anti-solvent other than water (e.g., heptane), the addition of the first portion may be Typically, a larger volume is typically used to form the selpercatinib solution. The amount is approximately 30-60% of the total volume of the initial solvent.

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

[0090] In some embodiments, the temperature at which the seeding occurs is selected to provide a kinetically stable temperature for selpercatinib. A suitable form (Form A) is preferred and is selected to reduce the likelihood of kinetic turnover. In such embodiments, the temperature is at the lower end of the above-specified temperature range (e.g., about 4 0°C).

[0091] The seed crystals were prepared as described in A. Cote, E. Sirota, A. Moment, "The Pur uit of a Robust Approach for Growing Cry stals Directly to Target Size” American P pharmaceutical review-The Review of Ameri can Pharmaceutical Business & Technology ,2010, and DJLamberto et.al., “Crystalliza tion Process Development for the Final S step of the Biocatalytic Synthesis of Isl atravir:Comprehensive Crystal Engineerin g for a Low-Dose Drug,” Organic Process R esearch & Development 2021 25(2),308-317 They can be prepared using methods known in the art, such as those described in Example 1. For example, the seed crystal may comprise, for example, an optically or polymorphically pure material, e.g., pure Celperca. The compound may be prepared, obtained, and / or isolated from a source of purified material containing tinib form A. In some embodiments, the seed crystals may be obtained from a previous source of seed crystals or may be obtained from a previous source. In yet some other embodiments, the seed crystals may be, for example, homogeneous seed crystal material. may be processed to provide the desired D 50 , D 90 Diameter of crystal size In some embodiments, the seed crystals are about 1 um to about 10 um (e.g., , about 1, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 μm) 90 It may contain stomach.

[0092] Seed crystal incubation time initial heating and cooling of a mixture containing starting selpercatinib (e.g., Form A); and After addition of seed crystals, if present, the solution is stirred for about 30-300 minutes, or for about 30-1 Incubate for 80 minutes, or for about 30 to 120 minutes, or for 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 Target incubation temperature: about 35°C to about 50°C, or about 35°C to about 45°C, or about 40°C Once the target incubation temperature has equilibrated, boil the second portion of water. The amount of water in the second portion is determined based on the amount of initial selpercatinib material added. about 0.1 to 3 mL / g, or about 1.0 to 2.5 mL / g, or about 1.1 mL / g, or about 1.2mL / g, 1.3mL / g, approx. 1.4mL / g, 1.5mL / g, approx. 1.6mL / g, 1.7mL / g, approx. 1.8mL / g, 1.9mL / g, approx. 2.0mL / g, approx. 2.1 mL / g, approx. 2.2mL / g, 2.3mL / g, approx. 2.4mL / g, 2.5mL / g, approx. 2.6 mL / g, 2.7 mL / g, about 2.8 mL / g, 2.9 mL / g, or about 3.0 m L / g of water (mL of water per g of selpercatinib (e.g., Form B)). In other words, the second addition of water (i.e., based on the weight of selpercatinib) ) about 0.1 to about 3.0 volumes of water. In some embodiments, the first part The water content was approximately 2.0mL / g, 2.1mL / g, 2.2mL / g, 2.3mL / g, and 2. In some embodiments, the amount is 4 mL / g, 2.5 mL / g, or about 2.6 mL / g. Now add the second portion of water at 2.5 volumes. After the second portion of water is added, The resulting amount of water in the resulting solution is approximately 80:20 (solvent:water, by volume).

[0094] The second portion of water is added over a period of time, typically from about 10 minutes to about 5 hours, or about 4 hours, about 3 hours, about 2 hours, about 30 to 90 minutes, about 45 to 60 minutes, or about 60 minutes Add at a slow rate between addition and the time required. Longer times may be used if necessary. As shown in Figure 1, the addition of the second portion of water is typically in the range of about 90:10 to about 75:25 ( Final solvent to water ratio (e.g., 90:10, 85:15, 80:20, 75:25) It is effective in providing (by volume).

[0095] In some other embodiments, the method does not include the addition of seed crystals, and the addition of an anti-solvent is Some of these other embodiments are effective to form lupercatinib Form A products. In either case, after the addition of the first portion of the anti-solvent, the mixture is brought to a target temperature (e.g., to ambient temperature). Cooling may be allowed to occur, and once the target temperature is reached, the second portion of the anti-solvent may be added to the selpercatinib Form A. in an amount (e.g., a volume about equal to the antisolvent of the first portion) effective to form In such an embodiment, after the addition of the second portion of the anti-solvent, the mixture is added to the crystallized cell. It may be incubated with stirring for a period of time to provide percatinib Form A.

[0096] cooling In some embodiments, after the second portion of water is added, the mixture is stirred for a period of time. The mixture is cooled to a temperature of about 0° C. to form a slurry. Cool to °C and maintain at that target temperature for at least about 60 minutes (e.g., about 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 290, 300, 310, 320, 330, 340, 350, 0, 100, 110, or approximately 120 minutes).

[0097] After the second portion of water is added, the mixture is heated at a rate of approximately 1 to 30°C / hour until the desired temperature is reached. Cool at a rate between about 10 and 30°C / hour, for example, or at a rate of about 20°C / hour. In one embodiment, the cooling rate is about 10°C / hr, about 11°C / hr, or about 12°C / hr. 13°C / hour, 14°C / hour, 15°C / hour, 16°C / hour, 17°C / hour The heating rate is 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, the separation comprises gravity filtration. In another embodiment, the separation comprises high vacuum filtration. In yet another embodiment, the separation comprises the use of centrifugation.

[0099] Ethanol, methanol, ACN, MTBE, water, or a combination of two or more of these Fresh solvent such as ethanol may be used to wash the Form A material. When alcohol and / or methanol are used to wash Form A material, they are preferably used at low temperatures, e.g. , should be 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 is used to remove any residual solvents (e.g., , DMSO / water) may be washed to obtain the final Form A material. The fresh solvent is heated to a temperature of about 0°C to less than about 20°C before being used to wash the Form A material. In these embodiments, the final wash solvent may be a volatile solvent (e.g., MT BE), which reduces solvent retention in the filter cake and shortens the drying time required. The use of a volatile solvent also allows for the use of lower temperatures, which is beneficial for Form B. Helps reduce, if not prevent, the formation of materials. Excessive drying time and / or temperature may cause the formation of Form B.

[0100] Isolated selpercatinib form A can be dried using methods known in the art. Typical methods include heating, passing an inert gas over the solid, and / or This includes the use of sub-atmospheric pressure. In one embodiment, drying under sub-atmospheric pressure is preferred. It's nice.

[0101] In embodiments where the solvent comprises DMSO and / or DMSO / water, the isolated serpentine Selpercatinib Form A was prepared by dissolving isolated selpercatinib Form A in less than 0.5% by weight of DMSO (or The solution may be washed with MTBE until it contains DMSO / water.

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

[0103] In embodiments relating to Form A, the selpercatinib provided by the present disclosure may be free from other polymorphs and and / or amorphous forms (e.g., Form B) of selpercatinib. It can demonstrate biological stability.

[0104] In any of the aspects and embodiments provided herein, the security provided by the present disclosure Lupercatinib may be prepared as the free amine. The methods described herein comprise: To prepare a particular crystalline form of selpercatinib (e.g., selpercatinib form A). and such forms are used in the manufacture of selpercatinib according to aspects and embodiments of the present disclosure. (i.e., directly from amorphous selpercatinib or another polymorphic form of selpercatinib) Whether obtained by synthetic methods or transformations, it furthermore It may be provided as an acceptable salt or a pharmaceutical composition thereof. Such compounds, salts, and compositions may contain other polymorphic and / or amorphous forms of Serpel. containing crystalline selpercatinib, which may exhibit higher thermodynamic stability compared to selpercatinib. or compared to other polymorphic and / or amorphous forms of selpercatinib. Either Form A or Form B of serpercatini can exhibit higher kinetic stability. The ribonucleotides retain their activity as RET inhibitors and are described, for example, in PCT International Publication No. 2014 / 014144. No. 8 / 071447 and U.S. Patent Application Publication No. 2018 / 0134702. Activity is assessed by any assay known in the art, including assays that can be assessed, each of which is incorporated by reference in its entirety. In the present invention, selpercatinib Form A is a tosylate or besylate salt. When the Form A material is a salt, the salt is a tosylate salt.

[0105] The present specification also provides a method for producing a cell pellet produced by any of the methods disclosed herein. Also disclosed is a pharmaceutical composition comprising lucatinib Form A. The pharmaceutical compound comprises at least one It may further comprise a pharmaceutically acceptable carrier, diluent or excipient. or the pharmaceutical composition contains less than about 20% by weight of other crystalline forms of selpercatinib; or containing less than about 10% by weight of other crystalline forms of selpercatinib, or about 5% by weight The pharmaceutical composition contains less than about 40 mg or about 8 mg of other crystalline forms of selpercatinib. Other pharmaceutical compositions contain about 120 mg or about 100 mg of selpercatinib Form A. It contains 60 mg of selpercatinib Form A. The pharmaceutical formulation may be a tablet. Alternatively, the pharmaceutical formulation may be a capsule.

[0106] Further provided herein are methods of treating cancer in a patient in need of such treatment. administering to a patient in need thereof an effective amount of a compound prepared according to any of the methods disclosed herein. selpercatinib Form A, or a pharmaceutical composition described herein. In a preferred embodiment, the cancer is a RET-associated cancer. Cancers that respond to RET inhibition.

[0107] In one embodiment, Form A and the compositions described herein can be used to treat Cancers include solid tumors, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, and recurrent refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or type 2B (respectively MEN2A or MEN2B), 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. Lung cancer is classified into small cell lung cancer, non-small cell lung cancer, bronchiolopulmonary cancer, and RET fusion cancer. 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 embodiments, the solid tumor has progressed during or following prior systemic therapy. or locally advanced disease with RET gene fusions that have no satisfactory alternative treatment options or a metastatic solid tumor. In another embodiment, the cancer is detected by an FDA-approved test. Locally progressive or locally advanced leukemia with recurrent transfection (RET) gene fusions, such as is metastatic non-small cell lung cancer (NSCLC). In this embodiment, the cancer requires systemic therapy and (when radioactive iodine is appropriate) ) a gene encoding the RET gene, as detected by an FDA-approved test, that is radioactive iodine refractory Advanced or metastatic thyroid cancer with fusions.

[0108] The following examples are within the scope of the methods described and claimed herein. It is provided only for purposes of illustrating and describing particular embodiments. [Example]

[0109] Selpercatinib (6-(2-hydroxy- 2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)methyl 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-3- (I)pyrazolo[1,5-a]pyridine-3-carbonitrile) is disclosed in U.S. Pat. The polymer was prepared using the techniques and methods described in US Pat. No. 12,942.

[0110] Example 1: Gram-scale cooling crystallization process to produce Form A A chemical synthesis reactor (Easymax, Mettler Toledo) was used. 5 g of selpercatinib was added to a reactor along with (11 volumes) of DMSO, and the selpercatinib was added to a reactor. Heat at 70°C until the catinib dissolves and the system reaches the target temperature of 70°C. The solution may optionally be polish filtered before being transferred to the crystallizer through a transfer line. The reactor and transfer lines are rinsed with (1 volume) DMSO and charged to the crystallizer. Combine with the lupercatinib solution. Cool the resulting solution to 40°C over 1.5 hours. Once the target temperature of 40 °C is reached, add approximately 0.5 volumes of water for 5 min to avoid self-seeding. Slowly add (above the surface) to the crystallizer over a period of 10 minutes to obtain approximately 96:4 DMSO:water ( 1% by weight of selpercatinib form A seed crystals (D90 is The solution is seeded by adding dry seeds (approximately 7 μm). or added as a slurry in a minimum volume of 80:20 DMSO:water (by volume) Incubate the seeded solution for approximately 30 minutes. After addition, 2.5 volumes of room temperature water are added over 1 hour. Upon completion of the water addition, the composition is It has a solvent ratio of approximately 80:20 DMSO:water (by volume).

[0111] Immediately after adding 2.5 volumes of water, the reactor was cooled to 0°C over a period of 2 hours. (at a rate of 20°C / hour). Once at 0°C, maintain the temperature of the slurry at 0°C for 1 hour. The solids are filtered, optionally cold, at a rate that maintains a wet filter cake. The filtered solid is dissolved in a first solution of 8 volumes of DMSO / water (80 / 20, by volume). The dried cake is washed with a further 8 volumes of a second wash solution and the cake is filtered and dried. Wash with a water wash solution, filter and dry. Add the dried cake to the mixture with stirring (e.g., 3 Add another 8 volumes of water for 0-60 seconds to resuspend the solid cake material. Continue until the amount of residual DMSO detected in the sample is 0.5% or less. Once the threshold is reached, wash the filter cake with 8 volumes of MTBE to displace the water. An optional additional displacement wash using E (8 volumes) is performed to remove residual moisture in the solid material. The amount may be further reduced. The obtained solid selpercatinib Form A is passed through a dryer under high vacuum. The resulting selpercatinib was dried at 45°C under a slight stream of nitrogen. , containing 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 Seth A chemical synthesis reactor (Easymax, Mettler Toledo) was used. 6 g of selpercatinib was added to a reactor along with (11 volumes) of degassed DMSO, Heat at 70°C under N2 until selpercatinib is dissolved and the system reaches the target temperature of 70°C. The reactor was charged with additional DMSO (1 volume). The resulting solution was stirred for 1.5 hours. Once the target temperature of 40°C is reached, 0.5 volumes of water are added to the flask to allow for self-seeding. Add slowly to the crystallizer (above the surface) over 5 minutes to avoid Provide a solvent ratio of DMSO:water (by volume) of 4. 1% by weight of selpercatinib form Seed the solution by adding seed crystals A. Let the seeded solution stand for approximately 30 minutes. Incubate for 30 minutes. After the 30 minute incubation, add 2.5 volumes of room temperature water for 1 hour. Immediately after the 2.5 volumes of water are added, the reactor is heated to 100°C for a period of 2 hours. Once at 0°C, the temperature of the slurry is maintained at 0°C for 1 hour. Transfer the contents from the container to a 10 micron disposable filter and drain thoroughly. The solids are then pumped under high vacuum (e.g., for 20 minutes). The filtered solids are then added to 8 volumes of D Wash with a first wash solution of MSO / water (80 / 20 by volume), filter the cake and dry it. The dried cake is washed with a second 8 volumes of water wash solution, filtered and dried. To the dried cake, add 8 volumes of water while stirring (e.g., for 10-30 seconds) to obtain a solid Resuspend the cake material. Isolate the solids by filtration. Add the dried cake with stirring ( Add 8 volumes of MTBE (e.g., 30 seconds) to resuspend the solid cake material. Isolate by filtration. An optional additional displacement wash using MTBE is performed to remove the solids. The residual water content in the material may be further reduced. The resulting solid selpercatinib Form A may be further reduced. Dry at 60°C under pressure with a slight nitrogen gas flow through the oven.

[0113] Using the methodology described above, a series of seven experiments were performed, all under baseline conditions, as shown in Table 2. In summary, any baseline process variability was identified. Two of the experiments were performed batch-by-batch. The results are from seeding experiments (032 and 033) with different starting material qualities, The quantity / quality and overall size of Form B in the seed crystals were used. Values ​​in italics indicate the respective The HPLC integrals of some known impurities present in the starting material used in the experiment are shown. The first set of impurity integrals for the in represents the impurity profile of the starting material, and the second Set 2 is the impurity profile of the isolated solid after crystallization.

[0114] [Table 2] 14-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridinyl Lysyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pi Lysine-3-carboxamide. 2 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridinyl Lysyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pi Lysine-3-carbonitrile. 3 4-[6-(6-ethyl-3,6-diazabicyclo[3.1.1]heptane-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 6 μm . (b) The seed was a single lot containing 3.3% Form B and having a d90 of 29 μm. Ta. (b1) The seed contains form B of ND, but is a single lot with a d90 of 67 μm. It was. 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 enhance growth and secondary nucleation of the desired form. This can reduce variability from non-seeding processes that rely on primary nucleation, for example. Seed crystal specifications can be used to control the amount of Form B content that is acceptable within the seed. This can be done.

[0117] Example 3: Reverse Addition Process for Direct Isolation of Form A DMSO was saturated with excess Form B at room temperature. From this slurry, the liquid 25 mL of saturated DMSO solution was taken in a syringe and added to 20°C water (approximately 63 / 37 D The solution was added at 1 mL / min to a pot containing 15 mL of HCl (MSO / H2O). Upon completion of the addition, a sample of the solid was taken and XRPD analysis showed that the It was found that form B was not detected. SO / HO ratio) is 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 The experiments were carried out using pure DMSO / water solvent systems, which were simultaneously added to pots containing seed beds in the corresponding DMSO / water solvent systems. By using pure selpercatinib / DMSO and water feed streams, the crystallization mixture The solvent composition of the mixture was either 80 / 20% or 90 / 10% by volume of DMSO / water. The simultaneous addition is designed to maintain the 80 / 20 process. The explanation is as follows:

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

[0120] Dissolve 1 equivalent basis of API (can be Form A or Form B) in 12 volumes of DMSO The API feed is prepared by heating to 65°C to obtain a solution. The feed was collected in an injection syringe. This feed should be kept at an elevated temperature to prevent crystallization. However, on short timescales of hours, it can be cooled to room temperature without crystallization. .

[0121] 3.2 volumes of DMSO, 0.8 volumes of water (80 / 20 ratio, suitable for stirring) Prepare the crystallizer pot by adding 100 ml of water (target volume) and keep the temperature at 20°C. Allow to equilibrate. Add 1 wt% (optional) Form A seeds and begin stirring.

[0122] Simultaneous addition was then initiated by feeding both feeds over a 4 hour period, with the volume The flow rate and volume are 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, with results for morphological purity. Some of the experiments were conducted in order to test the robustness of the conditions. A mixture of Form A and Form B species was utilized.

[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 of a different lot compared to (c). Form B was used. 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-pyridinyl Lysyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pi Lysine-3-carboxamide. 2 4-[6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-pyridinyl Lysyl]-6-(2-hydroxy-2-methyl-propoxy)pyrazolo[1,5-a]pi Lysine-3-carbonitrile. 3 4-[6-(6-ethyl-3,6-diazabicyclo[3.1.1]heptane-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 was more efficient than the 90 / 10 condition due to the higher supersaturation level. It has been shown that 50 / 50 or 20 / 80 provides better Form A control. Higher water / DMSO ratios such as DMSO may also be used to ensure high Form A purity. The simultaneous addition conditions shown can also be used with continuous feeding and removal of the slurry. This is a representative example of a continuous crystallization process that can be performed.

[0127] Example 5: Solvate preparation and conversion process Selpercatinib can form solvates with solvent molecules, most of which are In this example, Form A of selpercatinib is dissolved in dichloromethane (D CM) solvate.

[0128] In a reaction vessel, selpercatinib (0.8751 g, API) and water-saturated DCM (29 Mix and heat (35°C) to dissolve. Alternatively, use a Similar results can be achieved using the same volume of DCM as the solvent. Once the catinib has dissolved, add heptane (10 volumes) over 30 minutes. Addition of heptane After this is complete, the mixture is cooled to a target temperature of 25°C over 30 minutes. Then, add the second portion of heptane (10 volumes) to the mixture over 30 minutes. After the addition of heptane is complete, the mixture is stirred at ambient temperature (25° C.) for at least 8 hours. The resulting solid was isolated and washed (once with 4 volumes of heptane, and twice with 4 volumes of MTBE). Wash 2) and dry 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 a solvate is This appears to eliminate any dependence on crystal form or influence from seed crystal form.

[0130] Provided herein is a compound of formula I, wherein the compound of formula I is in the form of at least about 90% by weight. A compound of formula I is prepared by adding selpercatinib to DMSO to form a mixture; The mixture is heated to approximately 50-70°C to dissolve the selpercatinib, thereby forming a solution. The solution is cooled to about 40°C, and then the first and second batches of water are added. The compound of formula I is obtained by: 0.5 volumes of water, optionally in a selpercatinib / DMSO / water mixture. A second batch of water, about 2.5 volumes of water, seeded with seed crystals, was added, and the mixture was then Cool to about 0°C and isolate selpercatinib Form A. After adding the first batch of water The DMSO:water ratio is about 96:4. A second batch of water, e.g., 2.5 volumes of water, is added. After addition, the ratio of DMSO:water is about 80:20. Wash with DMSO:water (80:20), filter, dry and add 8 volumes of DMSO:water ( The cake is washed with water (80:20), filtered again and dried. The cake is then suspended in about 8 volumes of water. This process is continued until the amount of residual DMSO detected in the sample is 0.5% or less. The process is repeated. The filter cake is then washed with about 8 volumes of MTBE for at least 1 minute. Selpercatinib Form A is then dried under high vacuum at a temperature of about 45° C. do.

[0131] Embodiment Embodiment 1. A method for converting selpercatinib to selpercatinib Form A, comprising: a) Dissolving selpercatinib in a solvent containing DMSO, thereby forming a DMSO solution; b) adding water to the selpercatinib DMSO solution to form a slurry; c) isolating the 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 is in an amount of about 4 0.9, 9.7, and 15.5° 2θ.

[0132] Embodiment 2. A method for converting selpercatinib to selpercatinib form A. The method is as follows: a) Dissolving selpercatinib in a solvent containing DMSO, thereby forming a DMSO solution; b) adding water to the selpercatinib DMSO solution to form a slurry; c) isolating the 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. Dissolve about 1 gram of selpercatinib in about 10-15 mL of DMSO. 3. The method of embodiment 2.

[0134] Embodiment 4. Step a comprises heating DMSO and selpercatinib to a temperature of about 50 to 70°C. 4. The method of claim 2 or 3, comprising heating at .

[0135] Embodiment 5. Step b includes adding a first batch of water and a second batch of water. 5. The method of any one of embodiments 2 to 4, comprising:

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

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

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

[0139] Embodiment 9. Adding a second batch of water and cooling the DMSO:water to about 0°C 9. The method of any one of embodiments 5 to 8, comprising: How to post.

[0140] Embodiment 10. Step b includes adding about 0.1 to about 1 mL / g of water to the solution. 10. The method according to any one of embodiments 2 to 9.

[0141] Embodiment 11. Step b comprises adding about 0.2 mL / g or less of water to the solution. 11. The method according to any one of embodiments 2 to 10.

[0142] Embodiment 12. A method for producing a selpercatinib seed crystal preparation, further comprising adding selpercatinib seed crystals to DMSO:water. The method according to any one of embodiments 2 to 11.

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

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

[0145] Embodiment 15. Selpercatinib seed crystals are added before the second batch of water is added. 15. The method of any one of embodiments 12 to 14, comprising:

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

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

[0148] Embodiment 18. Selpercatinib Form A isolated from step c is treated with MTBE and / or or the method according to any one of embodiments 2 to 17, comprising washing with a solvent comprising water. .

[0149] Embodiment 19. The method of any one of embodiments 2 to 1, further comprising drying selpercatinib form A. 8. A method according to any one of claims 1 to 8.

[0150] Embodiment 20. A method for converting selpercatinib to selpercatinib form A. Well, this method is 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 is in an amount of about 4 0.9, 9.7, and 15.5° 2θ.

[0151] Embodiment 21. About 1 gram of selpercatinib in about 25-35 mL of dichloromethane 21. The method of embodiment 20, wherein the dissolving

[0152] Embodiment 22. Step a comprises dissolving selpercatinib and a solvent comprising dichloromethane in a distilled water solution for about 3 hours. 22. The method of any one of embodiments 20-21, comprising heating to 0-40°C.

[0153] Embodiment 23. Step b comprises mixing a first batch of heptane and a second batch of heptane. 23. The method of any one of embodiments 20 to 22, comprising adding:

[0154] Embodiment 24. The first batch of heptane contains about 8 to 12 heptane per gram of selpercatinib. mL of heptane.

[0155] Embodiment 25. The second batch of heptane is about 8-12 per gram of selpercatinib. 25. The method of embodiment 23 or 24, comprising mL of heptane.

[0156] Embodiment 26. Step b: Cooling to a temperature lower than about 30°C and higher than about 20°C 26. The method of any one of embodiments 20 to 25, comprising:

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

[0158] Embodiment 28. Embodiment 20, wherein step b comprises stirring for at least about 8 hours. 27. A method according to any one of claims 1 to 27.

[0159] Embodiment 29. A selpercatinib formulation prepared according to any one of embodiments 1 to 28. A pharmaceutical composition comprising:

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

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

[0162] Embodiment 32. The composition contains less than about 10% by weight of other crystalline forms of selpercatinib. 31. The pharmaceutical composition according to embodiment 29 or 30,

[0163] Embodiment 33. The composition contains less than about 5% by weight of other crystalline forms of selpercatinib. 31. The pharmaceutical composition according to embodiment 29 or 30,

[0164] Embodiment 34. An embodiment in which the composition comprising selpercatinib form A is substantially pure. 31. The pharmaceutical composition according to aspect 29 or 30.

[0165] Embodiment 35. A method of treating cancer in a patient in need of such treatment. administering to a patient having the condition an effective amount of a selpercatinib formulation prepared according to any of embodiments 1 to 28. A method comprising administering a pharmaceutical composition according to any one of embodiments A, B, C, C, D, E, E, F ... Law.

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

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

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

[0169] Embodiment 39. The cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, cytoplasmic lung cancer, 38. The method of embodiment 37, wherein the cancer is bronchial lung cancer, 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 solid tumor is a locally advanced or metastatic solid tumor. is the method described in 40.

[0172] Embodiment 42. The solid tumor has progressed during or following previous systemic therapy. locally advanced disease with RET gene fusions that are either unresponsive or have no satisfactory alternative treatment options 42. The method of embodiment 41, wherein the tumor is a primary or metastatic solid tumor.

[0173] Embodiment 43. The cancer is a transfected cancer, as detected by an FDA-approved test. Locally advanced or metastatic non-small cell lung cancer (NSCLC) with retrograde transcriptional rearrangement (RET) gene fusions 37. The method of embodiment 35 or 36, wherein the IL-16 is a CLC.

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

[0175] Embodiment 45. The pharmaceutical composition contains about 40 mg of selpercatinib form A. 45. The method of any one of aspects 35 to 44.

[0176] Embodiment 46. The pharmaceutical composition contains about 80 mg of selpercatinib form A. 45. The method of any one of aspects 35 to 44.

[0177] Embodiment 47. A pharmaceutical composition comprising about 120 mg of selpercatinib form A. The method according to any one of embodiments 35 to 44.

[0178] Embodiment 48. A pharmaceutical composition comprising about 160 mg of selpercatinib form A. The method according to any one of embodiments 35 to 44.

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

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

[0181] Embodiment 51. A pharmaceutical composition comprising at least about 80 % by weight of selpercatinib Form A, or a pharmaceutically acceptable salt thereof, , comprising selpercatinib form A made according to any one of embodiments 1 to 50. Pharmaceutical compositions.

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

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

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

[0185] Embodiment 55. The composition contains less than about 5% by weight of other forms of selpercatinib. 53. A pharmaceutical composition for use according to embodiment 51 or 52.

[0186] Embodiment 56. An embodiment in which the composition comprising selpercatinib form A is substantially pure. 53. A pharmaceutical composition for use according to aspect 51 or 52.

[0187] Embodiment 57. A method for treating cancer comprising administering to a subject a composition comprising at least about 80% by weight of cerpercival cysteine. A pharmaceutical composition comprising nib form A, or a pharmaceutically acceptable salt thereof.

[0188] Embodiment 58. A pharmaceutical composition comprising at least about 80 mg of niacin for use in treating cancer. % by weight of selpercatinib Form A, or a pharmaceutically acceptable salt thereof, , comprising selpercatinib form A made according to any one of embodiments 1 to 50. Pharmaceutical compositions.

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

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

[0191] Embodiment 61. The composition contains less than about 5% by weight of other forms of selpercatinib. 59. A pharmaceutical composition for use according to embodiment 57 or 58.

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

[0193] Embodiment 63. The cancer is a solid tumor, lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated Thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or MEN2A and MEN2B (respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer , colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer. 62. The pharmaceutical composition for use according to any one of embodiments 57 to 61, selected from the group consisting of:

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

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

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

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

[0198] Embodiment 68. The solid tumor is a locally advanced or metastatic solid tumor, 68. A pharmaceutical composition for use according to claim 67.

[0199] Embodiment 69. The solid tumor has progressed during or following previous systemic therapy. locally advanced disease with RET gene fusions that are either unresponsive or have no satisfactory alternative treatment options 69. For the use according to embodiment 63, 67, or 68, wherein the tumor is a primary or metastatic solid tumor. Pharmaceutical compositions.

[0200] Embodiment 70. The cancer is a transfected cancer, as detected by an FDA-approved test. Locally advanced or metastatic non-small cell lung cancer (NSCLC) with retrograde transcriptional rearrangement (RET) gene fusions 64. The pharmaceutical composition for use according to embodiment 63, wherein the IL-16-18 agonist is a steroid hormone receptor agonist (HTR), ...

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

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

[0203] Embodiment 73. The pharmaceutical composition contains about 80 mg of selpercatinib form A. 72. The pharmaceutical composition for use according to any one of Forms 51 to 71.

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

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

[0206] Embodiment 76. Any one of embodiments 51 to 75, wherein the pharmaceutical composition is provided in a tablet. A pharmaceutical composition for use as described in claim 1.

[0207] Embodiment 77. Any of embodiments 51 to 75, wherein the pharmaceutical composition is provided in a capsule. A pharmaceutical composition for use as described in 1.

Claims

1. 1. A method for converting selpercatinib to selpercatinib form A, said method comprising: but, a. Dissolving selpercatinib in a solvent containing DMSO, thereby forming a DMSO solution; b. adding water to the selpercatinib DMSO solution to form a slurry; c. isolating crystallized selpercatinib Form A from said slurry; Including, Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ; method.

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

3. Step a comprises heating the DMSO and selpercatinib to a temperature of about 50-70°C.

3. The method of claim 1 or 2, comprising:

4. 10. The method of claim 9, wherein step b comprises adding a first batch of water and a second batch of water.

4. The method according to any one of 1 to 3.

5. After the first batch of water is added, the ratio of DMSO to water is about 96:4 by volume. The method according to claim 4 .

6. The DMSO and selpercatinib were added for about 40 minutes before the first batch of water was added.

6. The method of claim 4 or 5, comprising cooling to °C.

7. After the second batch of water is added, the ratio of DMSO:water is about 80:

20. Item 7. The method according to any one of Items 4 to 6.

8. adding the second batch of water and cooling the DMSO:water to about 0°C; and (iii) forming a slurry. Law.

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

9. The method according to any one of 1 to 8.

10. 10. The method of claim 1, wherein step b comprises adding about 0.2 mL / g or less of water to the solution.

10. The method according to any one of claims 1 to 9.

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

10. The method according to any one of claims 1 to 9.

12. about 1-15 wt. % of selpercatinib Form A seed crystals are added to the DMSO:water; The method according to claim 11.

13. 10. The method of claim 1, wherein about 1% by weight of selpercatinib Form A seed crystals is added to the DMSO:water.

13. The method according to claim 1 or 12.

14. adding the selpercatinib seed crystals before adding the second batch of water. The method according to any one of claims 11 to 13, comprising:

15. 15. The method of any one of claims 1 to 14, wherein step c comprises high vacuum filtration.

16. The method of any one of claims 1 to 14, wherein step c comprises centrifugation.

17. Selpercatinib Form A isolated from step c) is dissolved in a solvent comprising MTBE and / or water. The method of any one of claims 1 to 16, comprising washing with a solvent.

18. Any of claims 1 to 17, further comprising drying the selpercatinib form A.

10. The method according to claim 1.

19. 1. A method for converting selpercatinib to selpercatinib form A, said method comprising: but, 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, Form A has XRPD peaks at about 4.9, 9.7, and 15.5 degrees 2θ.

20. Dissolve about 1 gram of selpercatinib in about 25 to 35 mL of dichloromethane. Item 20. The method according to item 19.

21. Step a) is a step of dissolving the solvent containing the selpercatinib and dichloromethane in a solvent containing the dichloromethane for about 30 to 4 21. The method of claim 19 or 20, comprising heating to 0°C.

22. Step b. adding a first batch of heptane and a second batch of heptane The method according to any one of claims 19 to 21, comprising:

23. The first batch of heptane was about 8-12 mL of heptane per gram of selpercatinib.

23. The method of claim 22, comprising:

24. The second batch of heptane was about 8-12 mL of heptane per gram of selpercatinib.

24. The method of claim 22 or 23, comprising tanning.

25. Step b includes cooling to a temperature below about 30°C and above about 20°C. The method according to any one of claims 19 to 24.

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

27. 27. Any of claims 19 to 26, wherein step b comprises stirring for at least about 8 hours.

10. The method according to claim 1.

28. A pharmaceutical composition comprising selpercatinib form A produced according to any one of claims 1 to 35. Pharmaceutical composition.

29. 29. The composition of claim 28, further comprising at least one pharmaceutically acceptable carrier, diluent, or excipient. The composition described in

30. The composition contains less than about 20% by weight of other crystalline forms of selpercatinib. Item 30. The pharmaceutical composition according to Item 28 or 29.

31. The composition contains less than about 10% by weight of other crystalline forms of selpercatinib. Item 30. The pharmaceutical composition according to Item 28 or 29.

32. 10. The composition of claim 9, wherein the composition contains less than about 5% by weight of other crystalline forms of selpercatinib.

30. The pharmaceutical composition according to claim 28 or 29.

33. 28. The method of claim 28, wherein the composition comprising selpercatinib Form A is substantially pure.

29. The pharmaceutical composition according to claim 29.

34. A method of treating cancer in a patient, comprising: charging a patient in need of such treatment 28. An effective amount of selpercatinib Form A prepared according to any one of claims 1 to 27, or A method comprising administering the pharmaceutical composition of any one of claims 28 to 33.

35. The method of claim 34, wherein the cancer is a RET-associated cancer.

36. The cancer is a solid tumor, lung cancer, papillary thyroid cancer, medullary thyroid cancer, or 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 cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastrointestinal mucosa, and cervical cancer.

36. The method of claim 34 or 35, wherein

37. 37. The method of claim 36, wherein the cancer is medullary thyroid cancer.

38. The cancer is lung cancer, and the lung cancer is small cell lung cancer, non-small cell lung cancer, bronchiolar cancer, The method of claim 36, wherein the cancer is lung cell carcinoma, RET fusion lung cancer, or lung adenocarcinoma.

39. 37. The method of claim 36, wherein the cancer is a solid tumor.

40. 40. The method of claim 36 or 39, wherein the solid tumor is a locally advanced or metastatic solid tumor. How to do it.

41. the solid tumor has progressed during or following previous systemic therapy; or Locally advanced or metastatic disease with RET gene fusions that do not have satisfactory alternative treatment options 41. The method of claim 40, wherein the tumor is a metastatic solid tumor.

42. The cancer is redistributed during transfection as detected by an FDA-approved test. In locally advanced or metastatic non-small cell lung cancer (NSCLC) with RET gene fusion The method according to claim 34 or 35,

43. The cancer requires systemic therapy and (if radioactive iodine is appropriate) with a RET gene fusion, as detected by an FDA-approved test, that is irradiated refractory 36. The method of claim 34 or 35, wherein the cancer is advanced or metastatic thyroid cancer.

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