Polymorphic forms of RAD1901-2hcl

Abstract

To provide polymorphic forms of RAD1901-2HCL.SOLUTION: The invention relates to crystalline forms of RAD1901-2HCl.SELECTED DRAWING: None

Description

Technical Field

[0001] Priority Claim This application claims the benefit of U.S. Provisional Patent Application No. 62 / 442,921, filed on Jan. 5, 2017, the contents of which including the drawings are incorporated herein by reference in their entirety.

[0002] The present invention relates to polymorphic forms of RAD1901-2HCl.

Background Art

[0003] Background RAD1901 is a selective estrogen receptor downregulator / degrader (SERD) that can cross the blood-brain barrier and is particularly useful for the treatment of metastatic breast cancer. RAD1901 has been shown to bind to estrogen receptors (ERs) with good selectivity and to have both estrogen-like and estrogen antagonist effects in different tissues. In many cancers, hormones similar to estrogen stimulate tumor growth, so the desired therapeutic goal is to block this estrogen-dependent growth while inducing apoptosis of cancer cells. Since SERDs have the potential to be an emerging class of endocrine therapies that can directly induce ER degradation, it may potentially be possible for SERDs to remove estrogen growth signals in ER-dependent tumors without causing ligand-independent resistance.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide polymorphic forms of RAD1901-2HCl. [Means for Solving the Problems]

[0006] Summary of the Invention In addition to pharmaceutical compositions of RAD1901-2HCl, methods for preparing the same, and uses thereof, various polymorphic forms of RAD1901-2HCl are disclosed herein.

[0007] That is, the gist of the present invention is as follows. [1] Crystal forms of RAD1901-2HCl. [Effects of the Invention]

[0008] According to the present invention, polymorphic forms of RAD1901-2HCl can be provided. [Brief Description of the Drawings]

[0009]

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Mode for Carrying Out the Invention

[0010] Detailed Description I. Polymorphic Forms of RAD1901-2HCl As described in the following Examples section, three crystalline forms and an amorphous form of RAD1901-2HCl were prepared and characterized.

Chemical formula

[0011] The definitions provided herein are meant to clarify, but not limit, the terms being defined. When a term used herein is not specifically defined, such term should not be considered to be ambiguous. Rather, the term is used within the scope of its accepted meaning.

[0012] As used herein, RAD1901-2HCl refers to a salt form in which the molar ratio of RAD1901 to HCl is about 2, such as about 1.7 to about 2.1, or 1.8 to about 2.0. Minor variations in the amount of HCl assayed can result, without limitation, from variables in the measurement as well as from minor losses of HCl due to storage and / or handling.

[0013] As used herein, "crystalline" refers to a solid having a highly regular chemical structure. In particular, a crystalline free base or salt form can be produced as one or more single crystal forms. For the purposes of this application, the terms "crystal form", "single crystal form" and "polymorph" are synonymous, and these terms distinguish crystals having different properties (e.g., different XRPD patterns and / or different DSC scan results). The term "polymorph" includes pseudopolymorphs whose properties differ from each other because their solvents are typically different. Thus, each distinct polymorph and pseudopolymorph of a free base or salt form is considered herein to be a distinct single crystal form.

[0014] The term "substantially crystalline" refers to a form that can be at least a specified weight percent crystalline. The specified weight percent can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or any percentage between 10% and 100%. In some embodiments, substantially crystalline refers to a free base or salt form that is at least 70% crystalline. In other embodiments, substantially crystalline refers to a free base or salt form that is at least 90% crystalline.

[0015] As used herein, "amorphous" refers to a solid material that includes an amorphous material. In one embodiment, an amorphous sample of the material can be prepared by lyophilization of a mixture of the material and a solvent that can be homogeneous (e.g., a solution) or heterogeneous (e.g., a slurry).

[0016] The term "substantially free" refers to forms and compositions that can be at least a specified weight percentage that do not contain impurities and / or crystalline compounds. The specified weight percentage can be 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% or any percentage between 60% and 100% that do not contain impurities and / or crystalline compounds. In some embodiments, substantially free refers to a free base or salt form that is at least 70% pure. In other embodiments, substantially crystalline refers to a free base or salt form that is at least 90% pure. In other embodiments, substantially free of crystalline compounds refers to a composition having less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1% crystalline compounds.

[0017] The term "hydrate" refers to a solvate in which the solvent molecule is H2O present in a defined stoichiometric or non-stoichiometric amount. Examples of stoichiometric solvates can include, for example, particularly hemihydrate, monohydrate, dihydrate or trihydrate forms. Examples of non-stoichiometric solvates can include, for example, channel hydrates such as those in which the water content can vary depending on the humidity of the environment.

[0018] The term "solvate or solvation" means a physical association of one or more solvent molecules with a compound of the invention, including the crystalline form of the compound. Such physical associations include hydrogen bonds. In certain examples, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate or solvation" encompasses both the liquid phase and separable solvates. Representative solvates include, for example, hydrates, ethanolates or methanolates.

[0019] The term "stable" in the context of the polymorphic forms disclosed herein refers to the stability of the polymorphic form to heat and / or humidity.

[0020] The relationship among three crystalline forms of RAD1901 is shown in Scheme 1 below: [Chemical formula]

[0021] As used herein, the crystalline forms of RAD1901-2HCl are referred to as Form 1, Form 2, and Form 3, respectively. Forms 1 and 2 are the anhydrous forms of RAD1901-2HCl, and Form 3 is the hydrated form of RAD1901-2HCl. Forms 1, 2, and 3 showed different X-ray powder diffraction (XRPD) patterns.

[0022] Sample 1 refers to a batch of RAD1901-2HCl that was initially not characterized and was subsequently determined to be mainly Form 1. Sample 2 refers to a batch of RAD1901-2HCl that was initially not characterized and was subsequently determined to be a mixture of Form 2 and Form 3.

[0023] The GVS experiment showed that Form 2 was hygroscopic with mass uptake from 0 to 40% RH, and the mass uptake reached a plateau above 40% RH. Thus, an equilibrium existed between the anhydrous Form 2 and the hydrated Form 3 at near ambient RH. The anhydrous Form 1 showed low hygroscopicity between 0 and 90% RH and started to convert to the hydrated Form 3 above 90% RH.

[0024] In many aspects disclosed herein, RAD1901-2HCl is disclosed to have a crystal structure.

[0025] In one aspect, the crystal structure in the present disclosure can be identified by having one or more characteristic peaks in the XRPD spectrum, as disclosed herein.

[0026] In some aspects, the crystal structure in the present disclosure has one or more characteristic endothermic peaks in differential scanning calorimetry, as disclosed herein.

[0027] In one aspect, a method for preparing and / or interconverting one or more crystalline forms of RAD1901-2HCl is provided. Further aspects describe the conversion of RAD1901-2HCl to a crystalline form having the desired stability under the expected storage conditions and the storage of the crystalline form.

[0028] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern that includes peaks at 7.1° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0029] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern that includes peaks at 7.1° 2θ ± 0.2° 2θ and / or 14.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0030] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, and 18.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0031] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, and 12.0° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0032] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern comprising at least 4 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, and 18.9° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0033] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern comprising at least 5 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, and 11.0° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0034] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 1, having an X-ray powder diffraction pattern comprising at least 7 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ, and 16.2° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0035] One aspect disclosed herein provides a solid form of RAD1901-2HCl, e.g., Form 1, having an X-ray powder diffraction pattern that includes at least 8 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ, and 16.2° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0036] One aspect disclosed herein provides a solid form of RAD1901-2HCl, e.g., Form 1, having an X-ray powder diffraction pattern that includes at least 9 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ, and 16.2° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0037] One aspect disclosed herein provides a solid form of RAD1901-2HCl, e.g., Form 1, having an X-ray powder diffraction pattern that includes the peaks of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ, and 16.2° 2θ ± 0.2° 2θ at a relative humidity of about 0%.

[0038] One aspect disclosed herein provides a solid form (Form 1) having an X-ray powder diffraction pattern that is substantially as shown in FIG. 3G at a relative humidity of about 0%.

[0039] One aspect disclosed herein provides a solid form of RAD1901 - 2HCl, such as Form 1, having a differential scanning calorimetry (DSC) thermogram that shows a melting onset at 218.2 °C and an endothermic peak at 232.1 °C.

[0040] One aspect disclosed herein provides a solid form of RAD1901 - 2HCl, such as Form 1, having a differential scanning calorimetry (DSC) thermogram substantially as shown in the graph below FIG. 7.

[0041] One aspect disclosed herein provides a solid form of RAD1901 - 2HCl, such as Form 1, having a thermogravimetric analysis (TGA) substantially as shown in the graph above FIG. 7.

[0042] One aspect disclosed herein provides a solid form of RAD1901 (such as Form 1) disclosed herein, said solid form comprising at least 1% w / w of the total sample of RAD1901 - 2HCl.

[0043] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 5% w / w of the total amount of RAD1901 is the solid form of RAD1901 (such as Form 1) disclosed herein.

[0044] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 10% w / w of the total amount of RAD1901 is the solid form of RAD1901 (such as Form 1) disclosed herein.

[0045] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 25% w / w of the total amount of RAD1901 is the solid form of RAD1901 (such as Form 1) disclosed herein.

[0046] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 50% w / w of the total amount of RAD1901 is the solid form of RAD1901 (such as Form 1) disclosed herein.

[0047] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 90% w / w of the total amount of RAD1901 is the solid form of RAD1901 (e.g., Form 1) disclosed herein.

[0048] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 95% w / w of the total amount of RAD1901 is the solid form of RAD1901 (e.g., Form 1) disclosed herein.

[0049] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 98% w / w of the total amount of RAD1901 is the solid form of RAD1901 (e.g., Form 1) disclosed herein.

[0050] One aspect disclosed herein provides a composition comprising RAD1901, wherein at least 99% w / w of the total amount of RAD1901 is the solid form of RAD1901 (e.g., Form 1) disclosed herein.

[0051] One aspect disclosed herein provides a pharmaceutical composition comprising Form 1 in any of its specific aspects and one or more pharmaceutically acceptable excipients.

[0052] One aspect disclosed herein provides a solid form of RAD1901-2HCl, e.g., Form 2, having an X-ray powder diffraction pattern that includes peaks at 6.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0053] One aspect disclosed herein provides a solid form of RAD1901-2HCl, e.g., Form 2, having an X-ray powder diffraction pattern that includes peaks at 6.3° 2θ ± 0.2° 2θ and / or 12.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0054] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 2, having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, and 15.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0055] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 2, having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, and 15.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0056] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 2, having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, 15.4° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, and 13.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0057] One aspect disclosed herein provides a solid form of RAD1901-2HCl, such as Form 2, having an X-ray powder diffraction pattern that is substantially as shown in FIG. 4H at a relative humidity of about 0%.

[0058] One aspect disclosed herein provides a pharmaceutical composition comprising a solid form of RAD1901-2HCl (such as Form 2) disclosed herein and one or more pharmaceutically acceptable excipients.

[0059] In some aspects, the solid form of RAD1901-2HCl is a crystalline mixture comprising less than 1% of Form 2.

[0060] In one aspect, the solid form of RAD1901-2HCl is a crystalline mixture comprising more than 0.1% but less than 2% of Form 2.

[0061] In some embodiments, the solid form of RAD1901-2HCl comprises at least 10% of Form 2.

[0062] In some embodiments, the solid form of RAD1901-2HCl comprises at least 25% of Form 2.

[0063] In some embodiments, the solid form of RAD1901-2HCl comprises at least 50% of Form 2.

[0064] In some embodiments, the solid form of RAD1901-2HCl comprises at least 75% of Form 2.

[0065] In some embodiments, the solid form of RAD1901-2HCl comprises at least 95% of Form 2.

[0066] In some embodiments, the solid form of RAD1901-2HCl comprises at least 97% of Form 2.

[0067] In some embodiments, the solid form of RAD1901-2HCl comprises at least 99% of Form 2.

[0068] Certain embodiments disclosed herein provide a solid hydrate form of RAD1901-2HCl, such as Form 3. In some embodiments, the solid hydrate form of RAD1901-2HCl is a dihydrate.

[0069] Certain embodiments disclosed herein provide a solid hydrate form of RAD1901-2HCl, such as Form 3, having an X-ray powder diffraction that includes a peak at about 5.8° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0070] Certain embodiments disclosed herein provide a solid hydrate form of RAD1901-2HCl, such as Form 3, having an X-ray powder diffraction pattern that includes peaks at about 5.8° 2θ ± 0.2° 2θ and / or about 21.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0071] One aspect disclosed herein provides a solid hydrate form of RAD1901-2HCl, such as Form 3, having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, and 24.8° 2θ ± 0.2° 2θ at a relative humidity of about 92%.

[0072] One aspect disclosed herein provides a solid hydrate form of RAD1901-2HCl, such as Form 3, having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ, and 9.5° 2θ ± 0.2° 2θ at a relative humidity of about 92%.

[0073] One aspect disclosed herein provides a solid hydrate form of RAD1901-2HCl, such as Form 3, having an X-ray powder diffraction pattern that includes at least four peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ, and 9.5° 2θ ± 0.2° 2θ at a relative humidity of about 92%.

[0074] One aspect disclosed herein provides a solid form of RAD1901-2HCl that is amorphous.

[0075] One aspect disclosed herein provides one or more crystalline and / or amorphous forms of RAD1901-2HCl dispersed in a matrix.

[0076] Aspects are disclosed that include dosage forms of RAD1901-2HCl comprising 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of one or more crystalline and / or amorphous forms, wherein the one or more crystalline and / or amorphous forms are dispersed in a solid or liquid matrix.

[0077] II. Pharmaceutical Compositions and / or Formulations of Polymorphic Forms of RAD1901-2HCl Pharmaceutical compositions are provided herein that include one or more polymorphic and / or amorphous forms of RAD1901-2HCl disclosed herein, and a physiologically acceptable carrier (also referred to as a pharmaceutically acceptable carrier or liquid or diluent). Such carriers and solutions include pharmaceutically acceptable salts and solvates of the compounds used in the methods of the invention, and mixtures comprising two or more of such compounds, pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of such compounds. Such compositions are prepared according to acceptable pharmaceutical procedures such as those described in Remington's Pharmaceutical Sciences, 17th Edition, Alfonso R. Gennaro, ed., Mack Publishing Company, Eaton, Pa. (1985), which is incorporated herein by reference.

[0078] The term "pharmaceutically acceptable carrier" refers to a carrier that does not cause an allergic reaction or other adverse effects in the subject to which it is administered and is compatible with the other components in the formulation. Pharmaceutically acceptable carriers include, for example, pharmaceutically diluents, excipients or carriers that are appropriately selected for the intended dosage form and do not conflict with conventional pharmaceutical practices. For example, solid carriers / diluents include, but are not limited to, rubber, starch (e.g., corn starch, pregelatinized starch), sugar (e.g., lactose, mannitol, sucrose, dextrose), cellulose materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethyl acrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof. Pharmaceutically acceptable carriers may further contain minor auxiliary substances such as wetting agents or emulsifiers, preservatives or buffers that enhance the shelf life or effectiveness of the therapeutic agent.

[0079] The term "patient" refers to a human subject.

[0080] One or more polymorphic and / or amorphous forms of RAD1901-2HCl and its pharmaceutical compositions disclosed herein can be formulated into unit dosage forms that mean physically discrete units suitable as unit doses for a subject under treatment, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect, optionally together with a suitable pharmaceutical carrier. The unit dosage form can be for one of a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage forms can be the same or different for each administration. In certain embodiments, the compound can be formulated for controlled release.

[0081] One or more polymorphic and / or amorphous forms of RAD1901-2HCl disclosed in this specification and its pharmaceutical compositions can be prepared according to any available conventional methods. Examples of preferred dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, etc. In formulation, generally used additives such as diluents, binders, disintegrants, lubricants, coloring agents, flavoring and odor-correcting agents, and if necessary, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. Also, formulation is made by combining compositions generally used as raw materials for pharmaceutical preparations according to conventional methods. Examples of these compositions include, for example, (1) oils such as soybean oil, beef tallow, and synthetic glycerides; (2) hydrocarbons such as liquid paraffin, squalane, and solid paraffin; (3) ester oils such as octyldodecyl myristate and isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicone resins; (6) silicone oils; (7) surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, solid polyoxyethylene castor oil, and polyoxyethylene polyoxypropylene block copolymers; (8) water-soluble macromolecules such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone, and methyl cellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate, and aluminum silicate; (13) purified water, etc.Examples of additives for use in the above formulation include, for example: 1) lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide as diluents; 2) polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block copolymer, meglumine, calcium citrate, dextrin, pectin, etc. as binders; 3) starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose / calcium, etc. as disintegrants; 4) magnesium stearate, talc, polyethylene glycol, silica, condensed vegetable oil, etc. as lubricants; 5) any coloring agent whose addition is pharmaceutically acceptable is suitable as a coloring agent; 6) cocoa powder, menthol, flavoring agent, peppermint oil, cinnamon powder as flavoring and odor-masking agents; 7) antioxidants such as ascorbic acid or alpha-tocopherol whose addition is pharmaceutically acceptable may be mentioned.

[0082] Some embodiments disclosed herein provide pharmaceutical dosage forms comprising RAD1901-2HCl Form 1 in amounts of 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg.

[0083] One embodiment disclosed herein provides a pharmaceutical dosage form as a tablet comprising RAD1901-2HCl Crystal Form 1 in amounts of 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg. In one embodiment, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99.5% of the RAD1901 in the tablet is RAD1901-2HCl Crystal Form 1.

[0084] One aspect disclosed herein provides a pharmaceutical composition comprising a solid form of RAD1901-2HCl (including, for example, Form 2 and / or Form 3) disclosed herein in an amount of 50 gm, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg and one or more pharmaceutically acceptable excipients.

[0085] In certain aspects, the pharmaceutical dosage form includes Form 2 as disclosed herein.

[0086] III. Use of Polymorphic Forms of RAD1901-2HCl Disclosed herein is a method for treating and / or preventing one or more conditions in a subject in which administration of RAD1901 may be beneficial, the method comprising administering to the subject a therapeutically effective amount of one or more polymorphic forms of RAD1901-2HCl disclosed herein or a pharmaceutical composition thereof.

[0087] In certain embodiments, one or more conditions treated / prevented by the methods disclosed herein are breast cancer, uterine cancer, and ovarian cancer and / or cancers having overexpression of estrogen receptor, as well as metastatic cancers and / or tumors. In certain embodiments, cancers and / or tumors treated in the methods disclosed herein are resistant ER-derived cancers or tumors (e.g., having a mutated ER binding domain (e.g., including but not limited to Y537X1 (wherein X1 is S, N or C), D538G, L536X2 (wherein X2 is R or Q), P535H, V534E, S463P, V392I, E380Q and one or more mutations including combinations thereof in ERα)), or overexpressors of ER or tumors and / or cancers where the growth is ligand-dependent, or tumors and / or cancers that progress after endocrine therapy such as treatment with SERDs (e.g., fulvestrant, TAS-108 (SR16234), ZK191703, RU58668, GDC-0810 (ARN-810), GW5638 / DPC974, SRN-927 and AZD9496), aromatase inhibitors (e.g., anastrozole, exemestane and letrozole), selective estrogen receptor modulators (e.g., tamoxifen, raloxifene, lasofoxifene and / or toremifene), Her2 inhibitors (e.g., trastuzumab, lapatinib, ado-trastuzumab emtansine and / or pertuzumab), chemotherapy (e.g., abraxane, adriamycin, carboplatin, cytoxan, daunorubicin, doxil, ellence, fluorouracil, gemzar, helaven, lxempra, methotrexate, mitomycin, micoxantrone, navelbine, taxol, taxotere, thiotepa, vincristine and xeloda), angiogenesis inhibitors (e.g., bevacizumab), cdk4 / 6 inhibitors, m-TOR inhibitors and / or treatment with rituximab.

[0088] Methods for modulating estrogen receptors in a subject are provided herein, the method comprising administering to the subject a therapeutically effective amount of one or more polymorphic forms of RAD1901-2HCl disclosed herein or a pharmaceutical composition thereof; one or more polymorphic forms of RAD1901-2HCl disclosed herein exhibit estrogen-like effects in the central nervous system, bone tissue and lipid metabolism and / or estrogen antagonist effects in the genitalia and mammary glands.

[0089] A therapeutically effective amount of one or more polymorphic forms of RAD1901-2HCl for use in the methods disclosed herein is an amount that, when administered over a particular period, results in the achievement of one or more therapeutic benchmarks (e.g., delay or cessation of tumor growth, cessation of symptoms, etc.). One of ordinary skill in the art can readily determine this amount based on either individual subject criteria (e.g., the amount of one or more polymorphic forms of RAD1901-2HCl necessary to achieve a particular therapeutic benchmark in the subject being treated) or population criteria (e.g., the amount of one or more polymorphic forms of RAD1901-2HCl necessary to achieve a particular therapeutic benchmark in the average subject from a given population). Ideally, the therapeutically effective amount does not exceed the maximum tolerated amount at which more than 50% of the subjects being treated experience nausea or other toxic reactions that prevent further drug administration. The therapeutically effective amount can vary for a given subject depending on various factors such as the variety and degree of symptoms, the sex, age, weight or general health of the subject, the mode of administration and the type of salt or solvate, variability in sensitivity to the drug, the particular type of disease, etc.

[0090] One or more polymorphic forms of RAD1901-2HCl or a pharmaceutical composition thereof for use in the methods disclosed herein can be administered to the subject one or more times. In these embodiments where the compound is administered multiple times, the compound can be administered at regular intervals, such as daily, every other day, weekly or monthly. Alternatively, the compound can be administered at irregular intervals, such as as needed based on criteria such as symptoms, the health of the patient, etc.

[0091] Some aspects disclosed herein provide a method of treating ER+ breast cancer that includes a daily administration of 400 mg of RAD1901-2HCl crystalline form 1 in a dosage form, where the dosage form is a tablet or a capsule and the administration is oral.

[0092] Some aspects disclosed herein provide a method of treating ER+ breast cancer in a subject, where the ER+ breast cancer is resistant to one or more endocrine therapies or the subject has progressed after prior treatment with one or more endocrine therapies, and the treatment includes a daily administration of 400 mg of RAD1901-2HCl crystalline form 1 in a dosage form, where the dosage form is a tablet or a capsule and the administration is oral.

[0093] Some aspects disclosed herein provide a method of treating ER+ breast cancer in a subject, where the ER+ breast cancer is resistant to one or more endocrine therapies or the subject has progressed after prior treatment with one or more endocrine therapies, and the treatment includes a first administration of 400 mg of RAD1901-2HCl crystalline form 1 daily in a dosage form, where the dosage form is a tablet or a capsule and the administration is oral, and the administration of RAD1901-2HCl crystalline form 1 is combined with a second administration of a cdk4 / 6 inhibitor and / or an m-TOR inhibitor, and the second administration is in a dosage regimen appropriate for the cdk4 / 6 inhibitor and / or the m-TOR inhibitor.

[0094] Some aspects disclosed herein provide a method of treating ER+ breast cancer in a subject, where the ER+ breast cancer is resistant to one or more endocrine therapies or the subject has progressed after prior treatment with one or more endocrine therapies, and the treatment includes a first administration of 400 mg of RAD1901-2HCl crystalline form 1 daily in a dosage form, where the dosage form is a tablet or a capsule and the administration is oral, and the first administration is combined with a second administration of palbociclib, ribociclib, abemaciclib, and / or everolimus.

[0095] Some aspects disclosed herein provide a method of treating ER+ breast cancer in a subject, where the ER+ breast cancer is resistant to one or more CDK4 / 6 inhibitors and / or m-TOR inhibitors, and the treatment comprises daily administration of 400 mg of RAD1901-2HCl crystalline form 1 in a dosage form that is a tablet or a capsule and the administration is oral.

[0096] Some aspects disclosed herein provide a method of treating breast cancer comprising administering to a subject in need of treatment for breast cancer a crystalline form of RAD1901-2HCl (e.g., form 1 disclosed herein). In some aspects, the breast cancer is ER+.

[0097] Some aspects disclosed herein provide a method of treating ovarian cancer comprising administering to a subject in need of treatment for ovarian cancer RAD1901-2HCl (form 1). In some aspects, the ovarian cancer is ER+.

[0098] In some aspects, provided herein is a method of treating ER+ breast cancer comprising administering a dosage form comprising one or more crystalline forms of RAD1901-2HCl disclosed herein.

[0099] In some aspects, provided herein is the manufacture of a medicament useful for treating a subject in need of RAD1901-2HCl, where the medicament comprises one or more crystalline and / or amorphous forms of RAD1901-2HCl disclosed herein.

[0100] IV. Preparation of Polymorphic Forms of RAD1901-2HCl Methods are provided herein for preparing forms 1, 2, and 3 of RAD1901-2HCl disclosed herein.

[0101] In one aspect, RAD1901-2HCl can be prepared by treating a solution of RAD1901 in an organic solvent (e.g., EtOH, EtOAc, and mixtures thereof) with at least 2 equivalents of HCl (e.g., in EtOH). In one aspect, the RAD1901-2HCl solution can be further concentrated, treated with an organic solvent (e.g., EtOAc), filtered, and provided with RAD1901 as its bis-HCl salt suitable for further processing according to the polymorph conversion methods shown in this disclosure.

[0102] In one aspect, Polymorph 1 can be prepared by treating RAD1901-2HCl with an organic solvent having a relatively low water content (e.g., less than 5% v / v) that is substantially free of methanol (e.g., less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% of the organic solvent is methanol). In one aspect, Polymorph 1 can be prepared by treating RAD1901-2HCl with an organic solvent (e.g., EtOH, etc.) having a relatively low water content (e.g., less than 5% v / v), and then treating the RAD1901-2HCl with another organic solvent (e.g., an ester such as EtOAc) in which the RAD1901 has lower solubility. As used herein, unless otherwise specified, the organic solvent can be a single organic solvent or a mixture of multiple organic solvents.

[0103] One aspect disclosed herein provides a method for preparing Polymorph 1 of RAD1901-2HCl, comprising the step of precipitating from a solution comprising RAD1901-2HCl and a solvent, or slurrying RAD1901-2HCl in a solvent, wherein the solvent comprises an organic solvent that is substantially free of methanol and has a water content of 5% v / v or less. In some aspects, the organic solvent is selected from the group consisting of n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, MIBK, MEK, 1-propanol, ethanol, TBME, 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, and mixtures thereof.

[0104] In certain embodiments, Form 2, Form 3, or a combination thereof can be prepared by treating RAD1901-2HCl with an organic solvent containing water and / or methanol. In certain embodiments, Form 2, Form 3, or a combination thereof can be prepared by treating RAD1901-2HCl with an organic solvent containing water and / or methanol, and then treating with another organic solvent (e.g., an ester such as EtOAc) in which RAD1901-2HCl has lower solubility. Form 3 can preferably be prepared by using a solvent having a water content of 5% or more. In certain embodiments, Form 2 can be prepared using MeOH having a water content of about 1% to about 2%.

[0105] In certain embodiments, a method for preparing Form 1 of RAD1901-2HCl includes the step of heating a composition containing Form 2, Form 3, or a combination thereof at a temperature higher than 175°C and at a RH of about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, or about 40% or less for a time sufficient for conversion.

[0106] In certain embodiments, a method for preparing Form 2 of RAD1901-2HCl includes the step of exposing a composition containing Form 3 thereof to about 0% RH (e.g., 0% RH for 6 hours) for a time sufficient for conversion.

[0107] In certain embodiments, a method for preparing Form 3 of RAD1901-2HCl includes the step of exposing a composition containing Form 2, Form 3, or a combination thereof to a RH of about 40% or more (e.g., 40% RH for about 2 weeks) for a time sufficient for conversion.

[0108] In certain embodiments, a method for preparing Form 3 of RAD1901-2HCl includes the step of exposing a composition containing Form 1 to a RH of about 90% or more (e.g., 90% RH for 1 week) for a time sufficient for conversion.

Examples

[0109] Examples Apparatus and Method A. X-ray Powder Diffraction (XRPD) Two X-ray diffractometers were used to collect X-ray diffraction patterns as described below.

[0110] A1. Bruker AXS C2 GADDS X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automatic sample placement, and a HiStar two-dimensional area detector. The X-ray optics consisted of a single Goebel multilayer mirror coupled with a 0.3 mm pinhole collimator. Weekly performance checks were performed using a guaranteed standard NIST 1976 Corundum (flat plate).

[0111] The beam divergence, i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm. With a sample-detector distance of 20 cm, a θ-θ continuous scan mode was used that yielded an effective 2θ range of 3.2° to 29.7°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP / 2000 4.1.43, and the data were analyzed and displayed using Diffrac Plus EVA v15.0.0.0.

[0112] A1-1) Ambient Conditions Samples tested under ambient conditions were prepared as flat plate specimens using the powder as received without grinding. The sample was lightly pressed on a slide glass to obtain a flat surface.

[0113] A1-2) Non-ambient Conditions Samples tested under non-ambient conditions were placed on a silicon wafer together with a thermal conductive compound. The sample was then heated from ambient temperature to the appropriate temperature at 20 °C / min, followed by holding isothermally for 1 minute, after which data collection was initiated. It was observed that the sample melted during the experiment and recrystallized when continuously heated above this temperature.

[0114] A2. Bruker AXS D8 Advance The X-ray powder diffraction pattern was collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), a θ-2θ goniometer, as well as V4 divergence and receiving slits, a Ge monochromator, and a Lynxeye detector. The instrument was investigated for performance using a guaranteed Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1, and the data was analyzed and displayed using Diffrac Plus EVA v15.0.0.0.

[0115] A2-1) Ambient conditions The sample was tried under ambient conditions as a flat plate specimen using the received powder. The sample was gently filled into the cavity and cut into a polished zero-background (510) silicon wafer. The sample was rotated about its own plane during the analysis. Data was collected in the angular range of 2 - 42° 2θ, with a step size of 0.05° 2θ and a collection time of 0.5 s / step.

[0116] A2-2) Non-ambient conditions The sample tried under non-ambient conditions was prepared by gently filling it into the cavity, cut into a silicon wafer to obtain a flat surface, and placed on a humidity stage with an Ansyco controller and a humidity sensor arranged adjacent to the sample holder. At a water temperature of 35.0 °C, data was collected at 298.15 K in the angular range of 3 - 31° 2θ, with a step size of 0.025° 2θ and a collection time of 2.0 s / step. The collection time at each %RH was 41 minutes and 28 seconds.

[0117] X-ray powder diffraction (XRPD) patterns were collected at variable humidity values from 0 to 95% RH based on the humidity behavior of each compound observed during the GVS experiments (described herein). For each of the variable humidity X-ray powder diffraction (VH-XRPD) experiments conducted, the % RH values selected are provided along with the relevant experimental results. Complete tables showing the % RH values at each recovery point and the details of the associated delay times at each value are shown in Tables 10 - 12.

[0118] Unless otherwise stated, the 2θ values recited in this disclosure are at ±0.2° 2θ.

[0119] B. Nuclear Magnetic Resonance (NMR): 1 1H NMR and 13 13C NMR NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. The automated experiments were acquired using ICON-NMR v4.0.7, which was tried in Topspin v1.3 using standard Bruker loading experiments. For non-conventional spectroscopy, the data were acquired by using Topspin only. Samples were prepared in DMSO-d6. Offline analysis was performed using ACD Spectrus Processor 2014.

[0120] C. Differential Scanning Calorimetry (DSC) DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Calibration for heat capacity was performed using sapphire, and calibration for energy and temperature was performed using guaranteed indium. Each sample (e.g., 1 mg, 2 mg) in a pinhole aluminum pan was heated from 25 °C to 300 °C at 10 °C / min. The purge of dry nitrogen at 50 ml / min over the sample was maintained. The modulated temperature DSC was performed using a base heating rate of 1 or 2 °C / min and temperature modulation parameters of ±0.318 or 0.636 °C (amplitude) every 60 seconds (cycle).

[0121] The machine control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3, and the data was analyzed using Universal Analysis v4.5A.

[0122] Unless otherwise stated, the DSC temperatures listed are ±3 °C.

[0123] D. Thermogravimetric Analysis (TGA) TGA data was collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel and nickel. Each sample (e.g., 5 mg) was placed in a pre-tared aluminum DSC pan and heated from ambient temperature to 300 °C at 10 °C / min. A nitrogen purge of 60 ml / min was maintained over the sample.

[0124] The machine control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3, and the data was analyzed using Universal Analysis v4.5A.

[0125] E. Polarizing Microscopy (PLM) Samples were tested on a Nikon SMZ1500 polarizing microscope equipped with a digital video camera linked to a DS camera control unit DS-L2 for image capture. A small amount of each sample was placed on a slide glass, mounted in immersion oil, and individual particles were separated as much as possible. Samples were viewed with appropriate magnification and partial polarization, linked to a λ false-color filter.

[0126] F. Scanning Electron Microscopy (SEM) Data was collected using a Phenom Pro Scanning Electron Microscope. A small amount of sample was placed on an aluminum stub using a conductive double-sided adhesive tape. A thin layer of gold was formed using a sputter coater (20 mA, 120 s).

[0127] G. Water measurement by Karl Fischer titration (KF) The moisture content of each sample was measured at 200 °C using a 851 Titrano Coulometer with Hydranal Coulomat AG oven reagent and nitrogen purge, and a Metrohm 874 Oven Sample Processor. The weighed solid sample was introduced into a sealed sample vial. Measurements were performed twice using a sample of approximately 10 mg per titration. Data collection and analysis were performed using Tiamo v2.2.

[0128] H. Chemical purity measurement by HPLC Purity analysis was performed using ChemStation software vB.04.03 on an Agilent HP1100 series system equipped with a diode array detector (255 nM with a 90 nM bandwidth). Samples were prepared at 0.4 - 0.6 mg / mL in an acetonitrile:water, 1:1 solution. HPLC analysis was performed on a Supelco Ascentic Express C18 reverse phase column (100 x 4.6 mm, 2.7 μm) with a gradient elution as shown in Table 1 at a flow rate of 2 mL / min. The column temperature was 25 °C and each sample injection was 2 or 3 μL.

[0129]

Table 1

[0130] I. Gravimetric Vapour Drption (GVS) The adsorption isotherm was obtained using an SMS DVS proprietary humidity adsorption analyzer controlled by DVS proprietary control software v1.0.1.2 (or v1.0.1.3). The sample temperature was maintained at 25 °C by instrument control. The humidity was controlled by mixing streams of dry nitrogen and humid nitrogen at a total flow rate of 200 ml / min. The relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0 - 100% RH) placed proximal to the sample. The weight change (mass relaxation) of the sample as a function of %RH was continuously monitored by a microbalance (accuracy ±0.005 mg).

[0131] The sample (e.g., 20 mg) was placed in a torn mesh stainless steel basket under ambient conditions. The sample was placed and removed at 40% RH and 25 °C (typical indoor conditions). The humidity adsorption isotherm was performed as outlined below (2 scans result in one complete cycle). The standard isotherm was performed at 25 °C at 10% RH intervals in the range 0 - 90% RH. Data analysis was performed using Microsoft Excel with DVS Analysis Suite v6.2 (or 6.1 or 6.0).

[0132] In the 2 - scan cycle, the first scan was performed by adsorption from 40 - 90% RH, followed by the second scan which was performed by adsorption from 90 - 0% RH and then from 0 - 40% RH, at 10% RH intervals, 25 °C, with a stability dm / dt of 0.002% °C / min. The adsorption time was a 6 - hour time out.

[0133] The sample was recovered after completion of the isotherm and re - analyzed by XRPD. To fully understand the adsorption / desorption behavior of the compound under high conditions, a custom humidity adsorption method was also performed at 25 °C at fixed %RH intervals over the range 0 - 95% RH. The custom methods performed for each GVS experiment are shown in Tables 2 - 4 below.

Table 2

Table 3

Table 4

[0134] J. Ion Chromatography (IC) Data was collected using a Metrohm 930 Compact IC Flex with an 858 Professional autosampler and an 800 Dosino dosing unit, using IC MagicNet software v3.1. The accurately weighed sample was prepared as a stock solution in an appropriate dissolution solution and diluted appropriately before testing. Quantification was achieved by comparison with a standard solution of known concentration of the ion being analyzed. The IC method for anion chromatography was performed on a Metrosep A Supp 5-150 IC column (4.0 X 150 mm) at a flow rate of 0.7 mL / min with ambient temperature and various μL injections. The eluent used was 3.2 mM sodium carbonate and 1.0 mM sodium bicarbonate in 5% aqueous acetone. A conductivity detector was used for detection.

[0135] Example 1. Preparation and Characterization of Crystal Forms 1, 2, and 3 of RAD1901-2HCl RAD1901 in EtOH was added to EtOAc and the resulting mixture was heated until dissolved. The solution was cooled to about 20 °C and treated with 2.1 equivalents of HCl in EtOH. The solution was concentrated and the resulting mixture was treated with EtOAc at about 20 °C and filtered to obtain RAD1901 as its bis HCl salt suitable for further processing according to the method of form conversion shown in the present disclosure.

[0136] Two samples of RAD1901-2HCl, Sample 1 and Sample 2, were prepared. Sample 1 was prepared by dissolving RAD1901-2HCl in a mixture of water and ethanol (1.5:19). The water content was reduced to <0.5% by azeotropic distillation, and the concentrated solution was diluted with ethyl acetate. The mixture was stirred at room temperature for at least 2 hours, and then the solid was recovered by filtration. Sample 2 was prepared by dissolving RAD1901-2HCl in methanol. Ethyl acetate was added to the solution, and the resulting mixture was stirred at room temperature for at least 1 hour. The solid was recovered by filtration.

[0137] Samples 1 and 2 were characterized by XRPD under various conditions. For the samples, the XRPD patterns were collected at the ambient conditions at which the samples were obtained; variable temperature (VT-XRPD); variable humidity (VH-XRPD); after the samples were exposed to 40 °C / 75% RH for 1 week and 25 °C / 97% RH for 1 week, respectively; and after GVS measurements in which the samples were exposed to 0-90% RH. Samples 1 and 2 were also 1 characterized by 1H NMR, TGA, DSC, KF, IC, GVS (exposed to 0-90% RH), PLM, SEM and HPLC (Table 5).

[0138] Characterization of Sample 1 (mostly Form 1) and Sample 2 (a mixture of Form 2 and Form 3) showed that Form 1 was more stable than Form 2, with low hygroscopicity and good thermal properties. Furthermore, Form 1 can be converted to the hydrate Form 3 at high RH (>90%) (e.g., for 7 days); Form 3 of RAD1901-2HCl can also be prepared by exposing Form 2 to >40% RH for 7 days; Sample 2 (a mixture of Form 2 and Form 3) can be converted to Form 1 when heated above 175 °C and <90% RH; Form 2 can also be prepared by exposing Form 3 to <40% RH for 8 hours. Thus, limiting the level of water / humidity in the preparation of RAD1901-2HCl can be beneficial for the preparation of Form 1 of RAD1901-2HCl. In one embodiment, the percentage of water present in the preparation method is less than 5% v / v, and the water content is determined, for example, by Karl Fischer titration (KF).

[0139]

Table 5-1

Table 5-2

[0140] RP-HPLC analysis of Samples 1 and 2 showed 99.2% AUC recovered at 255 nm (Figure 1A for Sample 1 and Figure 2A for Sample 2). Samples 1 and 2 recovered in d6-DMSO 1 1H-NMR was consistent with the RAD1901-2HCl structure (Figure 1B for Sample 1 and Figure 2B for Sample 2).

[0141] Most of Sample 1 was in Form 1 of RAD1901-2HCl and had the peaks summarized in XRPD Pattern 1, 0% RH, Figure 3G, Table 7. Sample 1 showed an XRPD pattern slightly different from ambient RH (Figure 3A, Table 6). Sample 2 was a mixture of Forms 2 and 3 of RAD1901-2HCl. Form 2 showed XRPD Pattern 2 (Sample 2 at 0% RH, Figure 4H, peaks summarized in Table 8), and Form 3 showed XRPD Pattern 3 (Sample 2 at 92% RH, Figure 4I, peaks summarized in Table 9).

[0142]

Table 6

Table 7

Table 8

Table 9

[0143] Form 1 was stable after storage at 40 °C / 75% RH for 1 week and after exposure to 0 - 90% RH in GVS, as confirmed by the unchanged XRPD pattern (Pattern 1) of the Form 1 sample before and after GVS. However, Form 1 converted to Form 3 after storage at 25 °C / 97% RH for 1 week.

[0144] Form 1 was relatively non - hygroscopic at 0 - 90% RH, as shown by the GVS data (Figures 5A - 5B). No change was observed in the XRPD pattern before and after GVS analysis (Figure 3D).

[0145] Form 1 was stable against storage at 40 °C / 75% RH for 7 days (from XRPD analysis), but conversion to the hydrated Form 3 occurred upon storage at 25 °C / 97% RH for 7 days (see Figure 3B).

[0146] An overlay of the new patterns obtained upon storage of Sample 1 and Sample 2 under high conditions is shown in Figure 4C, which substantially matches Form 3. Importantly, this indicates that Sample 1 (Form 1) converted to the hydrated Form 3 upon long exposure to high RH.

[0147] To further investigate the humidity behavior of Sample 1 (Form 1) upon exposure to high RH (>90%), a custom GVS experiment was designed and conducted. First, the sample was subjected to treatments of holding at 90 and then 95% RH for about 12 hours to examine whether a hydrated form could be observed (High RH method in Steps 1 and 2 of Table 2, Figures 5C - 5D).

[0148] Figures 5C - 5D (High RH method in Steps 1 and 2 of Table 2) show Sample 1 (Form 1) up to 5 - 6%wt when held at 95% RH for about 12 hours, which indicates hydrated formation. XRPD analysis of the sample after the subsequent GVS experiment (High RH, red in Figure 3E) showed significant changes with similarities to both the hydrated Form 3 and the anhydrous Form 1 compared to the analysis of Form 1 (black in Figure 3E). Figure 3E suggested a mixture of states or an incomplete conversion of Sample 1 to the hydrated form.

[0149] To investigate the stability of the hydrated state, the GVS method with a desorption step and subsequent adsorption, High RH_Desorp_3, was designed (see Table 2 having Steps 1 - 4, Figures 5E - 5F).

[0150] The GVS data in Figures 5E - 5F show that the hydrated state (at 95% RH) was stable against desorption up to approximately 0% RH, and upon adsorption in the range of 0 - 40% RH, the sample did not convert back to the anhydrous form 1, but instead irreversibly converted to a new state (indicating a mixture of hydrate and anhydrous). Further, the shape of the adsorption step from 0 to 40% was observed to be highly similar to the shape of Form 2 (see Figure 6A). XRPD analysis of the sample after the subsequent GVS experiment (''High RH_Desorp_3'') confirmed the presence of a mixture of Form 1 and Form 3, as indicated by the starred peaks (showing peaks present in the XRPD pattern of either the anhydrous or hydrated form) (see Figure 3E). The XRPD pattern obtained for Sample 1 after the subsequent GVS of High RH_Desorp_3 is shown in green.

[0151] Finally, to ensure complete conversion to the anhydrous and hydrated forms, GVS experiments were designed to increase both the lengths of the desorption step at 0% RH and the adsorption step at 95% RH (Table 3). Based on the weight stabilization observed in the reaction rate plots for Sample 1 in the above - mentioned High RH and High RH_Desorp_3 methods (Figures 5D and 5F), hold times of 800 minutes at 0% RH and 1600 minutes at 95% RH were selected. Two cycles were also recorded for this experiment (see Table 3, Figures 5G - 5H) to observe whether the sample would return to Form 1 or form a mixed anhydrous / hydrate species.

[0152] GVS data (Figs. 5G - 5H) indicate that after desorption at 0% RH and subsequent completion of re - adsorption, the sample continued to take up water and formed a mixed anhydrous / hydrate species. This species converted to a hydrate (form 3) that remained stable during desorption up to 40% at 90 - 95% RH, below which the sample clearly desorbed. After subsequent adsorption at 0 - 40% RH, this step - wise change continued, which can be clearly observed in the GVS isotherm plot of sample 2 (see Fig. 6A). This GVS data provides clear evidence that the sample 1 / form 1 material irreversibly converts to a hydrate (form 3) under exposure to high RH (>90%) and shifts to an equilibrium between the anhydrous state (form 2) and the hydrated state (form 3) during desorption. XRPD analysis of the sample after the GVS experiment (“High RH_DoubleCycle_2”) confirmed the formation of the hydrate (form 3) (see Fig. 3F).

[0153] To fully characterize the polymorphic behavior of samples 1 and 2 at variable humidity and to retrieve reference XRPD patterns for the “pure” anhydrous form 1 and form 2 materials as well as the “pure” hydrated form 3 material, variable humidity (VH) XRPD experiments were performed on samples 1 and 2. First, VH - XRPD experiments were conducted using sample 1 to retrieve XRPD diffractograms at humidity values selected along with those recovered during the GVS experiment (see Figs. 5E - 5F). XRPD diffractograms were recovered first at ambient RH, then at approximately 95% RH for 24 h, and finally during a desorption step down to 0% RH and at 0% RH for 10 h (see Fig. 3C). Details of the complete procedure are shown in Table 10 below.

[0154]

Table 10

[0155] The VH-XRPD experiment was unable to show the direct conversion from the starting material sample 1 (form 1) to the hydrated state (form 3) over 24 hours at approximately 95% RH (see Figure 3C). However, there were subtle changes in the diffractogram patterns observed at approximately 95% RH compared to those of the starting material at ambient RH and 0% RH (see starred peaks). These changes included a shoulder at 12° 2θ and an additional peak at 19° 2θ, indicating a gradual conversion towards the hydrated state (see after 25 / 97 in Figure 3C). Thus, form 1 can be converted to form 3 (hydrate) over time, as supported by the GVS data (Figure 5E - 5F). One possible explanation for the slower reaction rate in VH-XRPD is that the VH-XRPD experiment relied on changes in the crystal structure of the sample in the surface layer exposed to different humidities, whereas the GVS experiment enabled the exposure of all surfaces of the sample when it was suspended in the wire basket.

[0156] Thermal analysis of the applied materials showed that sample 1 was anhydrous (by TGA and KF) and had no thermal events prior to melting or decomposition. In comparison, sample 2 had a complex thermal profile by DSC (see Figure 8B) and was found to be a hydrate (by TGA and KF). The DSC trace showed that sample 2 desolvated upon heating from room temperature to 150 °C, melted at approximately 157 °C, and recrystallized at approximately 187 °C (see Figure 8B). The TGA data indicated that this desolvation event corresponded to the loss of 6.2 wt% equal to two molecules of water.

[0157] Therefore, variable temperature XRPD (VT-XRPD) experiments were conducted to investigate the thermal behavior of sample 2 observed by DSC (see Figure 8B). VT-XRPD analysis showed that sample 2 was converted to the anhydrous state (form 2, red) upon heating above 100 °C and then melted and recrystallized at approximately 175 °C (blue), similar to the form 1 material (Figure 4D).

[0158] This shows that by recrystallization above 175 °C, Sample 2 as a mixture of Form 2 and Form 3 can be converted to Form 1. However, it is clear that the Form 1 material is irreversibly converted to the hydrate Form 3 upon exposure to high RH (>90%).

[0159] VH-XRPD experiments were also performed using Sample 2, and XRPD diffractograms were collected at selected humidity values of 0% RH (Table 12) and 90% RH (Table 11) to obtain reference XRPD patterns for each of the “pure” anhydrous Form 2 and “pure” hydrated Form 3. Since the GVS reaction rate plot (see Figure 6B) recovered for Sample 2 showed a relatively fast reaction rate for the conversion from the anhydrous form to the hydrated form, XRPD patterns were recovered at time points up to 10 - 14 hours (see Figures 4E - 4F).

[0160] [Table 11] [Table 12]

[0161] As shown in Figure 4E, slight changes in the XRPD pattern of Sample 2 were observed between ambient RH (42% RH) and 92 - 93% RH (see starred peaks), which indicated conversion to the hydrated state (as shown by the XRPD pattern after storage at 25 °C / 97% RH). However, the reaction rate remained relatively slow. Based on these observations, the XRPD pattern of the anhydrous Sample 2 (at 0% RH) was recovered after drying the sample in a vacuum oven (RT, 8 hours) (see Figure 4F). Since the XRPD pattern recovered at 0% RH matched that of the sample of anhydrous Sample 2 generated by heating to 100 °C on the VT-XRPD stage (see the section of the above experiment and Figure 4D), a reference for anhydrous Form 2 was provided.

[0162] Form 3 in Sample 2 was converted to Form 2 when Sample 2 was heated to 100 °C. Sample 2 started to melt at about 160 °C and recrystallized above 175 °C in the same manner as Form 1. The characterization data of Samples 1 and 2 are summarized in Table 5.

[0163] From the GVS experiment, it was shown that Sample 2 was hygroscopic with a mass uptake of 6.7% wt. at 0% - 40% RH and reached a plateau above 40% RH (2.0% wt. at 40 - 90% RH) (see Figures 6A - 6B). Thus, an equilibrium existed between the anhydrous and hydrated states of Sample 2 at near ambient RH (e.g., 40 - 65% RH).

[0164] The XRPD patterns collected for Sample 2 changed depending on the dominant RH during the measurement. The XRPD diffractograms before and after GVS (see Figure 4G) showed the presence of a mixture of Form 2 and Form 3 between 0% RH and 90% RH (after GVS).

[0165] Example 2. Solubility Evaluation of Polymorphic Forms of RAD1901 - 2HCl Solubility evaluations were performed on Sample 1 of RAD1901 - 2HCl (mainly Form 1 as indicated by XRPD) in 24 solvent systems (Sample IDs: A1 - A24) in HPLC vials. RAD1901 - 2HCl (25 mg) was treated with increasing volumes of solvent until the material was completely dissolved or until a maximum of 60 vol was used (Table 13).

[0166] [Table 13 - 1] [Table 13 - 2]

[0167] After the addition of each solvent, the system was stirred at 25 °C for 5 - 10 minutes, then shaken at 50 °C for 5 - 10 minutes and observations were made. After the sample was allowed to stand at room temperature for 5 minutes, fresh aliquots of solvent were added. After the evaluation was completed, the resulting suspension was matured (maturation), the clear solution was cooled (cooling), and slowly evaporated (evaporation) as follows. All solids recovered from the maturation, cooling, and evaporation experiments were analyzed by high-resolution XRPD.

[0168] The suspension obtained during the solubility evaluation was matured by shaking in a maturation chamber at 50 °C to RT (8 hours per cycle) for up to 5 days. The mixture was then allowed to stand at room temperature for 10 minutes. The resulting solid was filtered, air-dried, and analyzed by XRPD. The clear solution obtained during maturation was evaporated under ambient conditions and the resulting residue was analyzed by XRPD.

[0169] The clear solution obtained during the course of the solubility evaluation was cooled from 50 °C to 5 °C at 0.1 °C / min using a Polar Bear device. The solid obtained upon cooling was recovered from the vial, air-dried, and analyzed by XRPD. If no solid was obtained, the solution was slowly evaporated through a needle inserted into the septum cap of the vial until a solid formed under ambient conditions. The resulting solid was filtered, air-dried, and analyzed by XRPD.

[0170] Solubility evaluations of Sample 1 in different solvent systems showed that the compound had low solubility in alcohol, ester, and hydrocarbon solvents, but was highly soluble in water. XRPD analysis of the solids recovered after maturation, cooling, and evaporation (in the solvents listed in Table 13) revealed that either anhydrous form 1 or hydrated form 3 occurred (Figures 13A - 13C). Consistent with the solid-state characterization of Sample 1 in Example 1, slurrying in water or a water / solvent system resulted in hydrated state form 3. Pattern 3 was also observed from slurrying in 2-propanol, acetone, and methanol, although hydrates may have formed from residual water present in the solvent stock solutions (anhydrous solvents were not used in this screening).

[0171] During these screening experiments, it was observed that one sample (A20) yielded plate-shaped crystals (see Figure 9B) and was subjected to single crystal analysis. However, these crystals were found to exist as deposits rather than single crystals (see Figures 11A - 11C as seen by SEM), so they were not suitable for recovery by SCXRD. Analysis of the crystals by XRPD revealed that the material was consistent with the hydrated state and was nearly similar to Pattern 3 (Figure 13C).

[0172] Example 3. Preparation and Characterization of Amorphous RAD1901 - 2HCl A) Preparation and Characterization of Amorphous RAD1901 - 2HCl As Sample 1 of RAD1901 - 2HCl showed high solubility in water and t - butanol / water (1:1), amorphous RAD1901 - 2HCl was prepared from each of these solvents by lyophilization. RAD1901 - 2HCl (100 mg) was placed in a scintillation vial, and appropriate solvent systems were tested for dissolution of the material. Water or t - butanol / water (1:1) (20 - 30 vol, 2 - 3 mL) was added to the sample at RT, the mixture was vortexed until dissolved, and filtered to remove any residual solid particles. The solution was frozen in a dry ice / acetone bath and the solvent was removed by lyophilization. The resulting solid was analyzed by XRPD for amorphous content (Figure 14A), by IC for counter - ion identity, by HPLC and NMR for purity, and by TGA and DSC for thermal properties (Table 14).

[0173] [Table 14]

[0174] B) Large - scale Preparation of Amorphous RAD1901 - 2HCl In the large-scale preparation of amorphous RAD1901-2HCl, RAD1901-2HCl (600 mg) was dissolved in water (20 vol, 12 mL), filtered to remove residual solid particles. Subsequently, the solution was divided into 24 HPLC vials, frozen in a dry ice / acetone bath, and the solvent was removed by lyophilization. The solid produced by lyophilization was used directly for the solubility evaluation and polymorph screening in Example 4.

[0175] Example 4. Solubility Evaluation and Polymorph Screening of Amorphous RAD1901-2HCl A) Solubility Evaluation and Polymorph Screening of Amorphous RAD1901-2HCl The amorphous RAD1901-2HCl prepared as described in Example 3B was used directly for solubility evaluation and polymorph screening (Table 15). XRPD patterns were further obtained for amorphous RAD1901-2HCl prepared using other solvents.

[0176] [Table 15-1] [Table 15-2]

[0177] In the polymorph screening of amorphous RAD1901-2HCl prepared as shown in Example 3B, aliquots of each sample were examined microscopically for their morphology both after maturation at 25 °C and after maturation at 50 °C / RT. If any crystalline material was observed at any stage of maturation, the resulting solid was filtered, air-dried, and analyzed by high-resolution XRPD. XRPD analysis of samples from the polymorph screening showed that only three distinct patterns: the patterns for the previously observed forms 1, 2, and 3 could be observed (Figures 17A - 17D). In some cases, the samples appeared to be mixtures of various polymorphic forms, such as a mixture of forms 2 and 3, similar to sample 2 having an equilibrium between two solid forms depending on the dominant RH (Figures 17B - 17C).

[0178] Similarly, samples prepared from 2-propanol and MEK can contain a mixture of the anhydrous form 1 and the hydrated form 3 material (Figure 17D).

[0179] PLM images were obtained for the crystals obtained during polymorph screening using amorphous RAD1901-2HCl prepared as described in Example 3B via each of cooling in methanol (Figure 18A), ripening in water (Figure 18B), or ripening in nitromethane (Figure 18C) (Figure 18).

[0180] Despite the collection of high-resolution XRPD data, some samples were poorly crystalline and their patterns could not be clearly assigned, but were very similar to those of form 1 (Figure 17D). Therefore, no additional new patterns were observed in these screenings using amorphous RAD1901-2HCl.

[0181] B) Solubility evaluation of amorphous RAD1901-2HCl in water / organic solvent systems Samples of amorphous RAD1901-2HCl were prepared in water / organic solvent mixtures containing different ratios of water. The selected organic solvents were absolute ethanol, methanol, and ethyl acetate. The percentage of water in the water / organic solvent mixture was varied from 0 to 10% (v / v) to provide a limit for the level of water that can be present during the production process and to maintain the formation of form 1. Beyond this limit of water activity, the hydrated form 3 is obtained as shown by GVS experiments (see Figures 5G and 19A). It should be noted that the samples prepared in ethyl acetate were slurried either in absolute ethyl acetate or in water-saturated ethyl acetate.

[0182] The results from the water / organic solvent experiments are shown in Table 16 and Figures 19A - 19C. The water activity values for each water / organic solvent mixture are shown in Table 16 and were calculated using the reference shown in Bell, Halling, Enzyme Microbiol. Technol. 1997, 20, 471, which is incorporated herein by reference.

[0183]

Table 16

[0184] The water / organic solvent experiments indicate a water activity limit beyond which the hydrated form 3 occurs. A sample of amorphous RAD1901 - 2HCl obtained from Example 3b prepared in absolute ethanol was consistent with the XRPD pattern obtained during the polymorph screening of amorphous sample 1 and crystallized as the form 1 material (see Table 15). Ethanol solvent is also known to be used in the production of the form 1 material of RAD1901 - 2HCl (sample 1) during the drug purification process (along with ethyl acetate). The crystals resulting from water / ethanol were in form 1 up to a ratio of 5% water / ethanol beyond which the hydrated form 3 occurs. This is equal to a water activity limit of 0.39 (see Table 16), indicating that at least on a small scale, up to 5% water can be present during the drug manufacturing process for the formation of form 1.

[0185] Amorphous RAD1901 - 2HCl in absolute methanol crystallized in a form similar to that with XRPD pattern 2. This is consistent with the supply batch of sample 2 known to form during the isolation of RAD1901 - 2HCl using methanol (and ethyl acetate) solvents. The crystals resulting from water / methanol were in form 2 (anhydrous) up to a ratio of 2% water / methanol beyond which the hydrated form 3 with XRPD pattern 3 occurs. This is equal to a low water activity limit of 0.08 (see Table 16) and may reflect the observation (by GVS, see Figure 6A) that the form 2 material converts to the hydrated form 3 or a mixture of forms 2 and 3 at relatively low (ambient) RH.

[0186] Slurrying amorphous RAD1901-2HCl in ethyl acetate anhydride results in the formation of crystals of Form 1 material, which supports the observation that Form 1 can be isolated using ethanol and ethyl acetate solvents in the drug manufacturing process, while Form 2 can be produced using methanol and ethyl acetate. Since water-saturated ethyl acetate has more than 2.7% (v / v) water (e.g., 3.3% water at 20 °C) equal to a water activity of 0.77, the water / ethyl acetate ratio was not changed. Hydrate Form 3 was produced by slurrying in water-saturated ethyl acetate.

[0187] Example 5 Crystal forms of RAD1901-2HCl.

[0188] Example 6 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes peaks at 7.1° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0189] Example 7 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes peaks at 7.1° 2θ ± 0.2° 2θ and / or 14.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0190] Example 8 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, and 18.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0191] Example 9 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, and 12.0° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0192] Example 10 A solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 4 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ and 18.9°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[0193] Example 11 A solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 5 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ and 11.0°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[0194] Example 12 A solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 5 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ, 11.0°2θ ± 0.2°2θ and 16.2°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[0195] Example 13 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 7 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ and 16.2° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0196] Example 14 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 8 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ and 16.2° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0197] Example 15 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 9 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ and 16.2° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0198] Example 16 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes peaks at about 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ and 16.2° 2θ ± 0.2° 2θ with a relative humidity of about 0%.

[0199] Example 17 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern substantially as shown in Figure 3G at a relative humidity of about 0%.

[0200] Example 18 The solid form of RAD1901-2HCl having a differential scanning calorimetry (DSC) thermogram that includes a melting onset at 218.2 °C and an endothermic peak at 232.1 °C.

[0201] Example 19 The solid form of Example 18 having a differential scanning calorimetry (DSC) thermogram substantially as shown in the lower graph of Figure 7.

[0202] Example 20 The solid form of RAD1901-2HCl having a thermogravimetric analysis (TGA) substantially as shown in the upper graph of Figure 7.

[0203] Example 21 A composition comprising RAD1901, wherein at least 5% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0204] Example 22 A composition comprising RAD1901, wherein at least 25% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0205] Example 23 A composition comprising RAD1901, wherein at least 50% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0206] Example 24 A composition comprising RAD1901, wherein at least 90% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0207] Example 25 A composition comprising RAD1901, wherein at least 95% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0208] Example 26 A composition comprising RAD1901, wherein at least 98% w / w of the total amount of RAD1901 is in the solid form of any one of the above examples.

[0209] Example 27 A pharmaceutical composition comprising a solid form of any one of Examples 5 to 26 and one or more pharmaceutically acceptable excipients.

[0210] Example 28 A process for preparing a solid form of any one of Examples 5 to 27, comprising the step of precipitating from a solution containing RAD1901-2HCl and a solvent, or the step of slurrying RAD1901-2HCl in a solvent, wherein the solvent comprises an organic solvent substantially excluding methanol and has a water content of 5% v / v or less.

[0211] Example 29 The process of Example 28, wherein the solvent is selected from the group consisting of n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), 1-propanol, ethanol, t-butyl methyl ether (TBME), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, and mixtures thereof.

[0212] Example 30 A method for treating breast cancer, comprising administering a solid form according to any one of Examples 5 to 26 to a subject in need of treatment for breast cancer.

[0213] Example 31 The method of Example 30, wherein the breast cancer is ER+.

[0214] Example 32 A method for treating ovarian cancer, comprising administering a solid form of RAD1901-2HCl according to any one of Examples 5 to 26 to a subject in need of treatment for ovarian cancer.

[0215] Example 33 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising peaks at 6.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0216] Example 34 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising peaks at 6.3° 2θ ± 0.2° 2θ and / or 12.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0217] Example 35 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ and 15.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0218] Example 36 A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, 15.4° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ and 13.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[0219] Example 37 The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern substantially as shown in Figure 4H at a relative humidity of about 0%.

[0220] Example 38 A pharmaceutical composition comprising the solid form of any one of Examples 32 to 37 and one or more pharmaceutically acceptable excipients.

[0221] Example 39 The solid form of RAD1901-2HCl which is a hydrate.

[0222] Example 40 The solid form of RAD1901-2HCl of Example 39 which is a dihydrate.

[0223] Example 41 The solid form of Example 39 or 40 having an X-ray powder diffraction pattern containing a peak at 5.8° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0224] Example 42 The solid form of any one of Examples 39 to 41 having an X-ray powder diffraction pattern containing a peak at 5.8° 2θ ± 0.2° 2θ and / or 21.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0225] Example 43 The solid form of any one of Examples 39 to 41 having an X-ray powder diffraction pattern containing at least two peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ and 24.8° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0226] Example 44 The solid form of any one of Examples 39 to 41 having an X-ray powder diffraction pattern containing at least three peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ and 9.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0227] Example 45 A solid form according to any one of Examples 39 to 41, having an X-ray diffraction pattern comprising at least four peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ, 12.1° 2θ ± 0.2° 2θ and 9.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[0228] Example 46 A solid form of RAD1901-2HCl that is amorphous.

[0229] Example 47 A form of RAD1901-2HCl as an amorphous material in a dispersion matrix.

[0230] Example 48 A tablet containing 400 mg of amorphous RAD1901-2HCl dispersed in a matrix.

[0231] Specific embodiments of the present invention are shown and described in detail herein, but the present invention is not limited thereto. The above detailed description is provided as an illustration of the present invention and should not be construed as constituting any limitation of the present invention. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

[0232] The following are examples of aspects of the present invention. [1] A crystalline form of RAD1901-2HCl. [2] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising a peak at 7.1° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [3] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising peaks at 7.1° 2θ ± 0.2° 2θ and / or 14.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [4] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 2 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, and 18.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [5] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 3 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, and 12.0° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [6] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 4 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, and 18.9° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [7] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 5 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, and 11.0° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [8] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern comprising at least 5 peaks selected from the group consisting of 7.1° 2θ ± 0.2° 2θ, 14.3° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, 13.8° 2θ ± 0.2° 2θ, 12.0° 2θ ± 0.2° 2θ, 25.1° 2θ ± 0.2° 2θ, 18.9° 2θ ± 0.2° 2θ, 27.2° 2θ ± 0.2° 2θ, 11.0° 2θ ± 0.2° 2θ, and 16.2° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%. [9]The solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 7 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ, 11.0°2θ ± 0.2°2θ and 16.2°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[10] The solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 8 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ, 11.0°2θ ± 0.2°2θ and 16.2°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[11] The solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising at least 9 peaks selected from the group consisting of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ, 11.0°2θ ± 0.2°2θ and 16.2°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[12] The solid form of RAD1901 - 2HCl having an X - ray powder diffraction pattern comprising the peaks of 7.1°2θ ± 0.2°2θ, 14.3°2θ ± 0.2°2θ, 18.3°2θ ± 0.2°2θ, 13.8°2θ ± 0.2°2θ, 12.0°2θ ± 0.2°2θ, 25.1°2θ ± 0.2°2θ, 18.9°2θ ± 0.2°2θ, 27.2°2θ ± 0.2°2θ, 11.0°2θ ± 0.2°2θ and 16.2°2θ ± 0.2°2θ with respect to 2θ at a relative humidity of about 0%.

[13] The solid form of RAD1901-2HCl having an X-ray powder diffraction pattern substantially as shown in Figure 3G at a relative humidity of about 0%.

[14] The solid form of RAD1901-2HCl having a differential scanning calorimetry (DSC) thermogram including a melting onset at 218.2 °C and an endothermic peak at 232.1 °C.

[15] The solid form according to

[14] , having a differential scanning calorimetry (DSC) thermogram substantially as shown in the lower figure of Figure 7.

[16] The solid form of RAD1901-2HCl having a thermogravimetric analysis (TGA) substantially as shown in the upper graph of Figure 7.

[17] A composition comprising RAD1901, wherein at least 5% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[18] A composition comprising RAD1901, wherein at least 25% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[19] A composition comprising RAD1901, wherein at least 50% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[20] A composition comprising RAD1901, wherein at least 90% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[21] A composition comprising RAD1901, wherein at least 95% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[22] A composition comprising RAD1901, wherein at least 98% w / w of the total amount of RAD1901 is in the solid form according to any one of the above.

[23] A pharmaceutical composition comprising the solid form according to any one of the above and one or more pharmaceutically acceptable excipients.

[24] A process for preparing the solid form according to any one of the above, comprising the step of precipitating from a solution comprising RAD1901-2HCl and a solvent, or the step of slurrying RAD1901-2HCl in a solvent, wherein the solvent comprises an organic solvent excluding methanol and has a water content of 5% v / v or less.

[25] The process according to

[24] , wherein the organic solvent is selected from the group consisting of n-heptane, propyl acetate, ethyl acetate, isopropyl acetate, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), 1-propanol, ethanol, t-butyl methyl ether (TBME), 1,4-dioxane, toluene, 1,2-dimethoxyethane, tetrahydrofuran, dichloromethane, acetonitrile, nitromethane, and mixtures thereof.

[26] A method of treating breast cancer, comprising administering to a subject in need of treatment for breast cancer a solid form as described in any one of [1] to

[16] .

[27] The method according to

[26] , wherein the breast cancer is ER+.

[28] A method of treating ovarian cancer, comprising administering to a subject in need of treatment for ovarian cancer a solid form of RAD1901-2HCl as described in any one of [1] to

[16] .

[29] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes peaks at 6.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[30] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes peaks at 6.3° 2θ ± 0.2° 2θ and / or 12.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[31] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, and 15.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[32] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 6.3° 2θ ± 0.2° 2θ, 12.5° 2θ ± 0.2° 2θ, 15.4° 2θ ± 0.2° 2θ, 18.3° 2θ ± 0.2° 2θ, and 13.4° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 0%.

[33] A solid form of RAD1901-2HCl having an X-ray powder diffraction pattern that is substantially as shown in FIG. 4H at a relative humidity of about 0%. A pharmaceutical composition comprising a solid form according to any one of

[34]

[28] to

[32] and one or more pharmaceutically acceptable excipients.

[35] A solid form of RAD1901-2HCl that is a hydrate.

[36] The solid form of RAD1901-2HCl according to

[35] , which is a dihydrate.

[37] The solid form according to

[35] or

[36] , having an X-ray powder diffraction pattern that includes peaks at 5.8° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[38] The solid form according to any one of

[35] to

[37] , having an X-ray powder diffraction pattern that includes peaks at 5.8° 2θ ± 0.2° 2θ and / or 21.3° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[39] The solid form according to any one of

[35] to

[37] , having an X-ray powder diffraction pattern that includes at least two peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, and 24.8° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[40] The solid form according to any one of

[35] to

[37] , having an X-ray powder diffraction pattern that includes at least three peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ, and 9.5° 2θ ± 0.2° 2θ with respect to 2θ at a relative humidity of about 92%.

[41] The solid form according to any one of

[35] to

[37] , having an X-ray diffraction pattern that includes at least four peaks selected from the group consisting of 5.8° 2θ ± 0.2° 2θ, 21.3° 2θ ± 0.2° 2θ, 24.8° 2θ ± 0.2° 2θ, 23.3° 2θ ± 0.2° 2θ, 12.1° 2θ ± 0.2° 2θ, and 9.5° 2θ ± 0.2° 2θ.

[42] A solid form of RAD1901-2HCl that is amorphous.

[43] A form of RAD1901-2HCl as an amorphous material in a dispersion matrix.

[44] A tablet containing 400 mg of amorphous RAD1901-2HCl dispersed in a matrix.

Claims

【Claim 1】 The crystalline form of RAD1901-2HCl.

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