Compositions of (Z)-Endoxifen and Methods for Concentrating the Same

Abstract

Described herein are methods for making (Z)-endoxifen, its salts, crystalline forms of endoxifen, and compositions comprising them. Also described herein are crystalline forms of (Z)-endoxifen. The methods for making (Z)-endoxifen can include one or more enrichment steps to enrich the amount of (Z)-endoxifen present in the composition. The enrichment can include one or more steps of crystallization, recrystallization, or fractional recrystallization to reduce the level of one or more impurities in the composition. These methods can be industrially scalable. Also described herein are compositions enriched in (Z)-endoxifen produced by the methods described herein.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 298,908, entitled "METHODS OF ENRICHING (Z)-ENDOXIFEN," filed January 12, 2022, and U.S. Provisional Application No. 63 / 437,045, entitled "METHODS OF ENRICHING (Z)-ENDOXIFEN," filed January 4, 2023, which applications are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Breast cancer is by far the most common form of cancer in women and the second leading cause of cancer death in humans.Selective estrogen receptor modulators, such as tamoxifen, are used to treat women with endocrine-responsive breast cancer, such as hormone-dependent or hormone-sensitive breast cancer.Endoxifen is a potent selective estrogen receptor modulator (SERM).However, the (Z)-isomer ((Z)-endoxifen) has stronger anti-estrogenic activity than the related (E)-isomer ((E)-endoxifen).Therefore, there remains a need for methods for purifying (Z)-endoxifen and for concentrating compositions containing (Z)-endoxifen. Summary of the Invention

[0003] The present disclosure provides an industrially scalable synthetic method for producing highly pure (Z)-endoxifen and pharmaceutical compositions containing the synthesized (Z)-endoxifen. The methods provided herein are particularly useful for reducing and / or removing mesityl oxide as an impurity. Also provided herein are crystalline forms of (Z)-endoxifen.

[0004] In various aspects, the present disclosure provides a method for purifying a compound of formula (IV), comprising: [ka] The method includes providing a compound of formula (III), which comprises a compound of formula (IV); [ka] The method includes: performing ethyl acetate fractional crystallization of the compound of formula (III) to produce a filtrate containing the compound of formula (IV); performing acetone recrystallization using the filtrate; and performing tetrahydrofuran recrystallization to purify the compound of formula (IV) to a purity of at least 94% (w / w).

[0005] In some embodiments, providing a compound of Formula (III) includes providing a compound of Formula (II); [ka] and performing a McMurry reaction on the compound of formula (II) and propiophenone to produce a compound of formula (III).

[0006] In some embodiments, the McMurry reaction comprises contacting a compound of Formula (II) and propiophenone with zinc and titanium(IV) chloride. In some embodiments, the McMurry reaction further comprises maintaining a temperature of 60° C. or greater for 8 hours or more. In some embodiments, the zinc, titanium(IV) chloride, or both are dissolved or suspended in tetrahydrofuran. In some embodiments, the zinc and titanium(IV) chloride are mixed at a temperature of 60° C. or greater for 2 hours or more prior to contacting with the compound of Formula (II).

[0007] In some embodiments, the compound of Formula (II) is in suspension with propiophenone. In some embodiments, the suspension is suspended in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof. In some embodiments, the organic solvent is tetrahydrofuran. In some embodiments, the suspension is mixed at a temperature of 60°C or higher before contacting the zinc and titanium(IV) chloride.

[0008] In some embodiments, the McMurry reaction further comprises extracting the product produced by contacting the compound of Formula (II) with zinc and titanium(IV) chloride with an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof. In some embodiments, the organic solvent is 2-methyltetrahydrofuran. In some embodiments, the product produced by contacting the compound of Formula (II) with zinc and titanium(IV) chloride is further extracted with a solution containing carbonate. In some embodiments, the carbonate is selected from the group consisting of potassium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, and calcium carbonate. In some embodiments, the carbonate is potassium carbonate.

[0009] In some embodiments, the product produced by contacting the compound of Formula (II) with zinc and titanium(IV) chloride is further extracted with a solution containing an Arrhenius base. In some embodiments, the Arrhenius base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. In some embodiments, the Arrhenius base is sodium hydroxide.

[0010] In some embodiments, the product produced by contacting the compound of Formula (II) with zinc and titanium(IV) chloride is further extracted with a solution containing a neutral salt. In some embodiments, the neutral salt is selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, potassium chlorate, sodium chlorate, potassium perchlorate, and sodium perchlorate. In some embodiments, the neutral salt is sodium chloride.

[0011] In some embodiments, providing a compound of Formula (III) further comprises concentrating the product produced by the McMurry reaction in acetone, acetonitrile, or both. In some embodiments, providing a compound of Formula (III) further comprises washing the product produced by the McMurry reaction in acetone, acetonitrile, or both.

[0012] In some embodiments, providing a compound of Formula (I) includes providing a compound of Formula (II); [ka] and performing a demethylation reaction on the compound of formula (I) to produce a compound of formula (II).

[0013] In some embodiments, the demethylation reaction comprises contacting the compound of Formula (I) with N-ethyldiisopropylamine. In some embodiments, the compound of Formula (I), N-ethyldiisopropylamine, or both, are dissolved in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof. In some embodiments, the organic solvent is tetrahydrofuran.

[0014] In some embodiments, the demethylation reaction comprises contacting the compound of Formula (I) with 1-chloroethyl chloroformate. In some embodiments, the compound of Formula (I) and 1-chloroethyl chloroformate are heated to reflux. In some embodiments, the compound of Formula (I) and 1-chloroethyl chloroformate are mixed at 60° C. or higher for 12 hours or longer.

[0015] In some embodiments, the demethylation reaction comprises contacting the compound of Formula (I) with a solution containing an Arrhenius acid. In some embodiments, the Arrhenius acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrosulfic acid, acetic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, chloric acid, perchloric acid, chlorous acid, phosphoric acid, phosphorous acid, and carbonic acid. In some embodiments, the Arrhenius acid is hydrochloric acid.

[0016] In some embodiments, the method further comprises increasing the pH of the demethylation reaction to at least about 13 or at least about 13.4. In some embodiments, increasing the pH comprises adding a solution comprising an Arrhenius base to the demethylation reaction. In some embodiments, the Arrhenius base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. In some embodiments, the Arrhenius base is sodium hydroxide.

[0017] In some embodiments, the method further comprises extracting the compound of Formula (II) with ethyl acetate. In some embodiments, the ethyl acetate fractional recrystallization comprises contacting the compound of Formula (III) with ethyl acetate and an Arrhenius acid to extract the compound of Formula (IV). In some embodiments, the Arrhenius acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrosulfic acid, acetic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, chloric acid, perchloric acid, chlorous acid, phosphoric acid, phosphorous acid, and carbonic acid. In some embodiments, the Arrhenius acid is hydrochloric acid. In some embodiments, the compound of Formula (III), ethyl acetate, and Arrhenius acid are mixed at 50°C to 70°C, or 55°C to 65°C, for 6 hours or more. In some embodiments, the ethyl acetate fractional recrystallization further comprises increasing the pH of the solution containing the compound of Formula (III) to 12 or higher by adding an Arrhenius base. In some embodiments, the Arrhenius base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide. In some embodiments, the Arrhenius base is sodium hydroxide.

[0018] In some embodiments, the ethyl acetate fractional recrystallization further comprises adding ethyl acetate to extract the compound of Formula (IV). In some embodiments, the ethyl acetate fractional recrystallization further comprises washing the compound of Formula (IV) with a solution containing a neutral salt. In some embodiments, the neutral salt is selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, potassium chlorate, sodium chlorate, potassium perchlorate, and sodium perchlorate. In some embodiments, the neutral salt is sodium chloride. In some embodiments, the ethyl acetate fractional recrystallization further comprises filtering the compound of Formula (IV).

[0019] In some embodiments, the acetone crystallization comprises contacting the compound of Formula (IV) with acetone. In some embodiments, the acetone crystallization further comprises contacting the compound of Formula (IV) and acetone with 2-propanol.

[0020] In some embodiments, the tetrahydrofuran crystallization comprises contacting the compound of Formula (IV) with tetrahydrofuran. In some embodiments, the tetrahydrofuran crystallization further comprises contacting the compound of Formula (IV) and tetrahydrofuran with 2-propanol.

[0021] In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of (E)-endoxifen in the compound of Formula (III) or the compound of Formula (IV). In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of (E)-endoxifen in the compound of Formula (III) or the compound of Formula (IV) by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 45%, 40%, 30%, 20%, 10%, or 5%. In some embodiments, the level of (E)-endoxifen is measured by HPLC. In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of mesityl oxide in the compound of Formula (III) or the compound of Formula (IV). In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of mesityl oxide in the compound of Formula (III) or the compound of Formula (IV) by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1%. In some embodiments, the level of mesityl oxide is measured by HPLC.

[0022] In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, or the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol in the compound of Formula (III) or the compound of Formula (IV). In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1%. In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1%. In some embodiments, ethyl acetate fractional recrystallization, acetone crystallization, tetrahydrofuran crystallization, or a combination thereof reduces the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1%.

[0023] In some embodiments, the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol is the level of (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2- levels of (4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; levels of (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; levels of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof. In some embodiments, the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, or the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol is measured by HPLC.

[0024] In some embodiments, the compound of formula (IV) is purified to a purity of at least 96% (w / w).

[0025] In various embodiments, the present disclosure provides a composition comprising at least 96% w / w of a compound of formula (IV) [ka] and A composition containing impurities is provided, the impurities comprising no more than 4% w / w of mesityl oxide, the impurities comprising no more than 25 ppm of mesityl oxide based on the total weight of the composition.

[0026] In some embodiments, the impurities comprise 3% (w / w) or less of (E)-endoxifen based on the total weight of the composition.

[0027] In various aspects, the present disclosure provides compositions comprising a compound of formula (IV) produced by the methods described herein.

[0028] In some embodiments, the composition contains 3%, 2.5%, 2%, 1.5%, or 1% or less of (E)-endoxifen by weight. In some embodiments, the composition contains 97%, 97.5%, 98%, 98.5%, or 99% or more of (Z)-endoxifen by weight. In some embodiments, the composition contains 5 ppm, 10 ppm, 15 ppm, 20 ppm, or 25 ppm or less of mesityl oxide. In some embodiments, the composition contains 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% or less of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol by weight. In some embodiments, the composition comprises 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight or less of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol. In some embodiments, the composition comprises 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% by weight or less of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol. In some embodiments, the composition comprises no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol. In some embodiments, the composition comprises no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol.In some embodiments, the composition comprises no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol. In some embodiments, the composition comprises no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol.

[0029] In some embodiments, the composition contains 5000 ppm or less of ethanol. In some embodiments, the composition contains 3000 ppm or less of methanol. In some embodiments, the composition contains 5000 ppm or less of acetone. In some embodiments, the composition contains 5000 ppm or less of 2-propanol. In some embodiments, the composition contains 410 ppm or less of acetonitrile. In some embodiments, the composition contains 5000 ppm or less of ethyl acetate. In some embodiments, the composition contains 720 ppm or less of tetrahydrofuran. In some embodiments, the composition contains 520 ppm or less of 2-methyltetrahydrofuran. In some embodiments, the composition contains 5000 ppm or less of n-heptane. In some embodiments, the composition contains 130 ppm or less of zinc. In some embodiments, the composition contains 2 ppm or less of benzene.

[0030] In various aspects, the present disclosure provides a composition comprising a crystalline form of a compound of formula (III): [ka] The crystalline forms of the compound of formula (III) are Form IV, characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3°2θ, 23.3±0.3°2θ, and 13.6±0.3°2θ; Form V, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°2θ, 19.6±0.3°2θ, and 8.9±0.3°2θ; Form VI, characterized by an X-ray powder diffraction pattern containing major peaks at 9.9±0.3°2θ, 13.4±0.3°2θ, and 13.7±0.3°2θ; Form VII, characterized by an X-ray powder diffraction pattern containing major peaks at 4.8±0.3°2θ, 18.9±0.3°2θ, and 9.5±0.3°2θ; Form VIII, characterized by an X-ray powder diffraction pattern containing major peaks at 19.0±0.3°2θ, 12.9±0.3°2θ, and 15.9±0.3°2θ; Form IX, characterized by an X-ray powder diffraction pattern containing major peaks at 7.2±0.3°2θ, 14.3±0.3°2θ, 18.7±0.3°2θ, 21.5±0.3°2θ, and 22 Form X, characterized by an X-ray powder diffraction pattern containing major peaks at 14.0±0.3°2θ, 17.7±0.3°2θ, 11.9±0.3°2θ, 18.4±0.3°2θ, 23.9±0.3°2θ, 17.3±0.3°2θ, 21.8±0.3°2θ, 20.8±0.3°2θ, and 23.0±0.3°2θ; Form XI, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°2θ, 15.6±0.3°2θ, and 19.0±0.3°2θ. Form XII characterized by an X-ray powder diffraction pattern with major peaks at 11.6±0.3°2θ, 21.3±0.3°2θ, and 19.3±0.3°2θ; Form XIV characterized by an X-ray powder diffraction pattern with major peaks at 9.8±0.3°2θ, 4.7±0.3°2θ, and 14.0±0.3°2θ; Form XV characterized by an X-ray powder diffraction pattern with major peaks at 4.7±0.3°2θ, 23.6±0.3°2θ, and 18.9±0.3°2θ; or a combination thereof.

[0031] In some embodiments, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XIX, or a combination thereof.

[0032] In some embodiments, the crystalline form of the compound of Formula (III) is stable at ambient temperature for at least 1 day, at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 30 days, at least 60 days, or at least 90 days at ambient temperature.

[0033] In some embodiments, the crystalline form comprises Form IV, or Form VII. In some embodiments, the crystalline form comprises Form IV, Form VI, Form VII, Form VIII, Form IX, Form X, or Form XIV. In some embodiments, the crystalline form comprises Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form XII, Form XIV, Form XV, or Form XIX.

[0034] In some embodiments, the crystalline form of the compound of Formula (III) is Form IV. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.8±0.3°2θ, 14.2±0.3°2θ, 22.5±0.3°2θ, and 15.7±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak or at least two peaks selected from 7.1±0.3°2θ and 20.2±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, including a peak at 9.5±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 13.

[0035] In some embodiments, the crystalline form of the compound of Formula (III) contains about 1% to about 30% solvent by weight, as determined by TGA analysis. In some embodiments, the crystalline form loses solvent upon heating to a temperature of 70° C. to 130° C., as determined by TGA analysis. In some embodiments, the solvent comprises 2-propanol, heptane, or a combination thereof.

[0036] In some embodiments, the crystalline form of the compound of Formula (III) is Form V. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 19.8±0.3°2θ, and 16.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.0±0.3°2θ, 13.5±0.3°2θ, or 14.4±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 27.

[0037] In some embodiments, the crystalline form of the compound of Formula (III) is Form VI. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.6±0.3°2θ, 18.6±0.3°2θ, 17.3±0.3°2θ, and 21.8±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 10.2±0.3°2θ, 19.5±0.3°2θ, and 14.2±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 29.

[0038] In some embodiments, the crystalline form of the compound of Formula (III) is Form VII. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 11.4±0.3°2θ, 16.4±0.3°2θ, 9.6±0.3°2θ, and 13.3±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 18.2±0.3°2θ, 13.1±0.3°2θ, and 27.0±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 31.

[0039] In some embodiments, the crystalline form of the compound of Formula (III) is Form VIII. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.7±0.3°2θ, 21.9±0.3°2θ, 21.2±0.3°2θ, and 12.9±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 25.0±0.3°2θ, 21.5±0.3°2θ, and 16.4±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 37.

[0040] In some embodiments, the crystalline form of the compound of Formula (III) is Form IX. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 21.1±0.3°2θ, and 8.9±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.4±0.3°2θ, 4.2±0.3°2θ, and 12.7±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 40.

[0041] In some embodiments, the crystalline form of the compound of Formula (III) is Form X. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak or at least two peaks selected from 17.1±0.3°2θ and 22.7±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.8±0.3°2θ, 27.3±0.3°2θ, and 29.4±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 52.

[0042] In some embodiments, the crystalline form of the compound of Formula (III) is Form XI. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak or at least two peaks selected from 22.2±0.3°2θ and 16.6±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 54.

[0043] In some embodiments, the crystalline form of the compound of Formula (III) is Form XII. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.9±0.3°2θ, 20.2±0.3°2θ, 16.0±0.3°2θ, and 21.6±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.4±0.3°2θ, 16.8±0.3°2θ, and 12.8±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 56.

[0044] In some embodiments, the crystalline form of the compound of Formula (III) is Form XIV. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.5±0.3°2θ, 15.4±0.3°2θ, 21.6±0.3°2θ, and 5.8±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.3±0.3°2θ, 21.9±0.3°2θ, and 23.9±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 71.

[0045] In some embodiments, the crystalline form of the compound of Formula (III) is Form XV. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 20.2±0.3°2θ, 7.1±0.3°2θ, 23.4±0.3°2θ, and 22.4±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.7±0.3°2θ, 22.7±0.3°2θ, and 18.8±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 6.

[0046] In some embodiments, the crystalline form of the compound of Formula (III) is Form XIX. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray powder diffraction pattern comprising at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 9.4±0.3°2θ, 23.3±0.3°2θ, 22.3±0.3°2θ, and 20.1±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern of the crystalline form further comprises at least one peak, at least two peaks, or at least three peaks selected from 19.6±0.3°2θ, 7.1±0.3°2θ, and 15.7±0.3°2θ. In some embodiments, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 25.

[0047] In various aspects, the present disclosure provides a composition comprising a crystalline form of a compound of formula (III): [ka] The composition provides a crystalline form of the compound of formula (III), wherein the crystalline form is Form XVII, characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0048] In various aspects, the present disclosure provides a composition comprising a crystalline form of a compound of formula (III): [ka] The composition provides a crystalline form of the compound of formula (III), wherein the crystalline form is Form XVIII, characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0049] In various aspects, the present disclosure provides a method of producing a crystalline form of a compound of formula (III), comprising: [ka] The method includes incubating a solid form of the compound of Formula (III) in a solvent system, wherein at least a portion of the solid form of the compound of Formula (III) remains solid; converting a portion of the solid form of the compound of Formula (III) to a crystalline form; and collecting the crystalline form.

[0050] In some embodiments, the crystalline form of the compound of Formula (III) is Form I. In some embodiments, the incubation is for about 3 to about 120 hours. In some embodiments, the solid form of the compound of Formula (III) comprises at least about 90% isomeric purity prior to incubation. In some embodiments, the crystalline form of the compound of Formula (III) comprises at least about 90% isomeric purity.

[0051] In some embodiments, the solid form of the compound of Formula (III) comprises at least one of Forms IV-XIX. In some embodiments, the solid form of the compound of Formula (III) is at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, or at least 99% amorphous. In some embodiments, about 0.1% to about 75%, about 0.1% to about 10%, about 0.1% to about 25%, about 1% to about 25%, about 5% to about 50%, about 20% to about 50%, or about 25% to about 75% of the solid form of the compound of Formula (III) is soluble in the solvent system.

[0052] In some embodiments, the solvent system during incubation comprises a temperature of about 5° C. to about 110° C., about 5° C. to about 90° C., about 5° C. to about 25° C., about 10° C. to about 60° C., about 25° C. to about 50° C., about 15° C. to about 50° C., about 15° C. to about 70° C., about 25° C. to about 40° C., or about 35° C. to about 60° C. In some embodiments, the incubation is carried out for about 0.1 to about 700 hours, about 1 to about 360 hours, about 3 to about 360 hours, about 3 to about 36 hours, about 6 to about 72 hours, about 12 to about 150 hours, about 24 to about 150 hours, about 48 to about 240 hours, or about 100 to about 700 hours.

[0053] In some embodiments, the solvent system comprises about 5 to about 10,000 mg / ml, about 5 to about 1,000 mg / ml, about 5 to about 300 mg / ml, about 5 to about 50 mg / ml, about 20 to about 300 mg / ml, about 50 to about 300 mg / ml, about 100 to about 1,000 mg / ml, or about 300 to about 10,000 mg / ml of the solid form of the compound of Formula (III) during incubation. In some embodiments, the solvent system comprises 2-propanol, acetonitrile, acetone, butyl acetate, butyl methyl ether, dimethylformamide, ethanol, ethyl acetate, water, heptane, methanol, methyl isobutyl ketone, tetrahydrofuran, toluene, or a combination thereof.

[0054] In some embodiments, the solvent system comprises a single solvent. In some embodiments, the solvent comprises multiple solvents. In some embodiments, the solvent system comprises two solvents in a ratio of about 99:1 to about 1:1, about 19:1 to about 1:1, about 19:1 to about 5:1, about 8:1 to about 1:1, about 4:1 to about 1:1, or about 2:1 to about 1:1. In some embodiments, the solvent system comprises less than about 25%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.25% water.

[0055] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising: (a) dissolving a compound of formula (III) in 2-propanol and evaporating at least a portion of the 2-propanol; (b) dissolving a compound of formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran at a first temperature and cooling the solvent system to a second temperature; (c) dissolving a compound of formula (III) in a solvent system comprising heptane and 2-propanol at a first temperature and cooling the solvent system to a second temperature; (d) dissolving a compound of formula (III) in a solvent system comprising 2-propanol and ethyl acetate at a first temperature and cooling the solvent system to a second temperature. (e) dissolving the compound of Formula (III) in tetrahydrofuran and combining the solvent system with water; (f) dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran and evaporating at least a portion of the solvent system; (g) dissolving the compound of Formula (III) in acetone and evaporating at least a portion of the acetone; (h) dissolving the compound of Formula (III) in a solvent system comprising acetone and tetrahydrofuran and evaporating at least a portion of the solvent system; or (i) combinations thereof, thereby producing a crystalline form of the compound of Formula (III).

[0056] In some embodiments, the method comprises any one of (a)-(f) or (h). In some embodiments, the crystalline form of the compound of Formula (III) is Form IV.

[0057] In some embodiments, the cooling is at a rate of about 0.02°C / min to about 10°C / min. In some embodiments, the first temperature is about 20°C to about 100°C, and the second temperature is about -20°C to about 25°C.

[0058] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising dissolving a compound of formula (III) in acetonitrile at a first temperature and cooling the acetonitrile to a second temperature, thereby producing a crystalline form of the compound of formula (III).

[0059] In some embodiments, the crystalline form of the compound of Formula (III) is Form V. In some embodiments, the cooling is at a rate of about 0.02° C. / min to about 10° C. / min.

[0060] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of Formula (III), the method comprising storing Form V at a temperature of about 20° C. to about 50° C., thereby producing a crystalline form of the compound of Formula (III).

[0061] In some embodiments, the crystalline form of the compound of formula (III) is Form VI.

[0062] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising: dissolving the compound of formula (III) in ethyl acetate and adding the ethyl acetate to heptane; dissolving the compound of formula (III) in toluene and evaporating at least a portion of the toluene; dissolving the compound of formula (III) in toluene and adding the toluene to heptane; dissolving the compound of formula (III) in a solvent system comprising heptane and toluene and heating the solvent system to about 20° C. to about 50° C.; or combinations thereof, thereby producing a crystalline form of the compound of formula (III).

[0063] In some embodiments, the crystalline form of the compound of Formula (III) is Form VII.

[0064] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising dissolving the compound of formula (III) in toluene at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of formula (III) in toluene, adding butyl methyl ether to the toluene to form a solvent system, and evaporating at least a portion of the solvent system; or a combination thereof, thereby producing a crystalline form of the compound of formula (III).

[0065] In some embodiments, the crystalline form of the compound of Formula (III) is Form VIII. In some embodiments, the cooling is at a rate of about 0.02° C. / min to about 10° C. / min.

[0066] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising: dissolving the compound of formula (III) in a solvent system comprising ethyl acetate, adding heptane to the solvent system, and incubating the solvent system at a temperature of about 20° C. to about −20° C.; dissolving the compound of formula (III) in a solvent system comprising butyl acetate and adding heptane to the solvent system; dissolving the compound of formula (III) in ethyl acetate and adding ethyl acetate to butyl methyl ether to form a solvent system and evaporating at least a portion of the solvent system; dissolving the compound of formula (III) in ethyl acetate and adding butyl methyl ether to ethyl acetate to form a solvent system and evaporating at least a portion of the solvent system; dissolving the compound of formula (III) in acetone, combining acetone with butyl methyl ether to form a solvent system and evaporating at least a portion of the solvent system; or a combination thereof, thereby producing a crystalline form of the compound of formula (III).

[0067] In some embodiments, the crystalline form of the compound of formula (III) is Form IX.

[0068] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising dissolving a compound of formula (III) in 4-methyl-2-pentanone at a first temperature and cooling the 4-methyl-2-pentanone to a second temperature, thereby producing a crystalline form of the compound of formula (III).

[0069] In some embodiments, the crystalline form of the compound of Formula (III) is Form X. In some embodiments, the cooling is at a rate of about 0.02° C. / min to about 10° C. / min.

[0070] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising dissolving less than about 100 micrograms of the compound of formula (III) in tetrahydrofuran, adding the tetrahydrofuran to acetone to form a solvent system, and evaporating at least a portion of the solvent system, thereby producing the crystalline form of the compound of formula (III).

[0071] In some embodiments, the crystalline form of the compound of Formula (III) is Form XII.

[0072] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising dissolving greater than about 100 micrograms of the compound of formula (III) in tetrahydrofuran, adding the tetrahydrofuran to acetone to form a solvent system, and evaporating at least a portion of the solvent system, thereby producing the crystalline form of the compound of formula (III).

[0073] In some embodiments, the crystalline form of the compound of formula (III) is Form XIV.

[0074] In various aspects, the disclosure provides a method for producing a crystalline form of the compound of formula (III), the method comprising dissolving the compound of formula (III) in ethyl acetate and adding the ethyl acetate to heptane, thereby producing the crystalline form of the compound of formula (III).

[0075] In some embodiments, the crystalline form of the compound of formula (III) is Form XV.

[0076] In various aspects, the disclosure provides methods for producing a crystalline form of the compound of formula (III), the method comprising: dissolving the compound of formula (III) in acetone at a first temperature, combining the acetone with heptane to form a solvent system, and cooling the solvent system to a second temperature; dissolving the compound of formula (III) in tetrahydrofuran at a first temperature, combining the tetrahydrofuran with heptane to form a solvent system, and cooling the solvent system to a second temperature; or a combination thereof, thereby producing a crystalline form of the compound of formula (III).

[0077] In some embodiments, the crystalline form of the compound of Formula (III) is Form XIX. In some embodiments, the cooling is at a rate of about 0.02° C. / min to about 10° C. / min.

[0078] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising dissolving a compound of formula (III) in ethyl acetate at a first temperature, combining the ethyl acetate with heptane to form a solvent system, and cooling the solvent system to a second temperature, thereby producing a crystalline form of the compound of formula (III).

[0079] In some embodiments, the crystalline form of the compound of Formula (III) is Form XVI. In some embodiments, the cooling is at a rate of about 0.02° C. / min to about 10° C. / min.

[0080] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising dissolving a compound of formula (III) in ethanol and evaporating at least a portion of the ethanol, thereby producing a crystalline form of a compound of formula (III).

[0081] In some embodiments, the crystalline form of the compound of Formula (III) is Form XVII.

[0082] In various aspects, the disclosure provides methods for producing a crystalline form of a compound of formula (III), the method comprising dissolving a compound of formula (III) in tetrahydrofuran and evaporating at least a portion of the tetrahydrofuran, thereby producing a crystalline form of the compound of formula (III).

[0083] In some embodiments, the crystalline form of the compound of formula (III) is Form XVIII.

[0084] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0085] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0086] [Figure 1] 1 provides X-ray powder diffraction (XRPD) spectra of some of the polymorphs corresponding to the present disclosure, including Form I, Form IV, and a slurry (SLHT-1D-2PR / THF (100 mg / ml)) from a high temperature experiment. [Figure 2] 1 provides X-ray powder diffraction (XRPD) spectra of several of the polymorphs corresponding to the present disclosure, including Form I and several slurries from high temperature experiments (SLHT-1D-H2O / ACN (100 mg / ml) and SLHT-1D-H2O / ACN (40 mg / ml)). [Figure 3]

[0023] Figure 1 provides X-ray powder diffraction (XRPD) spectra of several of the polymorphs corresponding to the present disclosure, including Form I and several slurries from high temperature experiments (SLHT-1D-HO / THF (40 mg / ml), SLHT-1D-ACT / ACN (40 mg / ml), SLHT-1D-ACT / ETA (40 mg / ml), and SLHT-1D-HO / 2PR (40 mg / ml)). [Figure 4] 1 provides X-ray powder diffraction (XRPD) spectra of several of the polymorphs corresponding to the present disclosure, including Form I and a slurry from a high temperature experiment (SLHT-1D-HEP / ETA (40 mg / ml)). [Figure 5] 1 provides X-ray powder diffraction (XRPD) spectra of some of the polymorphs corresponding to the present disclosure, including Form VII, Form I, and a slurry (SLHT-D-HEP / TOL (40 mg / ml)) from a high temperature experiment. [Figure 6] 1 provides an X-ray powder diffraction (XRPD) spectrum of the Form XV polymorph corresponding to the present disclosure. [Figure 7] 1 provides an X-ray powder diffraction (XRPD) spectrum of a Kapton film corresponding to the present disclosure. [Figure 8] 1 provides X-ray powder diffraction (XRPD) spectra of Forms XI and E-endoxifen. [Figure 9] 1 provides an X-ray powder diffraction (XRPD) spectrum of the Form I polymorph corresponding to the present disclosure. [Figure 10] 1 provides several XRPD spectra of Form I collected at several time points during incubation, including 7 days (Form I-7D-storage) and 42 days (Form I-42D-storage). [Figure 11] 1 provides differential scanning calorimetry (DSC) profiles of polymorphs corresponding to the present disclosure. [Figure 12] 1 provides thermogravimetric analysis (TGA) profiles of polymorphs corresponding to the present disclosure. [Figure 13] 1 provides an X-ray powder diffraction (XRPD) spectrum of Form IV polymorph corresponding to the present disclosure. [Figure 14]1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 15] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 16] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 17] 1 provides differential scanning calorimetry (DSC) profiles of polymorphs corresponding to the present disclosure. [Figure 18A] 1 provides thermogravimetric analysis (TGA) profiles of polymorphs corresponding to the present disclosure. [Figure 18B] The present disclosure provides two-dimensional gas evolution analysis of polymorphs corresponding thereto. [Figure 18C] The present disclosure provides a three-dimensional gas evolution analysis of polymorphs corresponding thereto. [Figure 18D] The kinetic gas evolution profiles of polymorphs corresponding to the present disclosure are provided. [Figure 19] 1 provides Fourier transform infrared (FT-IR) spectra of samples of evolved gas from 2-propanol, heptane, and polymorphs corresponding to the present disclosure. [Figure 20] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 21] 1 provides XRPD spectra of polymorphs corresponding to the present disclosure. [Figure 22] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 23] 1 provides XRPD spectra of polymorphs corresponding to the present disclosure. [Figure 24] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 25] 1 provides an XRPD spectrum of Form XIX polymorph corresponding to the present disclosure. [Figure 26]1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 27] 1 provides an XRPD spectrum of Form V polymorph corresponding to the present disclosure. [Figure 28] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 29] 1 provides an XRPD spectrum of Form VI polymorph corresponding to the present disclosure. [Figure 30] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 31] 1 provides an XRPD spectrum of the Form VII polymorph corresponding to the present disclosure. [Figure 32] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 33] 1 provides differential scanning calorimetry (DSC) profiles of polymorphs corresponding to the present disclosure. [Figure 34] 1 provides thermogravimetric analysis (TGA) profiles of polymorphs corresponding to the present disclosure. [Figure 35] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 36] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 37] 1 provides an XRPD spectrum of Form VIII polymorph corresponding to the present disclosure. [Figure 38] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 39] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 40] 1 provides an XRPD spectrum of the Form IX polymorph corresponding to the present disclosure. [Figure 41]1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 42] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 43] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 44] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 45] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 46] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 47] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 48] 1 provides thermogravimetric analysis (TGA) profiles of polymorphs corresponding to the present disclosure. [Figure 49] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 50] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 51] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 52] 1 provides an XRPD spectrum of the Form X polymorph corresponding to the present disclosure. [Figure 53] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 54] 1 provides an XRPD spectrum of Form XI polymorph corresponding to the present disclosure. [Figure 55] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 56] 1 provides an XRPD spectrum of Form XII polymorph corresponding to the present disclosure. [Figure 57] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 58] 1 provides an XRPD spectrum of a mixture of polymorphs corresponding to the present disclosure. [Figure 59] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 60] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 61] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 62] 1 provides an XRPD spectrum of a mixture of polymorphs corresponding to the present disclosure. [Figure 63] An enlarged view of Figure 58 is provided. [Figure 64] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 65] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 66] 1 provides XRPD spectra of several of the polymorphs corresponding to the present disclosure collected at several time points during incubation. [Figure 67] 1 provides differential scanning calorimetry (DSC) profiles of polymorphs corresponding to the present disclosure. [Figure 68] Differential scanning calorimetry (DSC) profiles of some of the polymorphs corresponding to the present disclosure are provided. [Figure 69] 1 provides thermogravimetric analysis (TGA) profiles of polymorphs corresponding to the present disclosure. [Figure 70] An enlarged view of Figure 69 is provided. [Figure 71] 1 provides an XRPD spectrum of Form XIV polymorph corresponding to the present disclosure. [Figure 72]1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 73] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 74] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 75] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 76] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 77] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 78] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 79] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 80] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 81] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 82] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 83] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 84] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 85] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 86] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 87] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 88] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 89] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 90] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 91] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. [Figure 92] 1 provides XRPD spectra of some of the polymorphs corresponding to the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0087] Described herein are highly pure compositions comprising (Z)-endoxifen and methods for synthesizing (Z)-endoxifen at high levels of purity, e.g., isomeric purity. In certain embodiments, the disclosure provides compositions comprising crystalline forms of the compound of formula (III) and methods for synthesizing the compound of formula (III) at high levels of purity: [ka] Compounds of formula (III) may include mixtures of (E)-endoxifen and (Z)-endoxifen.

[0088] In certain embodiments, the present disclosure provides compositions comprising a crystalline form of the compound of formula (IV), and methods for synthesizing the compound of formula (IV) with a high level of purity: [ka] Compounds of formula (IV) can include (Z)-endoxifen.

[0089] In certain embodiments, the present disclosure provides crystalline forms of (Z)-endoxifen free base, isomerically pure pharmaceutically acceptable salts of (Z)-endoxifen, and crystalline forms of mixtures of (E)-endoxifen and (Z)-endoxifen, as well as pharmaceutical compositions of endoxifen comprising the crystalline forms described herein. In some embodiments, the crystalline forms of (Z)-endoxifen free base or mixtures of (E)-endoxifen and (Z)-endoxifen are purified to reduce impurities.

[0090] In one aspect, the disclosure provides methods for making (Z)-endoxifen free base, a mixture of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and pharmaceutically acceptable salts thereof. In one aspect, the method is a synthetic method for making stable (Z)-endoxifen free base, E / Z-mix, and pharmaceutically acceptable salts thereof. In some embodiments, the method can be industrially scalable. For example, the method described herein can be scaled to produce up to 5 kg of (Z)-endoxifen free base, E / Z-mix, or pharmaceutically acceptable salts thereof. In another aspect, the disclosure provides methods for making compositions comprising stable (Z)-endoxifen free base, its polymorphs, E / Z-mix, and pharmaceutically acceptable salts thereof. In some embodiments, the methods provided herein can be used to synthesize (Z)-endoxifen free base, its polymorphs, mixtures of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and pharmaceutically acceptable salts thereof with high levels of purity (e.g., ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%).

[0091] Synthesis of (Z)-endoxifen Several methods can be used for the synthetic preparation of endoxifen a. For example, the synthetic preparation methods of endoxifen and their prodrugs and salts are disclosed in U.S. Patent No. 9,333,190 (Ahmad, Jina Pharmaceuticals); WO2008 / 070463 (Ahmad, Jina Pharmaceuticals), U.S. Publication No. 2010 / 0112041 (Ahmad, Jina Pharmaceuticals), WO2012 / 050263 (Ahmad, Jina Pharmaceuticals), WO2014 / 141292 (Desai, Intas Pharmaceuticals), WO2017 / 070651 (USA / Alchem ​​Lab.Corp.); WO2009 / 120999A2 (Kushner), U.S. Patent No. 8,063,249 (Kushner, Olema Pharmaceuticals), U.S. Patent Nos. 7,531,578 and 8,119,695 (Forman and Yu), or WO2012 / 050263 (Song, CJ Cheiljedang Corp).

[0092] Additional methods that can be used for the synthetic preparation of endoxifen include those described in Gauthier et al., J. Org. Chem, 61, 3890-3893 (1996); Fauq et al., Bioorg Med Chem Lett. 2010 May 15; 20(10): 3036-3038; Stearns et al., J. Natl. Cancer Inst. Vol. 95, No. 23, 2003; Johnson et al., Breast Cancer Research and Treatment. 85: 151-159, 2004; and Ogawa et al. Chem. Pharm. Bull. 39, 911-916, 1991. However, there remains an unmet need for large-scale, industrially scalable production. Furthermore, there is a need for methods, including industrially scalable methods, for synthesizing and purifying (Z)-endoxifen with high purity. The methods provided herein, such as those according to Scheme 1, can be used to prepare endoxifen in fewer steps than other synthetic methods. As shown in Scheme 1, the methods described herein can be used to synthesize and purify (Z)-endoxifen in three steps. The three-step process can have an increased yield of (Z)-endoxifen compared to methods with more steps (e.g., four- or five-step processes) because losses may occur at each step of the reaction.

[0093] The present disclosure addresses this need by providing methods for synthesizing highly pure (e.g., isomerically pure) and stable (Z)-endoxifen. Specifically, the disclosed methods include multiple crystallization steps for enrichment of (Z)-endoxifen from an isomeric mixture of (E) / (Z)-endoxifen. Such crystallization steps can include EtOAc-based crystallization, IPA / acetone-based crystallization, and THF-IPA-based crystallization. Thus, in some embodiments, stable (Z)-endoxifen can be prepared according to Scheme 1, as further described below and in Examples 1-3.

[0094] Scheme 1 - Synthesis of (Z)-endoxifen with improved purity and stability [ka] Synthesis Step 1 - Demethylation In one aspect, the present disclosure relates to an industrially scalable process for making substantially purified (Z)-endoxifen free base, E / Z-mix, or a pharmaceutically acceptable salt thereof, such process comprising demethylating a compound of formula (I), i.e., [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone (available, for example, from AstaTech Pharmaceuticals, Inc., China), to form a compound of formula (II), as described, for example, in Example 1 herein. Thus, in some embodiments, the industrial process comprises preparing a compound of formula (II) by demethylating [4-[2-(dimethylamino)ethoxy]phenyl](4-hydroxyphenyl)methanone (i.e., a compound of formula (I)) with a demethylating agent and a proton acceptor in an inert organic solvent to form a compound of formula (II). An industrially scalable process for making a compound of Formula (II) can involve demethylating a compound of Formula (I) in amounts ranging from 1 mg to 1000 kg per reaction. In some embodiments, about 0.1 kg to about 10 kg of a compound of Formula (I) is demethylated using the processes described herein.

[0095] In some embodiments, the compound of Formula (I) can be demethylated by reacting the compound of Formula (I) with a demethylating agent. The demethylating agent can be any agent suitable for the purpose. Examples of suitable demethylating agents include N-iodosuccinamide (NIS), ethyl chloroformates (e.g., 1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, α-chloroethyl chloroformate (ACE-Cl)), vinyl chloroformate (VO-Cl), cyanogen bromide (BrCN: von Braun reaction), diethyl azodicarboxylate, pyridinium chloride, etc.

[0096] In some embodiments, the demethylating agent is a chloroformate selected from the group consisting of 1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, α-chloroethyl chloroformate (ACE-Cl), and vinyl chloroformate (VO-Cl). In other embodiments, the demethylating agent is an ethyl chloroformate, such as an ethyl chloroformate selected from the group consisting of 1-chloroethyl chloroformate, dichloroethyl chloroformate, trichloroethyl chloroformate, and α-chloroethyl chloroformate (ACE-Cl). In at least one embodiment, the demethylating agent is 1-chloroethyl chloroformate.

[0097] In some embodiments, the demethylating agent is added to the reaction mixture at a wt / wt ratio of the compound of Formula (I) to the demethylating agent ranging from 1:0.5 to 1:10. In other embodiments, the demethylating agent is present at a ratio (wt / wt) of the compound of Formula (I) to the demethylating agent ranging from 1:2 to 1:5. In at least one embodiment, the demethylating agent is present at a ratio (wt / wt) of the compound of Formula (I) to the demethylating agent of 1:2. In at least one embodiment, the demethylating agent is present at a ratio (wt / wt) of the compound of Formula (I) to the demethylating agent of 1:3.3. In other embodiments, the demethylating agent 1-chloroethyl chloroformate is present at a ratio (wt / wt) of the compound of Formula (I) to the demethylating agent ranging from 1:0.5 to 1:10.

[0098] The demethylation reaction can be carried out in an inert organic solvent suitable for demethylation reactions in the presence of a proton acceptor. Examples of such inert organic solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, nitromethane, 1,2-dimethoxyethane (DME), pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, and decane, or a combination thereof. In one embodiment, an industrially scalable process includes one or more inert organic solvents for demethylation in a ratio (wt / wt) of the compound of Formula (I) to the inert organic solvent ranging from 1:1 to 1:50. In some embodiments, the demethylation solvent is THF in a ratio of the compound of Formula (I) to THF (wt / wt) ranging from 1:1 to 1:50, hi other embodiments, THF is present in a ratio of the compound of Formula (I) to THF (wt / wt) ranging from 1:1 to 1:20.

[0099] Suitable proton acceptors for purposes of the present disclosure include, but are not limited to, carbonates, e.g., sodium and potassium carbonate, and bicarbonates, e.g., sodium and potassium bicarbonate, proton sponge, and ethyldiisopropylamine (N,N-diisopropylethylamine, "DIPEA"). In one aspect, an industrially scalable process includes a proton acceptor added to the reaction mixture at a wt / wt ratio of compound of Formula (I) to proton acceptor ranging from 1:0.5 to 1:10. In some embodiments, the proton acceptor is present at a ratio (wt / wt) of compound of Formula (I) to proton acceptor of 1:1:8.

[0100] One of ordinary skill in the art would be able to readily determine other solvents and proton acceptors known in the art that are suitable for the demethylation reactions of the present disclosure.

[0101] The demethylating agent, the solvent for the demethylation reaction, and the compound of formula (I) can be added in any order. Each reagent can be added in a single bolus or in multiple boluses to a suitable reactor and stirred.

[0102] In some embodiments, a compound of Formula (I) is placed in a suitable reactor containing THF, an inert organic solvent, and a proton acceptor, DIPEA, for the demethylation reaction, and the mixture is heated to 55°C to 65°C, or 60°C, followed by the addition of one or more demethylating agents. This addition can be carried out under an inert gas, such as nitrogen. THF is added in a wt / wt ratio of 1:1 to 1:20, and the proton acceptor, DIPEA, is added to the demethylation reaction mixture in a wt / wt ratio of 1:0.5 to 1:10, where wt / wt is relative to the compound of Formula (I). In some embodiments, the reaction mixture is heated to 60°C or higher (NLT), followed by the gradual addition of one or more demethylating agents. The reaction can be carried out under inert conditions, such as nitrogen or argon.

[0103] A reaction mixture comprising a compound of Formula (I), one or more demethylating agents (e.g., 1-chloroethyl chloroformate) in one or more inert organic solvents can be heated at temperatures ranging from 20°C to 200°C, e.g., 40°C to 80°C, 50°C to 230°C, 50°C to 120°C, and 150°C to 200°C. In some embodiments, the reaction mixture is heated under reflux. In other embodiments, the compound of Formula (I) is reacted with the demethylating agent and proton acceptor for NLT 5 hours or more, NLT 8 hours, NLT 12 hours, NLT 24 hours, NLT 36 hours, NLT 48 hours, or NLT 72 hours. In at least one embodiment, the reaction is heated under reflux for NLT 12 hours. In some embodiments, the reaction mixture is held under reflux conditions with stirring for NLT 12 hours or less.

[0104] The mixture may be subjected to one or more rounds of distillation under reduced pressure. The distillation may be carried out at 100° C. NMT, 95° C. NMT, 90° C. NMT, 85° C. NMT, 80° C. NMT, or 70° C. NMT using a solvent suitable for distillation, such as ethyl acetate, lower alcohols (non-limiting examples include methanol, ethanol, n-propanol, and isopropanol), benzene, acetone, acetonitrile, toluene, dichloromethane, 1,2-dichloroethane, and chloroform. Those skilled in the art will be able to readily determine additional suitable solvents useful for this purpose.

[0105] In at least one embodiment, the solvent used for distillation is methanol. As a non-limiting example, methanol may be used for solvent exchange for 2 to 5 rounds of distillation under reduced pressure.

[0106] A solvent, such as methanol, may be used for the distillation at a (wt / wt) ratio of the compound of formula (I) to the solvent ranging from 1:1 to 1:10 per round of distillation.

[0107] The mixture can then be reacted with a solvent / acid mixture by adding the acid (wt / wt ratio of the compound of Formula (I) to the acid ranging from 1:1 to 1:10) to the solvent while stirring and heating under reflux. The acid can be any suitable acid. HCl is an example of a suitable acid for purposes of the present disclosure. Non-limiting examples of suitable solvent / acid mixtures include methanol / HCl, ethanol / HCl, propanol / HCl, isopropanol / HCl, methanol / sulfuric acid, methanol / phosphoric acid, ethanol / sulfuric acid, ethanol / phosphoric acid, propanol / sulfuric acid, propanol / phosphoric acid, isopropanol / sulfuric acid, isopropanol / phosphoric acid, methanol / acetic acid, ethanol / acetic acid, propanol / acetic acid, isopropanol / acetic acid, methanol / formic acid, ethanol / formic acid, propanol / formic acid, and isopropanol / formic acid. In at least one embodiment, the solvent / acid mixture is methanol / 6N HCl. As a non-limiting example, the methanol in the methanol / HCl mixture can be added at a wt / wt ratio of the compound of Formula (I) to the methanol in the solvent / acid mixture of 1:3.2, while the HCl in the methanol / HCl mixture can be at a wt / wt ratio of the compound of Formula (I) to the HCl in the solvent / acid mixture of 1:4. In at least one embodiment, the methanol / 6N HCl mixture is added at a wt / wt ratio of the compound of Formula (I) to the methanol / 6N HCl ranging from 1:1 to 1:10, e.g., from 1:1 to 1:5.

[0108] The distillation may be carried out under reduced pressure for NLT 5 hours, NLT 8 hours, NLT 10 hours, NLT 12 hours, or NLT 14 hours. The distillation may be carried out at a temperature of NMT 70°C, NMT 75°C, NMT 80°C, NMT 85°C, NMT 90°C, or NMT 90°C. After distillation, the mixture may be cooled to ambient temperature (e.g., 15°C to 25°C).

[0109] The pH of the reaction mixture can be increased with an alkaline agent, such as sodium hydroxide (NaOH), ammonium hydroxide, aminomethylpropanol, or the like. In some embodiments, the pH of the reaction mixture can be increased to at least pH 11, at least pH 12, at least pH 13, or at least pH 14. An organic solvent, such as ethyl acetate (EtOAc), can be added to obtain (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone, i.e., the compound of Formula (II). The addition of an organic solvent (e.g., ethyl acetate) can result in a phase separation comprising an aqueous layer and an organic layer. The aqueous layer can be cooled to a temperature of -5°C to 5°C and stirred for NLT 2 hours. The aqueous layer can be washed with water, an organic solvent, or a combination thereof.

[0110] The neutralizing agent can be in a wt / wt ratio of the compound of Formula (I) to the neutralizing agent ranging from 1:1 to 1:10. In some embodiments, the neutralizing agent is 8N sodium hydroxide in a wt / wt ratio ranging from 1:1 to 1:10. In other embodiments, the neutralizing agent is 8N sodium hydroxide in a wt / wt ratio ranging from 1:2 to 1:8.

[0111] In another aspect, an industrially scalable process for making (Z)-endoxifen free base, E / Z-mix, or a pharmaceutically acceptable salt thereof includes one or more steps of washing the filtered product (e.g., the compound of Formula (II)) with purified water (e.g., 1:1 to 1:5 wt / wt) and an organic solvent, such as ethyl acetate (EtOAc) (using a ratio of 1:0.5 to 1:10 wt / wt), where wt / wt is relative to the compound of Formula (I). The wet cake can be dried under reduced pressure / vacuum. The temperature for the drying step can range from 25°C to 60°C. In some embodiments, drying is performed at a temperature of 50°C NMT or 60°C NMT.

[0112] The demethylation reactions described herein may have a chemical yield of about NLT 50%, about NLT 60%, about NLT 65%, about NLT 70%, about NLT 75%, about NLT 80%, about NLT 85%, or about NLT 90%, based on the starting amount used for the compound of formula (I).

[0113] Synthesis Step 2 - McMurry Reaction In another aspect, the present disclosure relates to an industrially scalable process for making (Z)-endoxifen free base, E / Z-mix, and pharmaceutically acceptable salts thereof, the process comprising subjecting a compound of formula (II) to a McMurry reaction, for example, as described in Example 2 herein, to provide an E / Z-mix of endoxifen (i.e., a mixture of (E)-endoxifen and (Z)-endoxifen free base), described as formula (III).

[0114] The McMurry reaction can be used to prepare tamoxifen, for example, as described in European Patent Application No. 168175. The present disclosure relates to an industrially scalable process in which a compound of formula (II), i.e., (4-hydroxyphenyl)(4-(2-(methylamino)-ethoxy)phenyl)methanone, can be coupled to propiophenone mediated by the McMurry reaction using a titanium salt, e.g., a titanium chloride salt (e.g., titanium trichloride and / or titanium tetrachloride (titanium(IV) chloride, TiCl4)), and a reducing agent in an inert organic solvent to form an E / Z mix of formula (III).

[0115] Titanium salts useful for the present disclosure include titanium halides (e.g., titanium trichloride (TiCl), titanium tetrachloride (TiCl), titanium iodide, titanium bromide, and titanium fluoride), titanium trichloride isopropoxide, and titanium isopropoxide. In some embodiments, the titanium salt is TiCl. The titanium salt, e.g., TiCl, is added at a wt / wt ratio of the compound of Formula (II) to the titanium salt ranging from 1:0.1 to 1:12.

[0116] Reducing agents include zinc, zirconium, vanadium, niobium, molybdenum, tungsten, aluminum, magnesium, potassium, zinc-copper complexes, alkali and alkaline earth metals, butyllithium, and lithium aluminum hydride. In at least one embodiment, the reducing agent is zinc. The McMurry synthesis can be conveniently carried out using a reducing agent such as zinc in a wt / wt ratio of the compound of Formula (II) to reducing agent ranging from 1:0.1 to 1:10. In some embodiments, the ratio of reducing agent is in excess compared to the titanium salt.

[0117] The McMurry synthesis can be carried out in one or more inert organic solvents. Useful inert organic solvents for the McMurry reaction include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, nitromethane, 1,2-dimethoxyethane (DME), pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, and decane, or combinations thereof. In some embodiments, the inert organic solvent is present in a wt / wt ratio of the compound of Formula (II) to the solvent ranging from 1:1 to 1:50. In other embodiments, the inert organic solvent is present in a wt / wt ratio of the compound of Formula (II) to the solvent ranging from 1:1 to 1:20. In some embodiments, the inert organic solvent used for the McMurry reaction is THF, in some embodiments in a wt / wt ratio of the compound of Formula (II) to THF ranging from 1:1 to 1:20.

[0118] It may be advantageous to combine one or more titanium salt(s) and one or more reducing agent(s) in an inert organic solvent to form a premix. The titanium salt(s) may be added to the reducing agent and inert organic solvent at a rate to maintain an internal temperature at 75° C. NMT, e.g., 65° C. NMT, 55° C. NMT, 45° C. NMT, 40° C. NMT, 35° C. NMT, 30° C. NMT, 25° C. NMT, 20° C. NMT, or 15° C. NMT. ​​Thus, the titanium salt(s) and reducing agent(s) in the inert organic solvent are combined to form a premix. In some embodiments, Zn, TiCl4, and THF are combined to form a Zn / TiCl4 / THF mixture. In at least one embodiment, TiCl4 is added gradually to Zn and THF and mixed while maintaining an internal temperature at 20° C. NMT.

[0119] The preparation of the titanium salt and reducing agent in the inert organic solvent may further include heating the titanium salt and reducing agent in the inert organic solvent to a temperature ranging from 20°C to 100°C, e.g., 40°C to 80°C, 50°C to 100°C, 50°C to 80°C, or 50°C to 70°C. In some embodiments, the titanium salt and reducing agent in the inert organic solvent are heated to NLT 60°C. In some embodiments, the preparation of the titanium salt and reducing agent in the inert organic solvent further includes heating the titanium salt and reducing agent in the inert organic solvent. The titanium salt and reducing agent in the inert organic solvent are heated under inert conditions, e.g., nitrogen (N) or argon (Ar), for NLT 30 minutes, e.g., NLT 1 hour, NLT 2 hours, NLT 4 hours, NLT 6 hours, and NLT 8 hours.

[0120] It may be advantageous to premix the compound of Formula (II) with an inert organic solvent, such as THF and propiophenone, and then react the compound of Formula (II) with a premixed reducing agent / titanium salt / solvent mixture, such as a Zn / TiCl4 / THF mixture, to provide a mixture of (E)-endoxifen and (Z)-endoxifen, i.e., the compound of Formula (III). Propiophenone may be added in a wt / wt ratio of the compound of Formula (II) to propiophenone ranging from 1:0.01 to 1:5. The inert organic solvent may be in a wt / wt ratio of the compound of Formula (II) to solvent ranging from 1:1 to 1:20. In step 1, the compound of formula (II) is reacted with a titanium salt and a reducing agent in an organic solvent at a temperature of NLT 60°C or NLT 70°C for NLT 0.5 hours, NLT 1 hour, NLT 2 hours, NLT 4 hours, NLT 6 hours, NLT 8 hours, NLT 12 hours, NLT 24 hours, or NLT 48 hours. In at least one embodiment, the compound of formula (II) is gradually mixed with THF and propiophenone for NLT 1 hour. The mixture can be reacted with a premix of Zn, TiCl4, and THF and heated to NLT 60°C or NLT 70°C for NLT 8 hours. In another embodiment, the compound of formula (II) is mixed with THF and propiophenone, reacted with the Zn / THF / TiCl4 mixture described above, and heated for NLT 8 hours.

[0121] The mixture of (E)-endoxifen and (Z)-endoxifen in the reaction mixture can then be subjected to extractive purification, distillation, and crystallization to provide a purified mixture of (E)-endoxifen and (Z)-endoxifen. The mixture of (E)-endoxifen and (Z)-endoxifen in the reaction mixture can then be subjected to extractive purification by extraction with an inert organic solvent, such as THF and 2-methyltetrahydrofuran (MeTHF), or by adding a salt, such as potassium carbonate, ammonium chloride, sodium chloride, or sodium hydroxide, to the reaction mixture and extracting with an inert organic solvent, such as THF and MeTHF. The reaction mixture can then be cooled to a temperature of about 0°C to about 35°C or 30°C NMT. ​​An acid (e.g., HCl) can be added to the mixture, and the mixture can be stirred for NLT 30 minutes. In some embodiments, 1N HCl is added. The mixture can then be filtered and phase-separated.

[0122] In some embodiments, the reaction mixture is extracted one or more times with potassium carbonate (K2CO3), e.g., 40% K2CO3 (1:1 to 1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt). In some embodiments, the reaction mixture is extracted one or more times with ammonium chloride, e.g., 25% ammonium chloride (1:1 to 1:30 wt / wt); a silica (Celite®) bed (1:0.01 to 1:5 wt / wt); and / or a solvent, e.g., THF (1:1 to 1:10 wt / wt). In some embodiments, the E / Z mixture can be further extracted with NaOH, e.g., 1N NaOH (1:1 to 1:20 wt / wt). In at least one embodiment, NaCl (1:0.1 to 1:0.5 wt / wt) can be added to 1N NaOH for the extraction step.

[0123] In some embodiments, the reaction mixture can be further extracted one or more times with THF or MeTHF. In at least one embodiment, the reaction mixture is extracted three or more times with MeTHF. Without being bound by any theory, MeTHF has been found to be surprisingly suitable for the process of extracting a mixture of (E)-endoxifen and (Z)-endoxifen, providing a higher yield of a purified mixture of (Z)-endoxifen and (E)-endoxifen. In at least one embodiment, the mixture can still be further extracted with 20% sodium chloride (1:1 to 1:10 wt / wt).

[0124] The reaction mixture may be subjected to 2 to 5 rounds of solvent exchange and distillation with a suitable solvent, such as acetone, acetonitrile, or a combination thereof (1:1 to 1:10 wt / wt relative to the compound of Formula (III)). The distillation may be carried out under reduced pressure / vacuum at a temperature ranging from 30°C to 90°C. In some embodiments, the distillation may be carried out at a temperature of 30°C NMT, 35°C NMT, 40°C NMT, 45°C NMT, 50°C NMT, 55°C NMT, 60°C NMT, 65°C NMT, 70°C NMT, 75°C NMT, 80°C NMT, or 90°C NMT, and filtered. The filtered product can be washed with a solvent, such as pre-chilled acetonitrile, and then crystallized in a crystallization system, such as EtOAc / n-heptane (1:2 v / v) or IPA / n-heptane (1:2.7 v / v), at a wt / wt ratio of the compound of formula (III) to EtOAc / n-heptane or IPA / n-heptane ranging from 1:1 to 1:20, and dried, for example, at 60° C. NMT, to provide a crystalline solid mixture of (E)-endoxifen and (Z)-endoxifen free base, i.e., the compound of formula (III).

[0125] In yet another aspect, the present disclosure relates to an industrially scalable method for producing or re-equilibrating an E / Z-mix having an E / Z ratio of approximately 1:1 (45:55 to 55:45). A suitable reactor is charged with a compound of Formula (III) dissolved in an inert organic solvent, such as ethyl acetate, and can be prepared in a McMurry reaction as described above. The compound of Formula (III) can have an E / Z ratio of 99:1 to 60:40. The mixture can be concentrated at a temperature ranging from 40°C to 85°C. In some embodiments, the mixture is concentrated at a temperature of 75°C NMT until the volume reaches about 5% of the initial volume. The mixture can be heated to reflux and then cooled to a temperature ranging from 40°C to 60°C. In some embodiments, the temperature of the mixture is cooled to 50±5°C. n-Heptane may be added gradually to the mixture in a ratio of the compound of Formula (III) to n-heptane ranging from 1:1 to 1:20, and the mixture may then be cooled to 0±5°C. The mixture may be stirred at 0±5°C for NLT 0.5, NLT 1, NLT 2, NLT 4, NLT 8, NLT 12, or NLT 24 hours. The mixture may be filtered and washed with ethyl acetate / n-heptane (1:2 v / v) in a wt / wt ratio of the compound of Formula (III) to ethyl acetate / n-heptane ranging from 1:1 to 1:10. The wet cake may be dried under reduced pressure to provide an E / Z-endoxifen mixture having an E / Z-ratio of approximately 1:1. Drying may be carried out at a temperature ranging from 30°C to 70°C. In some embodiments, the infiltrated cake is dried under reduced pressure or vacuum at 60°C NMT to provide an E / Z-endoxifen mixture having an E / Z-ratio of approximately 1:1 (e.g., about 45:55 to about 55:45).

[0126] The McMurry reaction described herein may have a yield of about NLT 15%, about NLT 20%, about NLT 25%, about NLT 27%, about NLT 30%, about NLT 32%, about NLT 35%, or about NLT 40%, based on the amount of compound of formula (II) used.

[0127] In yet another embodiment, the compound of formula (III) can be further purified, or concentrated, or re-equilibrated to obtain substantially pure (Z)-endoxifen as described below.

[0128] Synthesis Step 3 - Concentration and Purification of (Z)-Endoxifen Free Base In yet another aspect, the present disclosure relates to an industrially scalable method for producing (Z)-endoxifen free base (by concentration and purification). Industrially scalable concentration and purification of (Z)-endoxifen can be carried out as described herein using the method of Step 3 of Scheme 1 and as further described in Example 3. The starting mixture of (E)-endoxifen and (Z)-endoxifen used for fractional crystallization can have any E / Z ratio, for example, an E / Z ratio ranging from 99:1 to 1:10. In some embodiments, the E / Z ratio of the starting (E) / (Z)-endoxifen mixture ranges from about 30:70 to about 70:30. In some embodiments, the E / Z ratio of the starting (E) / (Z)-endoxifen mixture ranges from 99:1 to 1:99. In some embodiments, the E / Z-ratio of the starting (E) / (Z)-endoxifen mixture is 51:1, 1:1.8, or 1:5.6.

[0129] The E / Z-mix can be a compound of Formula (III) obtained as described above. A mixture of (E)-endoxifen and (Z)-endoxifen (E / Z-mix) can be subjected to fractional crystallization to obtain a first crystalline solid and a first mother liquor enriched in (Z)-endoxifen free base. Fractional crystallization can be carried out using a first solvent capable of triturating endoxifen and its derivatives so that (Z)-endoxifen tends to remain in the filtrate. Suitable first solvents are those that differentially solubilize endoxifen isomers, including, but not limited to, ethyl acetate, isopropanol, isopropanol / PPW, acetonitrile, acetonitrile / PPW, and dichloromethane. In some embodiments, the first recrystallization solvent used in the methods described herein is ethyl acetate. The first solvent, e.g., ethyl acetate, is added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:20. In some embodiments, a compound of Formula (III) is dissolved in a solution comprising a first solvent and an acid, such as HCl. The resulting mixture can be heated to a temperature ranging from about 55° C. to about 65° C. and stirred for about 6 hours or more.

[0130] It has been surprisingly discovered that acidifying the mixture improves the conversion of (Z)-endoxifen to (E)-endoxifen. Thus, in some embodiments, a compound of formula (III) is pretreated with an acid and then conditioned with a base.

[0131] As a non-limiting example, a compound of Formula (III) is placed in a suitable reactor, to which a first solvent (e.g., ethyl acetate) is added and cooled to -5°C to 10°C. An acid, such as HCl or TFA, can then be added gradually while maintaining the temperature at NMT 10°C. In some embodiments, the acid is added to the E / Z-endoxifen mixture at a wt / wt ratio of the compound of Formula (III) to the acid ranging from 1:1 to 1:5. The reaction mixture can then be heated with stirring at a temperature ranging from 50°C to 70°C. The reaction can be carried out for NLT 4 hours, e.g., NLT 6 hours, NLT 12 hours, NLT 24 hours, or NLT 48 hours. The reaction mixture can be cooled to -5°C to 10°C, and the pH can be adjusted to about pH 12.

[0132] In some embodiments, the neutralizing agent is added to the reaction mixture at a wt / wt ratio of the compound of Formula (III) to the neutralizing agent ranging from 1:1 to 1:10. Suitable neutralizing agents include sodium hydroxide, potassium hydroxide, ammonium hydroxide, aminomethylpropanol, and the like. In some embodiments, the neutralizing agent is 8N sodium hydroxide. The pH of the reaction mixture is preferably alkaline. In some embodiments, the pH is ≥ 10, e.g., ≥ 11 or ≥ 12. During the pH adjustment, the temperature of the mixture may be maintained at a temperature of about 20°C or higher.

[0133] EtOAc-based crystallization In some embodiments, (Z)-endoxifen is then extracted into the organic layer, collected, and the aqueous phase is washed one or more times with a first solvent, e.g., ethyl acetate (added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:10). The organic layers are combined and washed one or more times with brine (20% NaCl; added at a wt / wt ratio of the compound of Formula (III) to NaCl ranging from 1:1 to 1:10). The organic layer may be filtered through an activated carbon / (Celite®) bed (e.g., added at a wt / wt ratio of the compound of Formula (III) to silica ranging from 1:0.01 to 1:0.5), washed one or more times with a first solvent, e.g., ethyl acetate (added at a wt / wt ratio of the compound of Formula (III) to the first solvent ranging from 1:1 to 1:10), and the filtrate may be concentrated to about 80%, 70%, or 60% of the volume of the washed filtrate. A first solvent, e.g., ethyl acetate, is added to the concentrated solution to increase its volume by about 20-50%, followed by another round of concentration under reduced pressure to about 80%, 70%, or 60% of the original volume. The resulting concentrated solution is cooled to about 5°C NMT, heated to about 40-60°C, and cooled again to about 5°C NMT. The cooled mixture is filtered and washed with a first solvent (e.g., ethyl acetate) to provide (i) a wet cake, which can be dried at 90°C NMT to recover the compound of formula (III), and (ii) a filtrate. The filtrate fractions, which can be defined as the first mother liquor, can be combined and concentrated.

[0134] The first mother liquor can be enriched in (Z)-endoxifen, for example, using one, two, three, or more rounds of crystallization, as described herein, for example, in Example 3. In some embodiments, the first mother liquor is enriched in (Z)-endoxifen by at least 50% when compared to the E / Z-ratio of the starting mixture of E-endoxifen and Z-endoxifen used in synthesis step 3. In other embodiments, the first mother liquor is enriched in (Z)-endoxifen by at least 70% when compared to the E / Z-ratio of the mixture of E-endoxifen and Z-endoxifen.

[0135] IPA / acetone-based recrystallization In some embodiments, the first mother liquor can be subjected to a second crystallization step using a second recrystallization solvent system (e.g., comprising a first and a second solvent) by concentrating the first mother liquor (e.g., comprising ethyl acetate), adding the first solvent, and / or exchanging the first solvent with the second solvent one or more times. Recrystallization can be performed using the second solvent for the exchange. The second solvent can be added at a wt / wt ratio of the compound of Formula (III) initially used to the second solvent ranging from 1:1 to 1:10 to generate a slurry. Suitable second solvents include IPA, IPA / PPW, acetone, acetone / MTBE, ethanol, EtOAc, and EtOAc / n-heptane. In some embodiments, the first solvent can be acetone. In some embodiments, the second solvent is IPA. Thus, in some cases, both acetone (first solvent) and IPA (second solvent) can be used consecutively in this step. Surprisingly, IPA has been found to triturate (Z)-endoxifen to a higher level of solid fractionation than EtOAc. Thus, in some embodiments, when the mother liquor solvent is EtOAc, a first solvent (e.g., acetone) can be used in the first exchange step, and the second solvent for the exchange is IPA or IPA / PPW, or a combination of acetone and IPA (e.g., using acetone first, followed by IPA). This can be useful when (Z)-endoxifen is first introduced into the filtrate (e.g., mother liquor(s)) from EtOAc and / or acetone, and then introduced into the solid fractionation from IPA or IPA / PPW (e.g., cooled IPA). In at least one embodiment, the second solvent comprises IPA / PPW. In yet another embodiment, the second solvent comprises acetone / MTBE. In another embodiment, as described in Example 3, the first solvent used in this step is acetone, and the second solvent is IPA or IPA / PPW.

[0136] Thus, in some embodiments, the concentrated first mother liquor can be diluted with acetone (e.g., about 7, 8, or 9 weight equivalents ("wt.") relative to the initial amount of Formula (III) used) at a temperature of about 30°C or higher and concentrated. Another round of the same amount of acetone can be added, followed by concentration under reduced pressure to about 20-30% of the initial volume. IPA (e.g., about 1-1.5 wt.) can then be added to the concentrate at a temperature of NLT 40°C, followed by concentration under reduced pressure until the solution reaches approximately the volume it had before the IPA addition. The resulting mixture can be cooled to about 0±5°C and stirred at that temperature for NLT 6 hours. The mixture can then be filtered and washed with pre-chilled IPA (about 1.6 wt.) to provide a crude second crystalline solid. The second crystalline solid was crude (Z)-endoxifen, (Z)-4-(1-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol, i.e., the compound of formula (IV) (molecular weight 373.49; molecular formula: C 25 H 27 NO2; melting point 139°C-143°C). The second crystalline solid can be ≥70% (Z)-endoxifen, e.g., ≥75% (Z)-endoxifen, ≥80% (Z)-endoxifen, or ≥90% (Z)-endoxifen. In some embodiments, the (crude) second crystalline solid can be ≥90% (Z)-endoxifen. In some embodiments, the product can be dried at a temperature of NMT 70°C, e.g., NMT 75°C, NMT 80°C, or NMT 85°C to produce a crude compound of Formula (IV). In some embodiments, the crude compound of Formula IV can comprise a polymorph of (Z)-endoxifen. Polymorphs can be characterized, for example, by X-ray powder diffraction patterns.

[0137] THF / IPA-based crystallization In some embodiments, the dried crude concentrated (Z)-endoxifen product may be subjected to a third round of crystallization to reduce or remove remaining impurities. The dried crude product may be treated with a third recrystallization solvent system, which may include a first solvent and a second solvent. The dried crude product may be resuspended in the first solvent. Suitable first solvents include, but are not limited to, acetone, THF, ethyl acetate, isopropanol, isopropanol / PPW, acetonitrile, acetonitrile / PPW, and dichloromethane. In some embodiments, the first solvent is THF. Recrystallization is performed using a second solvent for exchange. The second solvent may be added at a wt / wt ratio of starting compound of Formula (III) to second solvent ranging from 1:1 to 1:10 to generate a slurry. Suitable second solvents include IPA, IPA / PPW, acetone, acetone / MTBE, ethanol, EtOAc, and EtOAc / n-heptane. In some embodiments, the second solvent is IPA. In some embodiments, when the first solvent is THF, the second solvent is IPA or IPA / PPW, as described in Example 3.

[0138] In some embodiments, the slurry may be filtered and washed with a pre-chilled solvent, such as IPA, and the resulting wet cake may be dried at a temperature of about 80° C. NLT. The dried concentrated product may have a yield of about NLT 8%, about NLT 10%, about NLT 12%, about NLT 14%, about NLT 16%, about NLT 18%, about NLT 20%, about NLT 22%, or about NLT 25%. In some embodiments, the concentrated product may be a crystalline solid comprising (Z)-endoxifen. The crystalline solid can be ≥90% (Z)-endoxifen, ≥91% (Z)-endoxifen, ≥92% (Z)-endoxifen, ≥93% (Z)-endoxifen, ≥94% (Z)-endoxifen, ≥95% (Z)-endoxifen, ≥96% (Z)-endoxifen, ≥97% (Z)-endoxifen, ≥98% (Z)-endoxifen, or ≥99% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≥90% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≥95% (Z)-endoxifen. In some embodiments, the crystalline solid is ≥90% (Z)-endoxifen. In some embodiments, the crystalline solid is ≥95% (Z)-endoxifen. In some embodiments, the crystalline solid is ≧97% (Z)-endoxifen.

[0139] The second crystalline solid can optionally be further recrystallized to obtain a third crystalline solid, (Z)-endoxifen. The third crystalline solid can be ≥90% (Z)-endoxifen, ≥91% (Z)-endoxifen, ≥92% (Z)-endoxifen, ≥93% (Z)-endoxifen, ≥94% (Z)-endoxifen, ≥95% (Z)-endoxifen, ≥96% (Z)-endoxifen, ≥97% (Z)-endoxifen, ≥98% (Z)-endoxifen, or ≥99% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≥90% (Z)-endoxifen. In some embodiments, the purified crystalline solid is ≥95% (Z)-endoxifen. In some embodiments, the third crystalline solid is ≥97% (Z)-endoxifen. This optional recrystallization is carried out using a third solvent selected from the group consisting of ethanol, methanol, ethyl acetate, IPA, IPA / PPW, THF, acetone, acetone / MTBE, and EtOAc / n-heptane.

[0140] Additional recrystallization steps, such as a fourth, fifth, or sixth recrystallization step, can be performed to further concentrate the (Z)-endoxifen crystalline product. Further crystallization steps can be performed in a solvent selected from the group consisting of ethanol, methanol, ethyl acetate, IPA, IPA / PPW, THF, acetone, acetone / MTBE, and EtOAc / n-heptane.

[0141] In one aspect, the present disclosure relates to preheating the first solvent, the second solvent, and the third solvent prior to use. In some embodiments, one or more of the first solvent, the second solvent, and the third solvent can be independently preheated to a temperature ranging from 40° C. to 80° C. The fractional crystallization and recrystallization process can also include distillation at 60° C. to 80° C. and / or cooling the resulting solution to a temperature ranging from 0° C. to 35° C.

[0142] It should be understood that in some embodiments, the first, second, and third crystalline solids and the second mother liquor obtained as described herein can be further subjected to one or more fractional crystallization and recrystallization procedures as described herein to obtain purified (Z)-endoxifen. It should also be understood that the obtained first, second, and / or third crystalline solids can optionally be reprocessed using column chromatography techniques to obtain more (Z)-endoxifen.

[0143] In certain embodiments, the industrially scalable processes described herein independently include additional steps or procedures (e.g., to remove by-products or to work up, isolate, or purify the reaction product) as detailed in the Examples herein. In some embodiments, the (Z)-endoxifen free base has <2%, <1%, and <0.5% impurities. In other embodiments, the compound of Formula (III) has <2%, <1%, and <0.5% impurities.

[0144] Those skilled in the art will recognize several parameters of the foregoing processes that can be modified to obtain a desired outcome, including, for example, the method and means of purification of the reactants and solvent, the order of addition of the reactants and solvent to the reaction mixture, the duration of the reaction of the reactants and solvent, and the temperature and rate of stirring, mixing, or agitation of the reactants and solvent during the reaction.

[0145] Removal of impurities In some embodiments, one or more impurities may be present in the compound formed in the methods described herein. In some instances, the impurities may be present at or below the acceptable concentration limit. In some instances, the impurities may be present above the acceptable concentration limit. Impurities, including those present at concentrations above the acceptable limit, can be removed using the purification methods described herein, for example, by fractional crystallization, recrystallization, or a combination thereof. In some embodiments, the amount of impurities can be reduced using the purification methods described herein, for example, one, two, three, or more cycles of (re)crystallization using one or more solvent systems described herein. In some cases, the impurities may be present at concentrations above the acceptable limit before purification, and may be present at or below the acceptable concentration, below the detection limit, or absent after purification. In some embodiments, purified samples of compounds of formula (IV) herein may contain at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% (Z)-endoxifen by weight after purification.

[0146] Purification can be carried out after any of the synthetic steps described herein. In some embodiments, purification can be carried out after one or more steps of Scheme 1. For example, purification can be carried out after a demethylation reaction (e.g., the demethylation reaction described in Example 1) or a McMurry reaction (e.g., the McMurry reaction described in Example 2). In some embodiments, purification can be carried out on a commercially obtained sample, e.g., a commercial source of an (E) / (Z)-endoxifen mixture of Formula (III). Purification can include one or more steps of crystallization, recrystallization, or a combination thereof. In various embodiments, purification of the compound of Formula (IV) can include the steps of EtOAc crystallization, IPA / acetone recrystallization, and THF / IPA recrystallization (e.g., as described in Example 3). Performing these crystallization steps has been shown to effectively remove impurities, particularly impurities such as mesityl oxide, from the crude Formula (IV) product to provide isomerically pure Formula (IV), i.e., (Z)-endoxifen, in purities of >95%, >96%, >97%, >98%, or >99% by weight.

[0147] Impurities that may be reduced or removed using the purification methods described herein include, but are not limited to: (£)-endoxifen; mesityl oxide; 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol; 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol; (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)-phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)-phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; benzene; methanol; ethanol; acetone; 2-propanol; acetonitrile; ethyl acetate; THF; 2-methyltetrahydrofuran; n-heptane; zinc; titanium; or combinations thereof. For example, the purification methods described herein may reduce the levels of mesityl oxide, (E)-endoxifen, or both in compositions containing (Z)-endoxifen. In some cases, the level of mesityl oxide in compositions containing (Z)-endoxifen can be reduced using the purification methods described herein.

[0148] Impurities may be present at or below an acceptable concentration, below the detection limit, or absent in the compounds described herein (e.g., compounds of Formula (I), Formula (II), Formula (III), and / or Formula (IV)) after purification. An acceptable concentration of methanol in the compound may be about 3,000 parts per million (ppm) or less (NMT). An acceptable concentration of ethanol in the compound may be about 5,000 ppm NMT. ​​An acceptable concentration of acetone in the compound may be about 5,000 ppm NMT. ​​An acceptable concentration of 2-propanol (IPA) in the compound may be about 5,000 ppm NMT. ​​An acceptable concentration of acetonitrile in the compound may be about 410 ppm NMT. ​​An acceptable concentration of ethyl acetate in the compound may be about 5,000 ppm NMT. ​​An acceptable concentration of THF in the compound may be about 720 ppm NMT. An acceptable concentration of 2-methyltetrahydrofuran (MeTHF) in the compound may be about 520 ppm NMT. ​​An acceptable concentration of n-heptane in the compound may be about 5000 ppm NMT. ​​An acceptable concentration of zinc in the compound may be about 130 ppm NMT. ​​An acceptable concentration of benzene in the compound may be about 2 ppm NMT. ​​An acceptable concentration of mesityl oxide in the compound may be about 25 ppm NMT. ​​In some embodiments, the concentration of impurities may be measured using an appropriate analytical method, for example, gas chromatography. In some embodiments, a purified batch of Formula (IV) produced using the methods described herein contains NMT 3000 ppm methanol, NMT 5000 ppm ethanol, NMT 5000 ppm acetone, NMT IPA, 410 ppm NMT acetonitrile, 5000 ppm NMT ethyl acetate, 720 ppm NMT THF, 520 ppm NMT MeTHF, 5000 ppm NMT n-heptane, 130 ppm NMT zinc, 2 ppm NMT benzene, and 25 ppm NMT mesityl oxide.

[0149] (E)-Endoxifen Removal The level of (E)-endoxifen can be reduced in a compound of Formula (III) or a compound of Formula (IV) using one or more purification methods described herein. In some embodiments, (E)-endoxifen can be present in a commercially obtained compound of Formula (III), a compound of Formula (III) synthesized as shown in Scheme 1, or a compound of Formula (IV) synthesized as shown in Scheme 1. (E)-endoxifen can be formed during the McMurry reaction (e.g., step 2 of Scheme 1). Reducing the level of (E)-endoxifen in a compound (e.g., a compound of Formula (III) or a compound of Formula (IV)) can include ethyl acetate fractional crystallization (e.g., as described in Example 3). Reducing the level of (E)-endoxifen in a compound can include acetone recrystallization (e.g., as described in Example 3), for example, using an acetone / IPA solvent system. Reducing the level of (E)-endoxifen in a compound can include THF recrystallization (e.g., as described in Example 3), for example, using a THF / IPA solvent system. Prior to purification, (is)-endoxifen may be present in a compound (e.g., a compound of Formula (III)) at a level of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 7%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the compound by weight. After purification, (is)-endoxifen may be present in a compound (e.g., a compound of Formula (III)) at a level of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 10%, 15%, 20%, or 25% or less of the compound by weight. In such embodiments, (is)-endoxifen may be present in a compound of Formula (IV) at a level of about 1%, 2%, or 3% or less by weight.

[0150] The (is)-endoxifen impurity in a compound, e.g., a compound of Formula (IV), can be identified by analytical methods, e.g., HPLC or LC-MS. In some embodiments, (is)-endoxifen can have a relative retention time (RRT) of about 0.95 compared to (Z)-endoxifen, as measured by HPLC and LC-MS.

[0151] Removal of mesityl oxide The level of mesityl oxide can be reduced in a compound described herein (e.g., a compound of Formula (III) or a compound of Formula (IV)) using a purification method described herein, e.g., a crystallization step. For example, mesityl oxide can be reduced using THF / IPA recrystallization. In some embodiments, mesityl oxide can be introduced from raw materials used in the reaction. In some embodiments, mesityl oxide can be formed during one or more steps of the reaction of Scheme 1. For example, mesityl oxide can be formed via the aldol condensation of acetone, as shown in Scheme 2:

[0152] Scheme 2 - Formation of mesityl oxide via aldol condensation of acetone [ka] Prior to purification, mesityl oxide may be present in the compounds described herein at concentrations greater than the acceptable concentration. In some embodiments, mesityl oxide may be present in the compound formed during one or more steps of the reaction of Scheme 1. For example, mesityl oxide may be present in the compound of Formula (IV) at concentrations greater than the acceptable concentration prior to purification. The acceptable concentration of mesityl oxide in the compound of Formula (IV) may be about 25 ppm or less. In some embodiments, the acceptable concentration of mesityl oxide in the compound may be about 5 ppm, about 10 ppm, about 15 ppm, about 20 ppm, or about 25 ppm or less.

[0153] The level of mesityl oxide present in a compound, e.g., a compound synthesized as shown in Scheme 1, can be reduced or removed using one or more purification methods described herein. Reducing the level of mesityl oxide in a compound can include, for example, THF recrystallization (e.g., as described in Example 3) using a THF / IPA solvent system. Prior to purification (e.g., prior to THF recrystallization), mesityl oxide can be present in the compound (e.g., a compound of Formula (IV)) at levels greater than about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 45 ppm, about 50 ppm, about 60 ppm, about 70 ppm, about 80 ppm, about 90 ppm, about 100 ppm, about 150 ppm, about 200 ppm, about 250 ppm, about 300 ppm, about 350 ppm, about 400 ppm, about 450 ppm, or about 500 ppm. After purification, mesityl oxide may be present in the compound (e.g., a compound of Formula (IV)) at a level of about 5 ppm, about 10 ppm, about 15 ppm, about 20 ppm, or about 25 ppm or less, or the level of mesityl oxide may be below the detection limit of one or more analytical methods used, e.g., HPLC / HLPC-MS, GC / GC-MS, headspace-GC, etc.

[0154] The mesityl oxide impurity in a compound, e.g., a compound of Formula (IV), can be identified by analytical methods, e.g., headspace gas chromatography (GC). In some embodiments, mesityl oxide can have a retention time (RT) of about 14.1 minutes as measured by headspace-GC.

[0155] Reduction of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol The level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be reduced in a compound described herein (e.g., a compound of Formula (III) or a compound of Formula (IV)) using one or more purification methods described herein. In some embodiments, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be formed during one or more steps of the reaction of Scheme 1. For example, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be formed via displacement of a compound of Formula (II) in the presence of methanol, followed by condensation with propiophenone in the presence of Zn / TiCl4, as shown in Scheme 3:

[0156] Scheme 3 - Formation of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol via substitution of compounds of formula (II) [ka] Prior to purification, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compounds described herein at concentrations greater than the acceptable concentration. In some embodiments, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound formed during one or more steps of the reaction of Scheme 1. For example, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or the compound of Formula (IV) at concentrations greater than the acceptable concentration prior to purification. The acceptable concentration of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in the compound may be about 1% or less. In some embodiments, an acceptable concentration of 4-(1-(4-methoxy-phenyl)-2-phenylbut-1-en-1-yl)phenol in the compound may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0157] The level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol present in a compound, for example, a compound synthesized as shown in Scheme 1, can be reduced or removed using one or more purification methods described herein. Reducing the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound (e.g., a compound of Formula (III) or a compound of Formula (IV)) can include ethyl acetate fractional crystallization (e.g., as described in Example 3). Reducing the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound can include acetone recrystallization (e.g., as described in Example 3). Reducing the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound can include THF recrystallization (e.g., as described in Example 3). In some embodiments, all three crystallization steps can be applied.

[0158] Prior to purification, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound (e.g., the compound of Formula (III) or the compound of Formula (IV)) at a level greater than about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5%. After purification, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound (e.g., the compound of Formula (IV)) at a level of about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0159] The 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol impurity in a compound, e.g., a compound of Formula (IV), can be identified by analytical methods, e.g., HPLC or LC-MS. In some embodiments, 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can have a relative retention time (RRT) of about 1.53 compared to (Z)-endoxifen, as measured by HPLC and LC-MS.

[0160] Reduction of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol The level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be reduced in a compound described herein (e.g., a compound of Formula (III) or a compound of Formula (IV)) using one or more purification methods described herein. In some embodiments, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be formed during one or more steps of the reaction of Scheme 1. For example, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can be formed via displacement of a compound of Formula (III) in the presence of 2-propanol, as shown in Scheme 4:

[0161] Scheme 4 - Formation of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol via substitution of compounds of formula (III) [ka] Prior to purification, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compounds described herein at concentrations greater than the acceptable concentration. In some embodiments, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound formed during one or more steps of the reaction of Scheme 1. For example, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), and / or the compound of Formula (IV) at concentrations greater than the acceptable concentration prior to purification. The acceptable concentration of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in the compounds may be about 1% or less. In some embodiments, an acceptable concentration of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in the compound may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0162] The level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol present in a compound, for example, a compound synthesized as shown in Scheme 1, can be reduced or removed using one or more purification methods described herein. Reducing the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound (e.g., a compound of Formula (III) or a compound of Formula (IV)) can include ethyl acetate fractional crystallization (e.g., as described in Example 3). Reducing the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound can include acetone recrystallization (e.g., as described in Example 3). Reducing the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol in a compound can include THF recrystallization (e.g., as described in Example 3). In some embodiments, all three crystallization steps may be applied.

[0163] Prior to purification, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound (e.g., the compound of Formula (III) or the compound of Formula (IV)) at a level greater than about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5%. After purification, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol may be present in the compound (e.g., the compound of Formula (IV)) at a level of about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0164] The 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol impurity in a compound, e.g., a compound of Formula (IV), can be identified by analytical methods, e.g., HPLC or LC-MS. In some embodiments, 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol can have a relative retention time (RRT) of about 1.66 compared to (Z)-endoxifen, as measured by HPLC and LC-MS.

[0165] Reduction of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol The level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol can be reduced in a compound described herein (e.g., a compound of Formula (III) or a compound of Formula (IV)) using one or more purification methods described herein. 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol can exist as one or more possible stereoisomers. For example, 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol is (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4- (2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof. In some embodiments, 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol may be formed during one or more steps of the reaction of Scheme 1.For example, 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol can be formed via condensation of a compound of formula (II) in the presence of an acid followed by condensation with a compound of formula (II) in the presence of Zn / TiCl, as shown in Scheme 5:

[0166] Scheme 5 - Formation of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol via substitution of a compound of formula (I) and condensation with a compound of formula (II) [ka] In another example, 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol can be formed via condensation of a compound of formula (II) in the presence of Zn / TiCl4, followed by displacement in the presence of an acid, as shown in Scheme 6: [ka]

[0167] Before purification, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof may be present in the compounds described herein at concentrations that exceed the tolerable concentrations. In some embodiments, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof may be present in the compound formed during one or more steps of the reaction of Scheme 1.For example, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)-phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4 (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof may be present in the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), and / or the compound of Formula (IV) at concentrations that exceed acceptable concentrations prior to purification. In the compound (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4- An acceptable concentration of (2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or a combination thereof may be about 1% or less.In some embodiments, the compounds (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4 Acceptable concentrations of -(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof can be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0168] Compounds present in the compound synthesized as shown in Scheme 1 include, for example, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1 The levels of -(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof can be reduced or removed using one or more purification methods described herein. In the compound (e.g., the compound of formula (III) or the compound of formula (IV)), (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1- Reducing the level of (4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or a combination thereof can include ethyl acetate fractional crystallization (e.g., as described in Example 3).In the compound (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol Reducing the level of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or a combination thereof can include acetone recrystallization (e.g., as described in Example 3). In the compound (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol Reducing the level of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or a combination thereof may include THF recrystallization (e.g., as described in Example 3). In some embodiments, all three crystallization steps may be performed.

[0169] Before purification, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl) Ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof may be present in a compound (e.g., a compound of Formula (III) or a compound of Formula (IV)) at a level greater than about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5%.After purification, (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or combinations thereof may be present in a compound (e.g., a compound of Formula (IV)) at a level of about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% or less.

[0170] The 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol impurity in a compound, e.g., a compound of Formula (IV), can be identified by analytical methods, e.g., HPLC or LC-MS. In some embodiments, 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol can have a relative retention time (RRT) of about 1.76, 1.87, or 1.90, depending on the stereoisomer, compared to (Z)-endoxifen, as measured by HPLC and LC-MS.

[0171] Endoxifen Free Base Compositions In one aspect, the present disclosure provides a stable (Z)-endoxifen free base or a salt thereof, and a composition comprising the (Z)-endoxifen free base or a salt thereof. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as the (Z)-endoxifen free base.

[0172] In certain embodiments, the composition may comprise endoxifen as at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In at least one composition, the composition comprises ≧90% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In another embodiment, the composition comprises ≧95% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In yet another embodiment, the composition comprises ≧96%, ≧97%, ≧98%, ≧99%, or ≧99.5% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition.

[0173] In other embodiments, compositions comprising endoxifen comprise 0.01% to 20%, 0.05% to 15%, or 0.1% to 10% (Z)-endoxifen wt / wt or w / v of the composition. In at least one embodiment, compositions comprising endoxifen comprise 0.01% to 20% (Z)-endoxifen wt / wt or w / v of the composition. In various other embodiments, the compositions comprising endoxifen comprise 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% (Z)-endoxifen wt / wt of the composition.

[0174] In one aspect, the composition comprising (Z)-endoxifen further comprises (E)-endoxifen. In some embodiments, the endoxifen in the composition has an (E)-endoxifen to (Z)-endoxifen ratio (E / Z-ratio) of 1:99; 5:95; 10:90, 15:85; 20:80, 25:75; 30:70; 40:70, 45:55; 50:50; 55:45; 60:40; 65:45; and 70:30. In other embodiments, the composition comprises endoxifen with an E / Z-ratio ranging from 10:90 to 70:30. In yet other embodiments, the composition comprises endoxifen with an E / Z-ratio ranging from 45:55 to 55:45.

[0175] Unless otherwise indicated by the prefix (Z), (E), or (E / Z), endoxifen, as commonly used without a prefix, is used herein to include all endoxifen isoforms.

[0176] Endoxifen Salt Compositions In some embodiments, the disclosure provides compositions comprising a salt of endoxifen. In some embodiments, the disclosure provides compositions comprising a pharmaceutically acceptable salt of endoxifen. In certain embodiments, provided herein are compositions comprising 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.99%, or 100% endoxifen salt.

[0177] In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate ( The salt is selected from the group consisting of (Z)-endoxifen D-gluconate, (E)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen L-gluconate, or a combination thereof.

[0178] In some embodiments, compositions comprising endoxifen gluconate comprise 10% to 100% (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen gluconate in the composition. In some embodiments, compositions comprising endoxifen gluconate comprise 10% to 100% (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition.

[0179] In other embodiments, compositions comprising endoxifen gluconate comprise 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, 99.99%, or 100% (Z)-endoxifen D-gluconate or (Z)-endoxifen L-gluconate relative to total endoxifen gluconate. In some embodiments, the composition comprises at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.99% (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof.

[0180] In some embodiments, provided herein are compositions comprising (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate, which may be present in the composition in a ratio ranging from 10:90 to 99:1 wt / wt or v / v, respectively. In some embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate is 10:90 to 99:1 (wt / wt or v / v), respectively (e.g., 45:55, 50:50, 60:40, 70:30, 80:20, 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01). In certain embodiments, the ratio (wt / wt or v / v) of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate is 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01. One of skill in the art will recognize that other combinations of endoxifen gluconate isomers are encompassed by the present disclosure.

[0181] In some embodiments, the compositions comprising endoxifen gluconate comprise 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% endoxifen gluconate (wt / wt) or (w / v) of the composition. In some embodiments, the compositions comprising endoxifen gluconate comprise 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% (Z)-endoxifen gluconate (wt / wt) or (w / v) of the composition.

[0182] The compounds and compositions of the present disclosure can be administered to a subject in need thereof by any route known in the art, including, but not limited to, oral, parenteral, topical, and intraductal delivery. Thus, the compositions disclosed herein can be formulated to be compatible with the intended route of administration.

[0183] In some embodiments, a composition comprising endoxifen further comprises an excipient, which can be formulated to be compatible with the intended route of administration.

[0184] Polymorphic forms of endoxifen The present disclosure provides compositions and characterizations of various polymorphic crystalline forms of endoxifen. These polymorphic crystalline forms may have improved stability, dissolution rate, biological activity, or a combination thereof, compared to other forms of endoxifen (e.g., dissolved endoxifen or amorphous endoxifen). In certain embodiments disclosed herein, the disclosure provides compositions comprising crystalline forms of the compound of Formula (III), the crystalline form of the compound of Formula (III) being: (a) Form IV, characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3°2θ, 23.3±0.3°2θ, and 13.6±0.3°2θ; (b) Form V, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°2θ, 19.6±0.3°2θ, and 8.9±0.3°2θ; (c) Form VI, characterized by an X-ray powder diffraction pattern containing major peaks at 9.9±0.3°2θ, 13.4±0.3°2θ, and 13.7±0.3°2θ; (d) Form VII, characterized by an X-ray powder diffraction pattern containing major peaks at 20.0±0.3°2θ, 22.6±0.3°2θ, and 10.6±0.3°2θ; (e) Form VII, characterized by an X-ray powder diffraction pattern containing major peaks at 4.8±0.3°2θ, 18.9±0.3°2θ, and 9.5±0.3°2θ. (f) Form IX, characterized by an X-ray powder diffraction pattern containing major peaks at 19.0±0.3°2θ, 12.9±0.3°2θ, and 15.9±0.3°2θ; (g) Form X, characterized by an X-ray powder diffraction pattern containing major peaks at 7.2±0.3°2θ, 14.3±0.3°2θ, 18.7±0.3°2θ, 21.5±0.3°2θ, and 22.7±0.3°2θ; (h) Form X, characterized by an X-ray powder diffraction pattern containing major peaks at 14.0±0.3°2θ, 17.7±0.3°2θ, 11.9 (i) Form XI, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5 ± 0.3° 2θ, 15.6 ± 0.3° 2θ, and 19.0 ± 0.3° 2θ; (j) Form XII, characterized by an X-ray powder diffraction pattern containing major peaks at 11.6 ± 0.3° 2θ, 21.3 ± 0.3° 2θ, 18.4 ± 0.3° 2θ, 23.9 ± 0.3° 2θ, 17.3 ± 0.3° 2θ, 21.8 ± 0.3° 2θ, 20.8 ± 0.3° 2θ, and 23.0 ± 0.3° 2θ; (j) Form XII, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5 ± 0.3° 2θ, 15.6 ± 0.3° 2θ, and 19.0 ± 0.3° 2θ;(k) Form XIV characterized by an X-ray powder diffraction pattern containing major peaks at 9.8±0.3°2θ, 4.7±0.3°2θ, and 14.0±0.3°2θ; (l) Form XIX characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3°2θ, 23.6±0.3°2θ, and 18.9±0.3°2θ; or (m) a combination thereof.

[0185] In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, the compound of Formula (III) is a compound of Formula (IV).

[0186] In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compounds of Formula (III) are Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX, or a combination thereof. In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compounds of Formula (III) in the composition are the (Z)-isomer. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compounds of Formula (III) are Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is in a single crystalline form (e.g., Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX).

[0187] In some cases, the crystalline form comprises Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form XII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, the crystalline form comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form XII, Form XIV, Form XV, Form XIX, or a combination thereof. In some cases, the crystalline form comprises Form IV, Form VII, or a combination thereof. In some cases, the crystalline form comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of Form IV, Form VII, or a combination thereof.

[0188] In some cases, the crystalline form has a maximum dimension of at least about 500 nm, at least about 800 nm, at least about 1 μm, at least about 1.5 μm, at least about 2.5 μm, at least about 5 μm, at least about 10 μm, at least about 25 μm, at least about 50 μm, at least about 100 μm, at least about 200 μm, or at least about 500 μm (e.g., collected on a 500 μm filter).

[0189] In some embodiments, the polymorphic crystalline forms were characterized by X-ray powder diffraction (XRPD) analysis. In some embodiments, the polymorphic crystalline forms were characterized by differential scanning calorimetry (DSC). In some embodiments, the polymorphic crystalline forms were characterized by thermogravimetric analysis (TGA) and evolved gas analysis (EGA).

[0190] Form IV of the compound of formula (III) The composition can include Form IV of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form IV.

[0191] The crystalline form of Form IV of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 4.7±0.3°2θ, 23.3±0.3°2θ, and 13.6±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.8±0.3°2θ, 14.2±0.3°2θ, 22.5±0.3°2θ, or 15.7±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 7.1±0.3°2θ, 20.2±0.3°2θ, or 9.5±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 7.1±0.3°2θ, 9.5±0.3°2θ, 14.2±0.3°2θ, 15.7±0.3°2θ, 20.2±0.3°2θ, 22.5±0.3°2θ, and 23.8±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 13.

[0192] In some cases, the crystalline form of the compound of Formula (III) contains about 1% to about 30% solvent by weight, as determined by TGA analysis. In some cases, the crystalline form loses solvent upon heating to a temperature of 70° C. to 130° C., as determined by TGA analysis. In some cases, the solvent includes 2-propanol, heptane, or a combination thereof.

[0193] Form V of the compound of formula (III) The composition can include Form V of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form V.

[0194] The crystalline form of Form V of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 12.5±0.3°2θ, 19.6±0.3°2θ, and 8.9±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 19.8±0.3°2θ, or 16.0±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.0±0.3°2θ, 13.5±0.3°2θ, or 14.4±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 19.8±0.3°2θ, 16.0±0.3°2θ, 22.0±0.3°2θ, 13.5±0.3°2θ, and 14.4±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 27.

[0195] Form VI of the compound of formula (III) The composition can include Form VI of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form VI.

[0196] The crystalline form of Form VI of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 9.9±0.3°2θ, 13.4±0.3°2θ, and 13.7±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.6±0.3°2θ, 18.6±0.3°2θ, 17.3±0.3°2θ, or 21.8±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 10.2±0.3°2θ, 19.5±0.3°2θ, or 14.2±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 17.6±0.3°2θ, 18.6±0.3°2θ, 17.3±0.3°2θ, 21.8±0.3°2θ, 10.2±0.3°2θ, 19.5±0.3°2θ, or 14.2±0.3°2θ.

[0197] In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0198] Form VII of the compound of formula (III) The composition can include Form VII of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form VII.

[0199] The crystalline form of Form VII of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 20.0±0.3°2θ, 22.6±0.3°2θ, and 10.6±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 11.4±0.3°2θ, 16.4±0.3°2θ, 9.6±0.3°2θ, or 13.3±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 18.2±0.3°2θ, 13.1±0.3°2θ, or 27.0±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 11.4±0.3°2θ, 16.4±0.3°2θ, 9.6±0.3°2θ, 13.3±0.3°2θ, 18.2±0.3°2θ, 13.1±0.3°2θ, or 27.0±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 31.

[0200] Form VIII of the compound of formula (III) The composition can include Form VIII of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form VIII.

[0201] The crystalline form of Form VIII of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 4.8±0.3°2θ, 18.9±0.3°2θ, and 9.5±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 23.7±0.3°2θ, 21.9±0.3°2θ, 21.2±0.3°2θ, or 12.9±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 25.0±0.3°2θ, 21.5±0.3°2θ, or 16.4±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 23.7±0.3°2θ, 21.9±0.3°2θ, 21.2±0.3°2θ, 12.9±0.3°2θ, 25.0±0.3°2θ, 21.5±0.3°2θ, or 16.4±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 37.

[0202] Form IX of the compound of formula (III) The composition can include Form IX of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form IX.

[0203] The crystalline form of Form IX of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 19.0±0.3°2θ, 12.9±0.3°2θ, and 15.9±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 21.1±0.3°2θ, or 8.9±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.4±0.3°2θ, 4.2±0.3°2θ, or 12.7±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.7±0.3°2θ, 20.8±0.3°2θ, 21.1±0.3°2θ, 8.9±0.3°2θ, 16.4±0.3°2θ, 4.2±0.3°2θ, or 12.7±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 40.

[0204] Form X of the compound of formula (III) The composition can include Form X of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form X.

[0205] The crystalline form of Form X of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 7.2±0.3°2θ, 14.3±0.3°2θ, 18.7±0.3°2θ, 21.5±0.3°2θ, and 22.7±0.3°2θ. In some cases, the XRPD pattern further comprises a peak at 17.1±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.8±0.3°2θ, 27.3±0.3°2θ, or 29.4±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 52.

[0206] Form XI of the compound of formula (III) The composition can include Form XI of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XI.

[0207] The crystalline form of Form XI of the compound of Formula (III) can be characterized by an XRPD pattern including major peaks at 14.0±0.3°2θ, 17.7±0.3°2θ, 11.9±0.3°2θ, 18.4±0.3°2θ, 23.9±0.3°2θ, 17.3±0.3°2θ, 21.8±0.3°2θ, 20.8±0.3°2θ, and 23.0±0.3°2θ. In some cases, the XRPD pattern further includes at least one peak or at least two peaks selected from 22.2±0.3°2θ or 16.6±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 54.

[0208] Form XII of the compound of formula (III) The composition can include Form XII of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XII.

[0209] The crystalline form of Form XII of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 12.5±0.3°2θ, 15.6±0.3°2θ, and 19.0±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 21.9±0.3°2θ, 20.2±0.3°2θ, 16.0±0.3°2θ, or 21.6±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 22.4±0.3°2θ, 16.8±0.3°2θ, or 12.8±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 21.9±0.3°2θ, 20.2±0.3°2θ, 16.0±0.3°2θ, 21.6±0.3°2θ, 22.4±0.3°2θ, 16.8±0.3°2θ, or 12.8±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 56.

[0210] Form XIV of the compound of formula (III) The composition can include Form XIV of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XIV.

[0211] The crystalline form of Form XIV of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 11.6±0.3°2θ, 21.3±0.3°2θ, and 19.3±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 17.5±0.3°2θ, 15.4±0.3°2θ, 21.6±0.3°2θ, or 5.8±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 16.3±0.3°2θ, 21.9±0.3°2θ, or 23.9±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 17.5±0.3°2θ, 15.4±0.3°2θ, 21.6±0.3°2θ, 5.8±0.3°2θ, 16.3±0.3°2θ, 21.9±0.3°2θ, or 23.9±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 71.

[0212] Form XV of the compound of formula (III) The composition can include Form XV of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XV.

[0213] The crystalline form of Form XV of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 9.8±0.3°2θ, 4.7±0.3°2θ, and 14.0±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 20.2±0.3°2θ, 7.1±0.3°2θ, 23.4±0.3°2θ, or 22.4±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 21.7±0.3°2θ, 22.7±0.3°2θ, or 18.8±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 20.2±0.3°2θ, 7.1±0.3°2θ, 23.4±0.3°2θ, 22.4±0.3°2θ, 21.7±0.3°2θ, 22.7±0.3°2θ, or 18.8±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in FIG.

[0214] Form XIX of the compound of formula (III) The composition can include Form XIX of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XIX.

[0215] The crystalline form of Form XIX of the compound of Formula (III) can be characterized by an XRPD pattern comprising major peaks at 4.7±0.3°2θ, 23.6±0.3°2θ, and 18.9±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, at least three peaks, or at least four peaks selected from 9.4±0.3°2θ, 23.3±0.3°2θ, 22.3±0.3°2θ, or 20.1±0.3°2θ. In some cases, the XRPD pattern further comprises at least one peak, at least two peaks, or at least three peaks selected from 19.6±0.3°2θ, 7.1±0.3°2θ, or 15.7±0.3°2θ. In some cases, the XRPD pattern comprises at least one peak and further comprises at least two peaks, at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from 9.4±0.3°2θ, 23.3±0.3°2θ, 22.3±0.3°2θ, 20.1±0.3°2θ, 19.6±0.3°2θ, 7.1±0.3°2θ, or 15.7±0.3°2θ. In some cases, the crystalline form of the compound of Formula (III) is characterized by an X-ray diffraction pattern substantially as shown in Figure 25.

[0216] Form XVI of the compound of formula (III) The composition may comprise Form XVI of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XVI. In some cases, the crystalline form of the compound of Formula (III) is Form XVI, and may be present in a composition comprising Form XV, Form IX, Form XII, Form XIV, or a combination thereof.

[0217] Form XVII of the compound of formula (III) The composition can include Form XVII of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XVII. In some cases, the crystalline form of the compound of Formula (III) is Form XVII, and is characterized by an X-ray diffraction pattern substantially as shown in Figure 21.

[0218] Form XVIII of the compound of formula (III) The composition can include Form XVIII of the compound of Formula (III). In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is Form XVIII. In some cases, the crystalline form of the compound of Formula (III) is Form XVIII, and is characterized by an X-ray diffraction pattern substantially as shown in Figure 23.

[0219] Endoxifen crystallization In one aspect, the present disclosure provides a method for producing a crystalline form of the compound of Formula (III). The method may produce a single crystalline form, or a mixture of forms (e.g., a mixture of Form I and Form V). The method may produce a single form of the compound of Formula (III) with a purity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% (e.g., producing 99% pure Form IV of the compound of Formula (III)).

[0220] In some cases, the crystalline form of the compound of Formula (III) is collected via filtration. In some cases, the filtration collects a solid material having a maximum dimension of at least about 500 nm, at least about 800 nm, at least about 1 μm, at least about 1.5 μm, at least about 2.5 μm, at least about 5 μm, at least about 10 μm, at least about 25 μm, at least about 50 μm, at least about 100 μm, at least about 200 μm, or at least about 500 μm. In some cases, the crystalline form is dried after collection.

[0221] How to generate Form I Aspects of the present disclosure provide methods for producing Form I of compound of Formula (III). Form I can be characterized by an XRPD pattern comprising one or more peaks selected from 21.8±0.3°2θ, 17.2±0.3°2θ, 24.2±0.3°2θ, 16.9±0.3°2θ, 21.4±0.3°2θ, 20.9±0.3°2θ, 14.2±0.3°2θ, 18.2±0.3°2θ, 26.9±0.3°2θ, or 25.4±0.3°2θ. In some embodiments, Form I can be characterized by an X-ray diffraction pattern substantially as shown in Figure 9. In some cases, the method comprises converting another solid form of compound of Formula (III) to Form I. In certain examples, a method for producing a crystalline form of the compound of Formula (III) can include incubating a solid form of the compound of Formula (III) in a solvent system, wherein at least a portion of the solid form of the compound of Formula (III) remains solid; converting the portion of the solid form of the compound of Formula (III) to a crystalline form; and collecting the crystalline form. In some cases, the crystalline form of the compound of Formula (III) is Form I. In some cases, the incubation is for about 3 to about 120 hours, about 3 to about 20 hours, about 8 to about 50 hours, or about 30 to about 120 hours.

[0222] In some cases, the solid form of the compound of Formula (III) comprises an isomeric purity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% before incubation. In some cases, the solid form of the compound of Formula (III) comprises an isomeric purity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% before incubation. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound of Formula (III) is the (Z)-isomer before incubation.

[0223] In some cases, the crystalline form of the compound of Formula (III) comprises an isomeric purity of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the crystalline form of the compound of Formula (III) is the (Z)-isomer.

[0224] In some cases, the solid form of the compound of Formula (III) comprises at least one of Forms IV-XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the solid form of the compound of Formula (III) is one or more of Forms IV-XIX. In some cases, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the solid form of the compound of Formula (III) is one of Forms IV-XIX. In some cases, the solid form of the compound of Formula (III) is at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99% amorphous. In some cases, the solid form of the compound of Formula (III) is at most about 25%, at most about 50%, at most about 75%, at most about 90%, at most about 95%, or at most about 99% amorphous. In some cases, the compound of Formula (III) is Form IV. In some cases, the compound of Formula (III) is Form V. In some cases, the compound of Formula (III) is Form VI. In some cases, the compound of Formula (III) is Form VII. In some cases, the compound of Formula (III) is Form VIII. In some cases, the compound of Formula (III) is Form IX. In some cases, the compound of Formula (III) is Form X. In some cases, the compound of Formula (III) is Form XI. In some cases, the compound of Formula (III) is Form XII. In some cases, the compound of Formula (III) is Form XIII. In some cases, the compound of Formula (III) is Form XIV. In some cases, the compound of Formula (III) is Form XV. In some cases, the compound of Formula (III) is Form XVI. In some cases, the compound of Formula (III) is Form XVII. In some cases, the compound of Formula (III) is Form XVIII. In some cases, the compound of Formula (III) is Form XIX.

[0225] In some cases, about 0.1% to about 75%, about 0.1% to about 10%, about 0.1% to about 25%, about 1% to about 25%, about 5% to about 50%, about 20% to about 50%, or about 25% to about 75% of the solid form of the compound of Formula (III) is dissolved in the solvent system. In some cases, the solvent system comprises a temperature of about 5°C to about 110°C, about 5°C to about 90°C, about 5°C to about 25°C, about 10°C to about 60°C, about 25°C to about 50°C, about 15°C to about 50°C, about 15°C to about 70°C, about 25°C to about 40°C, or about 35°C to about 60°C. In some cases, the incubation is carried out for about 0.1 to about 700 hours, about 1 to about 360 hours, about 3 to about 360 hours, about 3 to about 36 hours, about 6 to about 72 hours, about 12 to about 150 hours, about 24 to about 150 hours, about 48 to about 240 hours, or about 100 to about 700 hours. In some cases, the solvent system comprises about 5 to about 10,000 mg / ml, about 5 to about 1,000 mg / ml, about 5 to about 300 mg / ml, about 5 to about 50 mg / ml, about 20 to about 300 mg / ml, about 50 to about 300 mg / ml, about 100 to about 1,000 mg / ml, or about 300 to about 10,000 mg / ml of a solid form of the compound of Formula (III) during incubation.

[0226] In some cases, the solvent system includes 2-propanol, acetonitrile, acetone, butyl acetate, butyl methyl ether, dimethylformamide, ethanol, ethyl acetate, water, heptane, methanol, methyl isobutyl ketone, tetrahydrofuran, toluene, or a combination thereof. In some cases, the solvent system includes a single solvent. In some cases, the solvent system includes multiple solvents. In some cases, the solvent system includes two solvents in a ratio of about 99:1 to about 1:1, about 19:1 to about 1:1, about 19:1 to about 5:1, about 8:1 to about 1:1, about 4:1 to about 1:1, or about 2:1 to about 1:1. In some cases, the solvent system includes less than about 25%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.25% water.

[0227] Method for generating Form IV Embodiments of the present disclosure provide methods for producing Form IV of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving the compound of Formula (III) in 2-propanol and evaporating at least a portion of the 2-propanol; dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of Formula (III) in a solvent system comprising heptane and 2-propanol at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and ethyl acetate at a first temperature and evaporating the solvent system. to a second temperature; dissolving the compound of formula (III) in tetrahydrofuran and combining the solvent system with water; dissolving the compound of formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran and evaporating at least a portion of the solvent system; dissolving the compound of formula (III) in acetone and evaporating at least a portion of the acetone; dissolving the compound of formula (III) in a solvent system comprising acetone and tetrahydrofuran and evaporating at least a portion of the solvent system; or combinations thereof, thereby producing a crystalline form of the compound of formula (III).In some cases, a method for producing a crystalline form of the compound of formula (III) comprises dissolving the compound of formula (III) in 2-propanol and evaporating at least a portion of the 2-propanol; dissolving the compound of formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of formula (III) in a solvent system comprising heptane and 2-propanol at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of formula (III) in a solvent system comprising 2-propanol and ethyl acetate at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of formula (III) in tetrahydrofuran and combining the solvent system with water; dissolving the compound of formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran and evaporating at least a portion of the solvent system; dissolving the compound of formula (III) in a solvent system comprising acetone and tetrahydrofuran and evaporating at least a portion of the solvent system; or a combination thereof, thereby producing a crystalline form of the compound of formula (III). In some cases, the crystalline form of the compound of formula (III) is Form IV.

[0228] In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20°C to about 100°C, and the second temperature is about -20°C to about 25°C. In some cases, the first temperature is about 20°C to about 50°C, about 40°C to about 70°C, about 60°C to about 100°C, or about 20°C to about 100°C. In some cases, the second temperature is about -30°C to about 30°C, about -30°C to about 0°C, or about 0°C to about 25°C. In some cases, the evaporation removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the solvent system. In some cases, the solvent or solvent system is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure (e.g., a 2-propanol solution contains at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% 2-propanol).

[0229] Method for generating Form V Embodiments of the present disclosure provide methods for producing Form V of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving the compound of Formula (III) in acetonitrile at a first temperature and cooling the acetonitrile to a second temperature, thereby producing a crystalline form of the compound of Formula (III). In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20°C to about 100°C, and the second temperature is about -20°C to about 25°C. In some cases, the first temperature is about 20° C. to about 50° C., about 40° C. to about 70° C., about 60° C. to about 100° C., or about 20° C. to about 100° C. In some cases, the second temperature is about −30° C. to about 30° C., about −30° C. to about 0° C., or about 0° C. to about 25° C. In some cases, the acetonitrile is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0230] How to generate a morphological VI Embodiments of the present disclosure provide methods for producing Form VI of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, the method for producing a crystalline form of the compound of Formula (III) includes storing Form V at a temperature of about 10°C to about 100°C, thereby producing a crystalline form of the compound of Formula (III). In some cases, the temperature is about 10°C to about 50°C, or 20°C to about 50°C. In some cases, Form V of the compound of Formula (III) is dry during storage. In some cases, the crystalline form of the compound of Formula (III) is Form VI. In some cases, the solvent or solvent system is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0231] Method for Producing Form VII Embodiments of the present disclosure provide methods for producing Form VII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of Formula (III) include dissolving the compound of Formula (III) in ethyl acetate and adding the ethyl acetate to heptane; dissolving the compound of Formula (III) in toluene and evaporating at least a portion of the toluene; dissolving the compound of Formula (III) in toluene and adding the toluene to heptane; dissolving the compound of Formula (III) in a solvent system comprising heptane and toluene and heating the solvent system to about 20°C to about 100°C; or combinations thereof, thereby producing a crystalline form of the compound of Formula (III). In some cases, the solvent system is heated to about 20°C to about 50°C. In some cases, the solvent system is heated to about 50°C to about 150°C. In some cases, the evaporation removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the toluene. In some cases, the crystalline form of the compound of Formula (III) is Form VII. In some cases, the solvent or solvent system is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0232] Methods for Producing Form VIII Embodiments of the present disclosure provide methods for producing Form VIII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, the method for producing a crystalline form of Formula (III) includes dissolving the compound of Formula (III) in toluene at a first temperature and cooling the solvent system to a second temperature; dissolving the compound of Formula (III) in toluene, adding butyl methyl ether to the toluene to form a solvent system, and evaporating at least a portion of the solvent system; or a combination thereof, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form VIII. In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20°C to about 100°C, and the second temperature is about -20°C to about 25°C. In some cases, the first temperature is about 20°C to about 50°C, about 40°C to about 70°C, about 60°C to about 100°C, or about 20°C to about 100°C. In some cases, the second temperature is about -30°C to about 30°C, about -30°C to about 0°C, or about 0°C to about 25°C. In some cases, the evaporation removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the solvent system. In some cases, the toluene is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0233] How to Generate Form IX Embodiments of the present disclosure provide methods for producing Form IX of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of Formula (III) include dissolving a compound of Formula (III) in a solvent system containing ethyl acetate, adding heptane to the solvent system, and incubating the solvent system at a temperature of about 20°C to about -20°C; dissolving a compound of Formula (III) in a solvent system containing butyl acetate and adding heptane to the solvent system; dissolving a compound of Formula (III) in ethyl acetate and adding ethyl acetate to butyl methyl ether to form a solvent system and evaporating at least a portion of the solvent system; dissolving a compound of Formula (III) in ethyl acetate and adding butyl methyl ether to ethyl acetate to form a solvent system and evaporating at least a portion of the solvent system; dissolving a compound of Formula (III) in acetone, combining acetone with butyl methyl ether to form a solvent system and evaporating at least a portion of the solvent system; or combinations thereof, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form IX. In some cases, the evaporation removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the solvent system. In some cases, the acetone, ethyl acetate, and / or butyl acetate is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0234] How to Generate Form X Embodiments of the present disclosure provide methods for producing Form X of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, the method for producing a crystalline form of the compound of Formula (III) includes dissolving the compound of Formula (III) in 4-methyl-2-pentanone at a first temperature and cooling the 4-methyl-2-pentanone to a second temperature, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form X. In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20° C. to about 50° C., about 40° C. to about 70° C., about 60° C. to about 100° C., or about 20° C. to about 100° C. In some cases, the second temperature is about −30° C. to about 30° C., about −30° C. to about 0° C., or about 0° C. to about 25° C. In some cases, the 4-methyl-2-pentanone is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0235] Method for Producing Form XII Embodiments of the present disclosure provide methods for producing Form XII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving less than about 100 micrograms of the compound of Formula (III) in tetrahydrofuran, adding tetrahydrofuran to acetone to form a solvent system, and evaporating at least a portion of the solvent system, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XII. In some cases, the evaporating removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the solvent system. In some cases, the tetrahydrofuran and / or acetone is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0236] Methods for Producing Form XIII Embodiments of the present disclosure provide methods for producing Form XIII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving more than about 100 micrograms of the compound of Formula (III) in tetrahydrofuran, adding tetrahydrofuran to acetone to form a solvent system, and evaporating at least a portion of the solvent system, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XIII. In some cases, the evaporating removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the solvent system. In some cases, the tetrahydrofuran and / or acetone is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0237] Method for generating Form XIV Embodiments of the present disclosure provide methods for producing Form XIV of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, a method for producing a crystalline form of the compound of Formula (III) includes dissolving the compound of Formula (III) in ethyl acetate and adding the ethyl acetate to heptane, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XV. In some cases, the ethyl acetate and / or heptane are at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0238] Method for generating Form XVI Embodiments of the present disclosure provide methods for producing Form XVI of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving the compound of Formula (III) in ethyl acetate at a first temperature, combining the ethyl acetate with heptane to form a solvent system, and cooling the solvent system to a second temperature, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XVI. In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20°C to about 100°C, and the second temperature is about -20°C to about 25°C. In some cases, the first temperature is about 20°C to about 50°C, about 40°C to about 70°C, about 60°C to about 100°C, or about 20°C to about 100°C. In some cases, the second temperature is about -30°C to about 30°C, about -30°C to about 0°C, or about 0°C to about 25°C. In some cases, the ethyl acetate is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure. In some cases, the heptane is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0239] Methods for Producing Form XVII Embodiments of the present disclosure provide methods for producing Form XVII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing a crystalline form of the compound of Formula (III) include dissolving the compound of Formula (III) in ethanol and evaporating at least a portion of the ethanol, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XVII. In some cases, the evaporation removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the ethanol. In some cases, the ethanol is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0240] Methods for Producing Form XVIII Embodiments of the present disclosure provide methods for producing Form XVIII of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, methods for producing the crystalline form of Form (III) include dissolving the compound of Formula (III) in tetrahydrofuran and evaporating at least a portion of the tetrahydrofuran, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XVIII. In some cases, the evaporating removes about 10% to about 70%, about 20% to about 50%, or about 10% to about 35% of the tetrahydrofuran. In some cases, the tetrahydrofuran is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0241] How to Generate Form XIX An embodiment of the present disclosure provides a method for producing Form XIX of the compound of Formula (III). In some cases, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer. In some cases, the method for producing a crystalline form of the compound of Formula (III) includes dissolving the compound of Formula (III) in acetone at a first temperature, combining the acetone with heptane to form a solvent system, and cooling the solvent system to a second temperature; dissolving the compound of Formula (III) in tetrahydrofuran at a first temperature, combining the tetrahydrofuran with heptane to form a solvent system, and cooling the solvent system to a second temperature; or a combination thereof, thereby producing a crystalline form of the compound of Formula (III). In some cases, the crystalline form of the compound of Formula (III) is Form XIX. In some cases, the cooling is at a rate of about 0.02°C / min to about 10°C / min, about 0.02°C / min to about 1°C / min, or about 2°C / min to about 10°C / min. In some cases, the first temperature is about 20°C to about 100°C and the second temperature is about -20°C to about 25°C. In some cases, the first temperature is about 20°C to about 50°C, about 40°C to about 70°C, about 60°C to about 100°C, or about 20°C to about 100°C. In some cases, the second temperature is about -30°C to about 30°C, about -30°C to about 0°C, or about 0°C to about 25°C. In some cases, the acetone is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure. In some cases, the heptane is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure. In some cases, the tetrahydrofuran is at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% pure.

[0242] Industrially scalable process In one aspect, the present disclosure provides an industrially scalable process for producing (Z)-endoxifen and its salts. The industrially scalable process can be used to produce up to about 1 kg, up to about 2 kg, up to about 3 kg, up to about 4 kg, or up to about 5 kg of (Z)-endoxifen in a single batch. In some embodiments, the industrially scalable process can be used to produce about 500 g to about 5 kg of (Z)-endoxifen in a single batch. In some embodiments, the industrially scalable process can be used to produce at least about 500 g, at least about 750 g, at least about 1 kg, at least about 2 kg, at least about 3 kg, at least about 4 kg, or at least about 5 kg of (Z)-endoxifen in a single batch.

[0243] In one aspect, the disclosure provides an industrially scalable process for producing (Z)-endoxifen, comprising: (a) reacting a mixture of (E)-endoxifen and (Z)-endoxifen, i.e., the compound of formula (III), with 6N HCl (1:1 to 1:5 wt / wt) in EtOAc (1:1 to 1:20 wt / wt); (b) neutralizing with 8N NaOH (1:1 to 1:20 wt / wt); (c) washing one or more times with EtOAc (1:1 to 1:10 wt / wt); (d) extracting with 20% NaCl (1:1 to 1:5 wt / wt); (e) reacting with activated carbon (1:0.01 to 1:1), optionally followed by crystallization using EtOAc to recover and / or remove any remaining compound of formula (III) and / or (E)-endoxifen; (f) reacting a first portion of acetone with 6N HCl (1:1 to 1:5 wt / wt); (g) neutralizing with 8N NaOH (1:1 to 1:20 wt / wt); (h) washing one or more times with EtOAc (1:1 to 1:10 wt / wt); (i) extracting with 20% NaCl (1:1 to 1:5 wt / wt); (j) reacting with activated carbon (1:0.01 to 1:1), optionally followed by crystallization using EtOAc to recover and / or remove any remaining compound of formula (III) and / or (E)-endoxifen; (g) recrystallizing in a first solvent of THF (1:0.1 to 1:10 wt / wt) and a second solvent of IPA (1:0.1 to 1:10 wt / wt), where wt / wt is relative to a mixture of (E)-endoxifen and (Z)-endoxifen, e.g., a compound of Formula (III). For example, an industrially scalable process for producing (Z)-endoxifen may include the steps described in Example 3.

[0244] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen (a compound of Formula (III)), comprising: (a) reacting a compound of Formula (II) with propiophenone in THF (4.4 wt / wt); (b) preparing a solution of TiCl (1.4 wt / wt) and Zn (0.9 wt / wt) in THF (8.9 wt / wt); and (c) reacting the compound of Formula (II) from step (a) with TiCl and Zn in THF from step (b) to form a mixture of (E)-endoxifen and (Z)-endoxifen, where wt / wt is relative to the compound of Formula (II). For example, an industrially scalable process for producing (Z)-endoxifen may include the steps described in Example 2.

[0245] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen, i.e., a compound of formula (III), from formula (II) as a starting material, comprising one or more of the following steps: (a) extraction with 25% ammonium chloride (1:20 wt / wt) and silica (Celite) (1:1 wt / wt); (b) one or more washes with THF (1:1 to 1:5 wt / wt); (c) one or more washes with 20% sodium chloride (1:3 wt / wt); (c) distillation with EtOAc (1:4.5 wt / wt); and (d) crystallization with (1:2 v / v) EtOAc / n-heptane (1:3.8 wt / wt), where wt / wt is relative to the compound of formula (II).

[0246] In one aspect, the present disclosure relates to an industrially scalable process for producing a mixture of (E)-endoxifen and (Z)-endoxifen, i.e., the compound of formula (III), further comprising one or more of the following steps: (a) one or more extractions with 40% K2CO3 (1:2 wt / wt); (b) extraction with 1 N NaOH (1:10 wt / wt) and MeTHF (1:1 to 1:10 wt / wt); (c) two or more extractions with MeTHF (1:1 to 1:20 wt / wt); (d) extraction with 20% sodium chloride (1:5 wt / wt); (e) distillation with IPA (1:4.5 wt / wt); and (f) crystallization with (1:2.7 v / v) IPA / n-heptane (1:3.4 wt / wt), where wt / wt is relative to the compound of formula (II).

[0247] In one aspect, the present disclosure relates to an industrially scalable process for producing a compound of Formula (II), comprising the steps of: (a) reacting 1 equivalent of a compound of Formula (I) with 3 wt / wt of DIPEA in 4.9 wt / wt of THF; (b) adding 3.3 wt / wt of 1-chloroethyl chloroformate; (c) distilling 1 to 5 times with 4.0 wt / wt of methanol; (d) distilling with 3.2 wt / wt of methanol; (e) reacting with 3.2 wt / wt of methanol in 4 wt / wt of 6N HCl; and (f) neutralizing with 5 wt / wt of 8N NaOH, where wt / wt is relative to the compound of Formula (I). For example, an industrially scalable process for producing (Z)-endoxifen may include the steps described in Example 1.

[0248] In one aspect, the present disclosure relates to (Z)-endoxifen, (E)-endoxifen, the compound of Formula (III), and the compound of Formula (II), and salts thereof, prepared according to the processes described herein. In one aspect, the present disclosure relates to (Z)-endoxifen prepared according to the processes disclosed herein, wherein the (Z)-endoxifen is stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, or at least 18 months.

[0249] In another embodiment, the (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities. In yet another embodiment, the (E) / (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities.

[0250] In various embodiments, (Z)-endoxifen free base prepared according to the processes disclosed herein has <1% impurities, e.g., less than 25 ppm mesityl oxide, and is stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, or at least 18 months.

[0251] How to use The compounds of Formulas (I), (II), (III), and (IV), endoxifen salts (e.g., pharmaceutically acceptable salts), and compositions comprising them disclosed herein can be used in the manufacture of a medicament for use in treating a subject in need thereof, e.g., a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both. In various examples, the compound used for such treatment is (Z)-endoxifen of Formula (IV), prepared using the methods described herein, e.g., those described in Examples 1-3.

[0252] The compositions of the present disclosure may be used as a primary therapy, as part of a neoadjuvant therapy (to a primary therapy), or as part of an adjuvant therapy regimen, the intent being to improve or cure a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both.

[0253] In certain embodiments, the disorder is a hormone-dependent breast disorder. In other embodiments, the disorder is a hormone-dependent reproductive tract disorder. In still other embodiments, the subject has both a hormone-dependent breast disorder and a hormone-dependent reproductive tract disorder. In some embodiments, the hormone-dependent disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0254] In some embodiments, the breast disorder is increased breast density, for example, the breast disorder is Class B (formerly Class II), Class C (formerly Class III), or Class D (formerly Class IV) breast density.

[0255] In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is precocious puberty. In other embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is McCune-Albright syndrome.

[0256] In some embodiments, the breast disorder is gynecomastia.In some embodiments, gynecomastia is secondary to an underlying disease.Therefore, in some embodiments, the subject also has an underlying disease selected from the group consisting of prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure and patients undergoing hemodialysis, or type I diabetes.In some embodiments, the subject has prostate cancer as the underlying disease, and the subject has or is at risk of having gynecomastia.

[0257] In certain embodiments, the breast cancer is DCIS, LCIS, ILC, IDC, MIC, inflammatory breast cancer, ER-positive (ER+) breast cancer, HER2+ breast cancer, adenoid cystic (adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular adenocarcinoma, metaplastic carcinoma, or micropapillary carcinoma. In at least one embodiment, a single breast cancer tumor may be a combination of the foregoing, or may be a mixture of invasive and carcinoma in situ.

[0258] The present disclosure contemplates the use of the compounds and compositions disclosed herein at various stages of tumor development and progression, including the treatment of progressive and / or malignant neoplasms, i.e., overt disease, metastatic disease, or locally advanced disease in subjects who are not amenable to cure by local modalities of treatment such as surgery or radiotherapy.Thus, in some embodiments, breast cancer is precancerous, early cancer, non-metastatic cancer, pre-metastatic cancer, or locally advanced cancer.In at least one embodiment, breast disorder is metastatic cancer.In some embodiments, the subject also has prostate cancer.

[0259] The current choice of therapeutic agent for such disorders remains tamoxifen, despite serious adverse effects, poor patient compliance and drug resistance due to low plasma endoxifen levels found in subjects.Such subjects may have low endoxifen levels when taking tamoxifen due to any number of reasons, for example, they have CYP gene mutations in CYP2D6, CYP3A4 or CYP2C9, which makes them unable to metabolize tamoxifen into its active metabolite endoxifen, or because of low or reduced functioning estrogen receptors, which prevent (or reduce) sufficient tamoxifen uptake, or other reasons that have not yet been identified. The reported therapeutic level of plasma tamoxifen in subjects dosed with 20 mg oral tamoxifen is ≧30 nM ((Lyon et al. Genet Med. 2012 Dec;14(12):990-1000). Regardless of the mechanism underlying low plasma endoxifen in a subject, the compositions of the present disclosure are useful for any condition in which the subject has low endoxifen, or has or is at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder. As such, the compositions of the present disclosure may be particularly important in treating subjects with tamoxifen-resistant hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder.

[0260] In certain embodiments, patient populations for which the pharmaceutical compositions are particularly useful are provided herein. The compositions of the present disclosure are also particularly important in the treatment of tamoxifen-refractory subjects with hormone-dependent breast disorders or hormone-dependent reproductive tract disorders. Thus, in some embodiments, the compositions disclosed herein are useful for treating tamoxifen-refractory or tamoxifen-resistant subjects with or at risk of having hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both. In some embodiments, a composition comprising an endoxifen salt, such as endoxifen gluconate, administered to such subjects at the doses disclosed herein would be advantageous.

[0261] Drug interactions between tamoxifen and selective serotonin reuptake inhibitor (SSRI) drugs, such as Prozac and Paxil (paroxetine), can occur and can be harmful to breast cancer subjects. SSRI drugs reduce or stop the hepatic metabolism of tamoxifen to endoxifen in subjects taking SSRI drugs. Thus, in certain embodiments, provided herein are patient populations being or to be treated with SSRI drugs that would benefit from treatment with the compositions of the present disclosure.

[0262] Orally administered compositions disclosed herein maintain a subject's plasma endoxifen at a steady-state level greater than 30 nM, e.g., at a level in the range of 30 nM to 80 nM or at a level in the range of 30 nM to 300 nM. In some embodiments, the plasma steady-state endoxifen level is maintained at >40 nM. Maintaining such plasma endoxifen at a steady-state level greater than 30 nM is advantageous in that it reduces the likelihood of recurrence (relapse) of hormone-dependent breast disorders or hormone-dependent reproductive tract disorders, particularly breast cancer, at plasma endoxifen levels less than 30 nM. This is particularly advantageous for subjects who are poor metabolizers of tamoxifen (having plasma endoxifen levels lower than 16 nM) or intermediate metabolizers of tamoxifen (having plasma endoxifen levels lower than 27 nM) who are administered compositions disclosed herein. It is also advantageous for subjects who are being treated or will be treated with an antidepressant, e.g., an SSRI drug, e.g., citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), vilazodone (Viibryd), etc., e.g., subjects who have or are likely to have depression.

[0263] Whether a subject is tamoxifen refractory can be determined by administering an initial dosage of tamoxifen to the subject and determining the subject's plasma endoxifen steady-state level.The plasma endoxifen steady-state level in the subject who has been administered tamoxifen serves as a biomarker for tamoxifen refractory subjects.Plasma endoxifen level (acute and / or steady-state) can be determined by obtaining a test sample from the subject, which can be a plasma sample collected from the subject after the subject is administered tamoxifen.Plasma or serum can be obtained from blood samples to test biomarker endoxifen level.The initial dosage can include administering tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. The subject may also be administered a first composition comprising tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years.

[0264] A subject's plasma endoxifen steady-state level can be determined by measuring endoxifen in a test sample.The subject's plasma endoxifen steady-state level is compared with a reference plasma endoxifen level.For the purposes of this disclosure, the reference plasma level is 30nM.If a subject's plasma endoxifen level is determined to be less than 30nM, then the subject is defined as tamoxifen-refractory.Such tamoxifen-refractory subjects who have or may be at risk of having hormone-dependent breast disorders or hormone-dependent reproductive tract disorders are treated by administering to the subject an oral composition comprising (Z)-endoxifen or a salt thereof disclosed herein, or a polymorphic form of endoxifen disclosed herein.In some embodiments, the composition administered to such subjects comprises (Z)-endoxifen free base. In other embodiments, the composition administered to such a subject comprises an endoxifen gluconate selected from the group consisting of (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the composition comprising endoxifen is endoxifen HCl or endoxifen citrate. The present disclosure also contemplates that a subject's plasma endoxifen level be tracked or monitored periodically or as needed. If needed, a subject administered an initial dosage of tamoxifen can have their plasma endoxifen steady-state level adjusted by administering a composition comprising endoxifen.

[0265] In some embodiments, the tamoxifen-refractory state of a subject can be determined by determining the subject's tamoxifen-metabolite profile, which is compared with the reference tamoxifen-metabolite profile found in control or normal subjects.Compared to the reference tamoxifen-metabolite profile, subjects with low plasma endoxifen levels in the subject's tamoxifen-metabolite profile are administered an oral composition comprising endoxifen or its salt.Such compositions can include synthetically prepared endoxifen.

[0266] Plasma endoxifen can be measured by any method known in the art. The plasma endoxifen level in a test sample can be determined based on the subject's genetic, DNA, RNA, protein, tamoxifen-metabolite profile, or a combination thereof. The tamoxifen-metabolite profile can include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or endoxifen. In some embodiments, the plasma endoxifen and / or tamoxifen-metabolite profile level in a test sample is measured by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative PCR (qPCR), etc. In some embodiments, the tamoxifen-metabolite profile is predicted based on the subject's genetic composition. In some embodiments, the subject's CYP genotype includes, but is not limited to, analysis of the CYP2D6, CYP3A4, and CYP2C9 genes. In some embodiments, the subject's estrogen receptor levels may be analyzed. In other embodiments, plasma endoxifen determination may be performed by a third-party laboratory.

[0267] Thus, provided herein are methods for maintaining plasma endoxifen a levels above 30 nM in a subject in need thereof by administering to the subject a composition comprising endoxifen or a salt thereof. In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level above 30 nM. In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level in the range of 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level of >40 nM.

[0268] In another embodiment, subjects can have their test samples tested for their biomarker profile, which can indicate or monitor hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both. Such biomarkers are known in the art and include, but are not limited to, biomarkers such as CYP2D6, BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki67, cytokeratin, cancer tumor antigens, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests. Subjects with a biomarker profile indicating that they have or are at risk of having hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both can be administered the compositions disclosed herein. In one aspect, the present disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, comprising determining the subject's tamoxifen-refractory or tamoxifen-resistant status and administering to the subject a composition described herein.

[0269] In some aspects, provided herein are methods of treating a tamoxifen-refractory or tamoxifen-resistant subject, the method comprising administering to the subject a composition comprising endoxifen, or a salt or polymorph thereof.

[0270] In some embodiments, disclosed herein is a method for treating a tamoxifen-refractory subject with or at risk of having a hormone-sensitive breast disorder, a hormone-sensitive reproductive tract disorder, or both, comprising administering to the subject an oral composition comprising endoxifen or a salt thereof, wherein the subject has a plasma endoxifen level of less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 5 nM, or less than 1 nM. In some embodiments, the endoxifen salt is endoxifen gluconate, endoxifen HCl, or endoxifen citrate. In other embodiments, an oral solid dosage form comprising at least 90% (Z)-endoxifen or a salt thereof is administered.

[0271] Also provided herein is a method for treating a tamoxifen-refractory subject, the method comprising: (a) determining or having determined a plasma endoxifen level in a test sample obtained from the subject; (b) comparing or having determined the plasma endoxifen level in the test sample with a reference plasma endoxifen level; (c) determining or having determined a reduced plasma endoxifen level in the test sample compared to the reference plasma endoxifen level; and (d) administering to the subject a composition comprising endoxifen or a salt or polymorph thereof. Administration of a composition comprising endoxifen or a salt or polymorph thereof maintains the plasma endoxifen level in the subject at a steady-state level greater than 30 nM. In some embodiments, the plasma endoxifen level in the subject is maintained at a steady-state level in the range of 30 nM to 80 nM.

[0272] Provided herein is a method for treating a subject who has or is at risk of having hormone-dependent breast disorders or hormone-dependent reproductive tract disorders, the method comprises: (a) administering a first composition comprising tamoxifen to the subject; (b) determining or determining the plasma endoxifen level in a test sample obtained from the subject; (c) determining or determining the plasma endoxifen level in the test sample compared with the reference level of plasma endoxifen; and (d) administering an oral composition disclosed herein to the subject.The subject can be administered a first composition comprising tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or 10 years.In some embodiments, administering an oral composition comprising endoxifen or its salt or polymorph maintains the plasma endoxifen of the subject at a level greater than 30 nM. In other embodiments, administration of an oral composition comprising endoxifen or a salt or polymorph thereof maintains the subject's plasma endoxifen at levels ranging from 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject is administered an oral composition comprising (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the oral composition comprising an endoxifen salt is endoxifen HCl or endoxifen citrate.

[0273] Provided herein is a method for treating a subject with hormone-dependent breast disorder or hormone-dependent reproductive tract disorder, the method comprising: (a) administering to the subject a first composition comprising tamoxifen; (b) determining or having determined the subject's tamoxifen-metabolite profile in a test sample obtained from the subject; (c) determining the subject's reduced plasma endoxifen level based on the subject's tamoxifen-metabolite profile compared with the reference plasma endoxifen level in the reference tamoxifen-metabolite profile; and (d) administering to the subject an oral composition comprising endoxifen or its salt or polymorph.In some embodiments, the composition comprising endoxifen is endoxifen gluconate, endoxifen HCl, or endoxifen citrate.

[0274] Provided herein are methods for adjusting plasma endoxifen levels in a subject being treated for a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder, who has one or more CYP2D6 or CYP3A4 mutations, or who has already received an initial dose of tamoxifen and has a plasma endoxifen level below a reference plasma endoxifen level, the method comprising: (a) measuring the subject's plasma endoxifen level after the initial dose of tamoxifen; (b) comparing the subject's plasma endoxifen level with a reference plasma endoxifen level; and (c) administering to the subject an oral composition containing endoxifen or a salt or polymorph thereof to maintain the subject's plasma endoxifen level at a level greater than 30 nM. In some embodiments, administering the oral composition containing endoxifen or a salt or polymorph thereof comprises maintaining the subject's plasma endoxifen at a level in the range of 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen level is maintained at a steady-state level. The subject may be administered an initial dosage of tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0275] Provided herein are methods for adjusting plasma endoxifen levels in a subject being treated for a hormone-dependent breast disorder or hormone-dependent reproductive tract disorder who has already received an initial dosage of tamoxifen and has a plasma endoxifen level of less than 30 nM, the method comprising: (a) measuring the subject's plasma tamoxifen-metabolite endoxifen level after the initial dosage of tamoxifen; (b) comparing the plasma level of tamoxifen-metabolite endoxifen to a reference level for normal tamoxifen-metabolite endoxifen levels; and (c) administering an adjustment dosage of a composition comprising synthetically prepared endoxifen, wherein the dosage of synthetically prepared endoxifen is sufficient to maintain the subject's plasma endoxifen at a level greater than 30 nM. In some embodiments, administration of a second composition comprising synthetically prepared endoxifen maintains the subject's plasma endoxifen at a level in the range of 30 nM to 300 nM (e.g., 30 nM to 200 nM, 30 nM to 80 nM). In some embodiments, steps (a)-(c) may be repeated until the subject exhibits the desired plasma level of endoxifen.

[0276] In one aspect, the present disclosure contemplates a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, the method comprising administering to the subject ablation of the subject's breast tissue or radiation therapy and administering an oral composition comprising endoxifen, or a salt or polymorph thereof, as disclosed herein. In another aspect, the present disclosure contemplates a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, the method comprising administering to the subject an oral composition disclosed herein prior to administering to the subject ablation of the subject's breast tissue or radiation therapy.

[0277] The dosage administered to a subject will typically be in a unit dosage form. An example range for endoxifen in each dosage unit form is 0.01 mg to 200 mg. The dosage should typically be an effective amount and equivalent amount on a molar basis of the pharmacologically active (Z) form produced by the dosage formulation through metabolic release of the active free drug to achieve its desired pharmacological and physiological effect. In some embodiments, a composition comprising endoxifen or an endoxifen salt or polymorph is administered to a subject at a dose of 0.01 mg to 200.0 mg. In other embodiments, an oral composition comprising endoxifen or an endoxifen salt or polymorph is administered to a subject at a dose of 1 mg to 200.0 mg. In some embodiments, oral compositions containing endoxifen or an endoxifen salt or polymorph are administered to a subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In certain embodiments, oral compositions containing endoxifen that are at least 95%, 97%, or at least 99% (Z)-endoxifen (wt / wt) are administered at a dose of 1 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, compositions containing endoxifen gluconate are administered at a dose ranging from 0.01 to 20 mg. In some embodiments, compositions containing (Z)-endoxifen D-gluconate are administered at 0.5 mg, 1 mg, 2 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and 200 mg per unit dose. In some embodiments, compositions containing 1 mg of (Z)-endoxifen D-gluconate are administered. In other embodiments, compositions containing 1 mg of (Z)-endoxifen L-gluconate are administered. In yet other embodiments, compositions containing 2 mg of (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate are administered.In certain embodiments, oral compositions comprising at least 90% polymorphic forms of endoxifen, e.g., polymorphic Form I, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX (wt / wt), are administered at a dose of 1 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, or 200 mg per unit dose. In some embodiments, compositions comprising polymorphic forms of endoxifen, e.g., Form I, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIX, are administered at a dose ranging from 0.01 to 20 mg.

[0278] Breast cancer growth rate studies, using mammography screening of subjects with breast cancer, have shown that breast cancer growth rates in the 25th percentile of women aged 50-59 indicate an unmet need for rapid exposure of subjects to therapeutic agents (Weeden-Fekjaer et al. Breast Cancer Research 2008 10:R41). Rapid absorption and bioavailability of anti-cancer therapeutic agents such as endoxifen, which could further reduce cancer growth rates, are highly desirable.

[0279] In one aspect, rapid achievement of maximum and steady-state plasma levels of endoxifen is a particular aspect of the present disclosure. The present disclosure provides that administration of a composition disclosed herein to a subject achieves maximum plasma levels of endoxifen within 2 to 30 hours, 3 to 20 hours, 2 to 10 hours, or 4 to 8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen is within 2 to 10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen is within 4 to 8 hours after administration of a composition disclosed herein.

[0280] Rapid achievement of steady-state plasma levels of endoxifen is also highly desirable. The plasma levels of endoxifen in subjects administered a composition disclosed herein comprising (Z)-endoxifen, or a salt or polymorph thereof, rapidly achieve steady state. Steady-state plasma levels can be achieved between days 7 and 21. In some embodiments, steady-state plasma levels can be achieved by day 7 following daily administration of a composition disclosed herein.

[0281] In one aspect, the present disclosure provides that circulating endoxifen released from the compositions disclosed herein may be eliminated faster than tamoxifen. The terminal elimination half-life of tamoxifen is said to be 5 to 7 days (Jordan C. Steroids. 2007 Nov;72(13):829-842), with tamoxifen's peak concentration time being approximately 5 hours after administration. Endoxifen released from the compositions disclosed herein may have a terminal elimination half-life in the range of 30 to 60 hours, significantly shorter than tamoxifen. In some embodiments, the mean half-life is in the range of 40 to 53 hours. AUC 24時間 (Day 21) / AUC 0-inf The mean ratio (Day 1) typically ranges from 0.7 to 1.2 for compositions containing 1 mg to 4 mg of (Z)-endoxifen, or a salt or polymorph thereof. Thus, the accumulation of endoxifen released from the compositions disclosed herein does not change significantly over time.

[0282] In another aspect, the present disclosure provides that administration of the compositions disclosed herein achieves therapeutically effective absorption of endoxifen.

[0283] Area under the curve AUC (0-24時間) ("AUC 24時間") represents a subject's total exposure to the drug from the time of dosing (hour 0) over a 24-hour period. Compositions containing (Z)-endoxifen or a salt thereof typically have a mean AUC of 150 h*ng / mL to 600 h*ng / mL on Day 1 for an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. 24時間 Compositions containing (Z)-endoxifen or a salt thereof typically achieve a mean AUC of 400 h*ng / mL to 2500 h*ng / mL on Day 21 following an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. 24時間 Achieve this.

[0284] AUC, the time-averaged concentration of a drug circulating in the body fluid being analyzed (usually plasma, blood, or serum) (0-inf) ("AUC 0-inf ") represents a subject's total exposure to the drug. The present disclosure provides a measure of a subject's exposure to endoxifen (AUC 0-inf ) can be dose-proportional. In some embodiments, the AUC 0-inf In another embodiment, AUC 0-inf is in the range of 300 h*ng / mL to 8000 h*ng / mL. In certain embodiments, AUC 0-inf is 400 h*ng / mL to 6000 h*ng / mL over the dosage range of 1 mg to 4 mg of (Z)-endoxifen.

[0285] A healthcare professional, for example, an attending physician, can adjust the dosing regimen based on the pharmacokinetic profile of the composition in the subject.

[0286] In one embodiment, the compositions of the present disclosure can be used alone or in combination therapy. For example, the compositions disclosed herein can be used in combination with one or more therapeutic agents as part of primary therapy, neoadjuvant therapy, or adjuvant therapy. In one embodiment of the present disclosure, the compositions of the present disclosure can be used in combination with other therapies, such as surgery and radiation, as neoadjuvant or adjuvant therapy. The combination of compositions can act to improve the effectiveness of therapeutic agents and thus can be used to improve standard cancer therapy. For example, if a subject has prostate cancer and is receiving bicalutamide or enzalutamide therapy for the treatment of prostate cancer, the subject is likely to develop gynecomastia as a result of the therapy. The compositions disclosed herein can be administered as combination therapy to a subject with prostate cancer to prevent and / or treat gynecomastia. As another example, a subject with ER+ / Her2+ positive breast cancer will receive combination therapy with trastuzumab or other cancer drug, e.g., an anti-neoplastic or immunotherapy, and the compositions disclosed herein can be used to treat such a subject with ER+ / Her2+ positive breast cancer. Thus, in some embodiments, the composition further comprises bicalutamide, enzalutamide or an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (multiple brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and an ATP-cassette binding protein inhibitor.

[0287] In another aspect, the compositions disclosed herein may contain a therapeutic agent that increases the bioavailability of endoxifen in a subject. P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed in the brain, liver, and small intestine, but also in cancer cells, that affects pharmacokinetics and confers therapy resistance to many anticancer drugs. Therefore, in some embodiments, the composition further contains an inhibitor of an ATP-binding cassette (ABC family) transporter, such as an inhibitor of breast cancer resistance protein (BCRP) and P-gp. Several inhibitors of BCRP and P-Gp are known in the art. For example, BCRP inhibitors include cyclosporine, omeprazole, pantoprazole, saquinavir, and tacrolimus.

[0288] Non-limiting examples of P-gp inhibitors include first generation inhibitors such as verapamil, cyclosporine A, reserpine, quinidine, yohimbine, tamoxifen, and toremifene, second generation inhibitors such as dexverapamil, dexniguldipine, valspodar (PSC833), and dofequidar fumarate (MS-209), third generation P-gp inhibitors such as cyclopropyldibenzosuberansoquidar (LY335979), laniquidar (R101933), mitotane (NSC-38721), biricodar (VX-710), elacridar (GF120918 / GG918), ONT-093, tariquidar (XR9576), and HM30181, and anti-P-gp monoclonal antibodies such as MRK-16.

[0289] The present disclosure additionally provides therapeutic kits containing one or more compositions for use in treating subjects with or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both. The kits of the present disclosure may include an oral composition disclosed herein, a sealed container for containing the composition, and instructions for use of the orally administered composition. In one embodiment, the kits of the present disclosure may include a second therapeutic agent. Such a second therapeutic agent may be bicalutamide, enzalutamide, or an anticancer drug such as trastuzumab, an anti-neoplastic agent such as capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), or epirubicin. (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (multiple brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP-binding cassette (ABC transporter) inhibitors, such as P-gp inhibitors.

[0290] Oral formulation In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral delivery. Compositions intended for oral use can be prepared in solid or fluid unit dosage forms. For example, the compounds of formula (IV), including the prepared and purified (Z)-endoxifen described herein, can be formulated for oral delivery. In at least some embodiments, the compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gum, dragees, lozenges, etc.

[0291] In some embodiments, the oral dosage form is a solid oral dosage form, such as a tablet, caplet, or capsule. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, a gelatin-free capsule, a "cap-in-cap" capsule, an alginate capsule, a hydroxypropyl methylcellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule. An example of an oral dosage form of (Z)-endoxifen may include the compound of Formula (IV) encapsulated in an enteric-coated, resistant, delayed-release hypromellose capsule.

[0292] Exemplary, non-limiting compositions are provided below. As stated above, percentages (%) refer to amounts by weight (wt / wt) based on the total weight of the composition. The sum of the different components of the composition adds up to 100% (wt / wt) of the total composition. At least 90% (≧90%) of (Z)-endoxifen free base refers to the weight percent of the (Z)-endoxifen isomer compared to the total weight of endoxifen in any composition.

[0293] In some embodiments, the compounds of formula (IV) described herein having a purity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% can be prepared as oral formulations. Compounds of formula (IV) can be prepared, for example, as described herein in Scheme 1 and Examples 1-3.

[0294] In one aspect, the present disclosure relates to a composition comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the methods disclosed herein.

[0295] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen free base or a salt thereof prepared according to any of the methods disclosed herein, wherein the (Z)-endoxifen is at least 90% (Z)-endoxifen free base wt / wt of the total endoxifen in the composition.

[0296] In yet another embodiment, the composition further comprises (E)-endoxifen, wherein the ratio of (E)-endoxifen to (Z)-endoxifen (E / Z-ratio) is 1:99; 5:95; 10:90, 15:85; 20:80, 25:75; 30:70; 40:70, 45:55; 50:50; 55:45; 60:40; 65:45; or 70:30.

[0297] In a further embodiment, the composition further comprises (E)-endoxifen, wherein the E / Z-ratio ranges from 45:55 to 55:45, or is approximately 1:1.

[0298] In one aspect, a composition comprises (Z)-endoxifen or a salt or polymorph thereof prepared according to any of the methods disclosed herein, wherein the (Z)-endoxifen is stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, or at least 18 months.

[0299] In another embodiment, a composition comprises (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition has an aerobic plate count of 20,000 g / mL or less, the water content of the composition is 1.0% or less when tested by USP 921, Method Ic; the water activity (Aw) of the composition is less than 0.9; the residue on ignition is 0.1% or less when tested by USP 281, Method II; heavy metals are 20 ppm or less when tested by USP 231, Method II; and / or the content of heavy metals is 20 ppm or less when tested by a validated HPLC method. In this case, methanol is 3000 ppm NMT, ethanol is 5000 ppm NMT, tetrahydrofuran is 720 ppm NMT, acetone is 5000 ppm NMT, isopropanol is 5000 ppm NMT, ethyl acetate is 5000 ppm NMT; n-heptane is 5000 ppm NMT, acetonitrile is 410 ppm NMT, MeTHF is 520 ppm NMT, zinc is 130 ppm NMT, benzene is 2 ppm NMT, and mesityl oxide is 25 ppm NMT.

[0300] In yet another embodiment, a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein can contain 0.01 mg to 200 mg of (Z)-endoxifen or a salt thereof per unit dose. In yet another embodiment, a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains 1 mg to 80 mg of (Z)-endoxifen or a salt thereof per unit dose. In a further embodiment, a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein contains 0.01% to 20% (wt / wt) endoxifen or a salt thereof.

[0301] In another aspect, the disclosure relates to compositions formulated for oral administration, comprising 1 mg to 200 mg of endoxifen per unit dose, wherein the compositions are stable for at least 6 months. In some embodiments, compositions formulated for oral administration comprise 1 mg to 80 mg of endoxifen per unit dose, 2 mg to 80 mg per unit dose, 4 mg to 80 mg per unit dose, or 4 mg to 40 mg per unit dose. In some embodiments, compositions formulated for oral administration comprise about 1 mg, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 20 mg, about 40 mg, or about 80 mg per unit dose.

[0302] In still further aspects, the present disclosure relates to compositions comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition comprises 0.1% to 10% (wt / wt) of (Z)-endoxifen or a salt thereof. In some cases, the (Z)-endoxifen or a salt thereof is a solid. The solid (Z)-endoxifen of the compositions disclosed herein can be amorphous, polycrystalline, or in a single crystalline form.

[0303] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, the composition further comprising one or more excipients.

[0304] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, further comprising one or more excipients, wherein the excipients are binders, fillers, disintegrants, lubricants, glidants, controlled-release agents, enteric coating agents, film-forming agents, plasticizers, sweeteners, flavoring agents, or combinations thereof.

[0305] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, further comprising one or more excipients, wherein the excipients are from about 0.1% to about 99% wt / wt of the composition.

[0306] In a further aspect, the disclosure provides a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is an acid-insoluble polymer, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succin ... The present invention relates to a composition comprising one or more controlled-release agents selected from the group consisting of waxes including acrylate copolymer, shellac, cellulose acetate trimellitate, sodium alginate, zein, synthetic waxes, microcrystalline wax, paraffin wax, carnauba wax, and beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-, tribenates, glyceryl monostearate, glyceryl distearate, long-chain alcohols such as stearyl alcohol, cetyl alcohol, polyethylene glycol, and mixtures thereof.

[0307] In one aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral, parenteral, topical, and intraductal delivery.

[0308] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and is a tablet, caplet, capsule, pill, powder, troche, elixir, suspension, syrup, wafer, chewing gum, dragee, and lozenge.

[0309] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition formulated for oral delivery is a tablet formulated as an enteric-coated tablet, a caplet formulated as an enteric-coated caplet, or a capsule formulated as an enteric-coated capsule. For example, a composition comprising (Z)-endoxifen can be formulated for oral delivery in an enteric-coated capsule containing hypromellose (e.g., CAPSUGEL® DRCAPS™). In some embodiments, the composition can be formulated as an enteric-coated, resistant, delayed-release hypromellose capsule.

[0310] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition formulated for oral delivery is a tablet formulated as a delayed-release tablet, a caplet formulated as a delayed-release caplet, or a capsule formulated as a delayed-release capsule.

[0311] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, releases less than 10% of the endoxifen in the stomach 2 hours after administration; less than 20% of the endoxifen in 2 hours after administration; or less than 30% of the endoxifen in 2 hours after administration.

[0312] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, releases less than 10% of the (Z)endoxifen in the stomach two hours after administration; or less than 20% of the (Z)endoxifen in the stomach two hours after administration. In some aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, releases less than 20% of the (Z)endoxifen in the stomach two hours after administration.

[0313] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by dissolution methods, the composition releases at least 20%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the endoxifen in the intestine.

[0314] In another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, the composition releases at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen in the intestine 3.5 hours after administration.

[0315] In another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, the composition releases at least 20%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the endoxifen in the intestine 3 hours after administration.

[0316] In another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, releases at least 20%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the endoxifen in the intestine 4 hours after administration. In some aspects, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and releases at least 80% of the (Z)-endoxifen in the intestine 2 hours, 3 hours, 3.5 hours, 4 hours, or 8 hours after administration.

[0317] In another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and, when tested by a dissolution method, releases in the small intestine at least 10% endoxifen after 4 hours of administration; at least 30% endoxifen after 6 hours of administration; at least 40% endoxifen after 7 hours of administration; at least 50% endoxifen after 8 hours of administration; at least 50% endoxifen after 2 hours of administration; at least 60% endoxifen after 2 hours of administration; at least 70% endoxifen after 2 hours of administration; at least 80% endoxifen after 2 hours of administration; or at least 90% endoxifen after 2 hours of administration.

[0318] In another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt thereof prepared according to any of the methods disclosed herein, wherein the composition is formulated for oral delivery and wherein the composition is formulated to release at least 80% of the endoxifen in the colon 3.5 hours after administration when tested by a dissolution method.

[0319] In another aspect, the disclosure relates to a composition formulated for oral administration comprising 1 mg to 200 mg of endoxifen per unit dose, wherein the endoxifen is 90% (Z)-endoxifen free base; the composition has an aerobic plate count of 20,000 g / ml or less; the water content of the (Z)-endoxifen is 1% or less as determined by Method Ic of USP 921; the residue on ignition of the (Z)-endoxifen is 0.10% or less as tested by Method II of USP 281; or heavy metals are 20 ppm or less as tested by Method II of USP 231.

[0320] In another aspect, the disclosure relates to a composition formulated for oral administration, comprising 1 mg to 200 mg of endoxifen per unit dose, wherein the composition is formulated as an enteric-coated tablet, enteric-coated caplet, or enteric-coated capsule; wherein the composition is formulated to release at least 25% of the endoxifen in the small intestine after 4 hours following administration; at least 30% of the endoxifen after 6 hours following administration; at least 40% of the endoxifen after 7 hours following administration; or at least 50% of the endoxifen after 8 hours following administration, as determined by dissolution methods; or wherein the composition is formulated to release at least 50% of the endoxifen in the colon, as determined by dissolution methods.

[0321] In another aspect, the disclosure provides an oral solid dosage form composition comprising 1 mg to 200 mg of endoxifen per unit dose, wherein the endoxifen is 90% (Z)-endoxifen free base; the composition has an aerobic plate count of 20,000 g / ml or less; the water content of the (Z)-endoxifen is 1% or less as determined by Method Ic of USP 921; the residue on ignition of the (Z)-endoxifen is 0.10% or less as tested by Method 281 of USP; or or heavy metals are 20 ppm or less when tested by Method II of USP 231; the composition is formulated as an enteric coated tablet, enteric coated caplet, and enteric coated capsule; the endoxifen is intact; or the composition further comprises excipients selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, controlled-release agents, enteric coating agents, film formers, plasticizers, colorants, sweeteners, and flavoring agents, or combinations thereof.

[0322] In another aspect, the present disclosure relates to enteric coated capsules comprising (Z)-endoxifen free base prepared by the processes described herein.

[0323] In another aspect, the disclosure relates to enteric-coated capsules comprising 1 mg to 200 mg of intact endoxifen per unit dose, wherein the endoxifen is 90% (Z)-endoxifen free base; the composition has an aerobic plate count of 20,000 g / ml or less; the water content of the (Z)-endoxifen is 1% or less as determined by Method Ic of USP 921; the residue on ignition of the (Z)-endoxifen is 0.10% or less as tested by Method II of USP 281; and heavy metals are 20 ppm or less as tested by Method II of USP 231.

[0324] In another aspect, the disclosure provides a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the endoxifen salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camsylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methyl methacrylate ... In one aspect, the present invention relates to a composition comprising an amine-containing compound selected from the group consisting of phosphate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0325] In yet another aspect, the present disclosure relates to compositions comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both.

[0326] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, wherein the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0327] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, wherein the hormone-dependent breast disorder is breast cancer.

[0328] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both, wherein the hormone-dependent breast disorder is breast cancer, and the breast cancer is precancerous, early stage, non-metastatic, pre-metastatic, locally advanced, or metastatic.

[0329] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both, wherein the hormone-dependent breast disorders or hormone-dependent reproductive tract disorders are tamoxifen-refractory or tamoxifen-resistant.

[0330] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof.

[0331] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both.

[0332] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder in the subject is benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0333] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both, wherein the composition is administered to a subject in need thereof, wherein the subject has breast cancer, and the breast cancer is precancerous, early stage, non-metastatic, pre-metastatic, locally advanced, or metastatic.

[0334] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject has prostate cancer, and the subject is undergoing or about to begin prostate cancer therapy.

[0335] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject in need thereof, wherein the subject has prostate cancer and the subject has or is at risk of having gynecomastia.

[0336] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, wherein the subject's hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen-resistant.

[0337] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject at a unit dose of 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 80 mg, 120 mg, 160 mg, or 200 mg of (Z)-endoxifen.

[0338] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject at a dose of 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 80 mg, 120 mg, 160 mg, or 200 mg of (Z)-endoxifen.

[0339] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every two weeks, twice monthly, monthly, quarterly, once every six months, or yearly.

[0340] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein oral administration of the composition maintains plasma endoxifen in a subject at a level greater than 30 nM.

[0341] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject as a combination therapy.

[0342] In yet another aspect, the present disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered as primary therapy, neoadjuvant therapy, or adjuvant therapy.

[0343] In yet another aspect, the disclosure relates to a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject either alone or in combination with a second therapeutic agent.

[0344] In yet another aspect, the disclosure provides a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared by any of the processes described herein, wherein the composition is administered to a subject either alone or in combination with a second therapeutic agent, wherein the second therapeutic agent is bicalutamide, enzalutamide, or an anti-cancer drug, e.g., trastuzumab, an antineoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Ta xotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (several brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), or an inhibitor of an ATP-binding cassette transporter.

[0345] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition prepared according to any one of the processes disclosed herein.

[0346] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein.

[0347] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both.

[0348] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, and the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

[0349] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has breast cancer.

[0350] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has breast cancer, and the breast cancer is precancerous, early stage, non-metastatic, pre-metastatic, locally advanced, or metastatic.

[0351] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has prostate cancer and the subject further has or is at risk of having gynecomastia.

[0352] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the subject has a tamoxifen-refractory or tamoxifen-resistant hormone-dependent breast disorder or hormone-dependent reproductive tract disorder.

[0353] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject in a unit dose of 1.0 mg, 1.5 mg, 2.0 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 20 mg, 25 mg, 40 mg, 50 mg, 80 mg, 100 mg, 120 mg, 160 mg, or 200 mg.

[0354] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is administered once daily, twice daily, three times daily, four times daily, every other day, twice weekly, weekly, every two weeks, twice monthly, monthly, quarterly, once every six months, or yearly.

[0355] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein oral administration of the composition maintains plasma endoxifen in the subject at a steady-state level greater than 30 nM.

[0356] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein oral administration of the composition achieves a plasma endoxifen level in the subject of greater than 30 nM by day 14 after administration of the first dose (day 1).

[0357] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein oral administration of the composition achieves a plasma endoxifen level in the subject of greater than 30 nM by day 14 after administration of the first dose (day 1).

[0358] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein administering the composition orally achieves a time to maximum plasma levels of endoxifen in the subject of 2 to 10 hours post-administration (post-dosing).

[0359] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administering the composition orally achieves a time to maximum plasma levels of endoxifen in the subject of 2 to 10 hours post-administration (post-dosing).

[0360] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the mean terminal elimination half-life of endoxifen in the subject is in the range of 30 to 60 hours after dosing.

[0361] In yet another aspect, the disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the mean terminal elimination half-life of endoxifen in the subject is in the range of 40 to 55 hours after dosing.

[0362] In another aspect, the disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administration of the composition achieves a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma level of endoxifen ranging from 2 hours to 10 hours after administration; and a steady-state plasma level of endoxifen greater than 30 nM.

[0363] In another aspect, the disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof, wherein administration of the composition achieves a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma level of endoxifen ranging from 2 hours to 10 hours after administration; and a steady-state plasma level of endoxifen greater than 30 nM.

[0364] In another aspect, the disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering an oral composition comprising (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administration of the composition achieves a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma level of endoxifen ranging from 2 hours to 10 hours after administration; and a steady-state plasma level of endoxifen greater than 30 nM.

[0365] In another aspect, the disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering to a subject a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering to a subject a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of an enteric-coated tablet, an enteric-coated caplet, an enteric-coated capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule. and a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestine.

[0366] In another aspect, the disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, wherein the method comprises administering to a subject a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder comprising administering to a subject a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder, the ... and a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestine.

[0367] In another aspect, the disclosure relates to a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising daily administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administration of the composition achieves a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma level of endoxifen ranging from 2 hours to 10 hours after administration; and a steady-state plasma level of endoxifen greater than 30 nM.

[0368] In another aspect, the disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising administering to a subject a therapeutically effective amount of ... formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule. and a steady-state plasma level of endoxifen greater than 30 nM; and wherein at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestine.

[0369] In another aspect, the disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder selected from the group consisting of benign breast disorders, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, the method comprising daily administering an oral composition comprising 0.01 mg to 200 mg of (Z)-endoxifen or a salt or polymorph thereof formulated as an enteric-coated tablet, enteric-coated caplet, enteric-coated capsule, delayed-release tablet, delayed-release caplet, or delayed-release capsule, wherein administering the composition has a mean half-life of endoxifen in subjects ranging from 30 hours to 60 hours after administration; a time to maximum plasma level of endoxifen ranging from 2 hours to 10 hours after administration; and achieves a steady-state plasma level of endoxifen greater than 30 nM; and a mean area under the curve extrapolated to infinity (AUC0-inf) of 200 h*ng / mL to 10,000 h*ng / mL, 300 h*ng / mL to 8,000 h*ng / mL, 400 h*ng / mL to 6,000 h*ng / mL, or 700 h*ng / mL to 6,000 h*ng / mL; and at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestine.

[0370] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the method is primary therapy, neoadjuvant therapy, or adjuvant therapy.

[0371] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject as a combination therapy.

[0372] In yet another aspect, the present disclosure relates to a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is administered to the subject either alone or in combination with a second therapeutic agent.

[0373] In yet another aspect, the disclosure provides a method of treating a subject in need thereof, comprising administering a composition comprising (Z)-endoxifen or a salt or polymorph thereof prepared according to any one of the processes disclosed herein, wherein the composition is selected from the group consisting of bicalutamide, enzalutamide, or an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel (Docefrez, Taxotere), doxorubicin, and the like. the method is administered to the subject in combination with a second therapeutic agent selected from the group consisting of rifabutin (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (several brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and ATP-cassette binding protein transport inhibitors.

[0374] In yet another aspect, the present disclosure relates to a use for the treatment and prevention of hormone-dependent breast disorders, hormone-dependent reproductive tract disorders, or both in a subject, the use comprising administering to the subject a first composition comprising tamoxifen; determining the subject's tamoxifen-metabolite profile in a test sample obtained from the subject; determining a reduced level of plasma endoxifen in the subject based on the subject's tamoxifen-metabolite profile when compared to the level of plasma endoxifen in a reference tamoxifen-metabolite profile; and administering a composition of the present disclosure to the subject.

[0375] In yet another aspect, the disclosure provides a use for the treatment and prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both in a subject, the use comprising: administering to the subject a first composition comprising tamoxifen; determining the subject's tamoxifen-metabolite profile in a test sample obtained from the subject; determining a reduced level of plasma endoxifen in the subject based on the subject's tamoxifen-metabolite profile as compared to a level of plasma endoxifen in a reference tamoxifen-metabolite profile; and administering a composition of the disclosure to the subject, wherein the composition is administered orally at a dose sufficient to maintain the subject's plasma endoxifen at a steady-state level of greater than 30 nM; and the tamoxifen-metabolite profile comprises at least tamoxifen, 4-hydroxybenzoates ... the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, precocious puberty, McCune-Albright syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer; the hormone-dependent breast disorder is pre-cancerous, early stage cancer, non-metastatic cancer, pre-metastatic cancer, locally advanced cancer, or metastatic cancer; the hormone-dependent breast disorder is non-metastatic cancer; the subject has prostate cancer, and the subject further has or is at risk of having gynecomastia; or the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen-resistant.

[0376] In yet another aspect, the present disclosure relates to a kit for treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder in a subject in need thereof, the kit comprising: (a) a composition of the present disclosure; and (b) a sealed container for containing the composition; and c) instructions for use of the orally administered composition.

[0377] In yet another aspect, the present disclosure provides a kit for treating a subject having or at risk of having a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder in a subject in need thereof, the kit comprising: (a) a composition of the present disclosure; and (b) a sealed container for housing the composition; and c) instructions for use of the orally administered composition, wherein the kit comprises bicalutamide, enzalutamide, and an anti-cancer drug, e.g., trastuzumab, an anti-neoplastic agent, e.g., capecitabine (Xeloda), carboplatin (Paraplatin), cisplatin (Platinol), cyclophosphamide (Neosar), docetaxel. (Docefrez, Taxotere), doxorubicin (Adriamycin), PEGylated liposomal doxorubicin (Doxil), epirubicin (Ellence), fluorouracil (5-FU, Adrucil), gemcitabine (Gemzar), methotrexate (multiple brand names), paclitaxel (Taxol), protein-bound paclitaxel (Abraxane), vinorelbine (Navelbine), eribulin (Halaven), ixabepilone (Ixempra), and an ATP-cassette binding protein transport inhibitor.

[0378] In yet another aspect, the present disclosure relates to a method of administering to a subject in need thereof a composition prepared according to any of the processes described herein according to instructions for use included in a kit containing the composition.

[0379] excipients In some embodiments, oral compositions comprising (Z)-endoxifen or a salt thereof further comprise one or more excipients. In some embodiments, oral compositions comprising endoxifen or a polymorph thereof further comprise one or more excipients. Thus, compositions designed for oral administration can be made with inert or active excipients or with edible carriers disclosed herein.

[0380] In various embodiments, the compositions provided herein comprise from about 1% to about 99.99%, from about 5% to about 95%, from about 5% to about 90%, from about 10% to about 80%, from about 15% to about 70%, from about 20% to about 60%, from about 30% to about 95%, from about 50% to about 90%, from about 60% to about 90%, from about 60% to about 80%, or from about 70% to about 80% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise from about 99.99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 99.99%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, or about 85% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 85%, about 84%, about 83%, about 82%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, or about 65% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, or about 45% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, or about 20% by weight of one or more excipients.

[0381] Examples of excipients that may be used in compositions formulated for oral administration are provided herein and may include, but are not limited to, one or more of a filler, binder, filler, disintegrant, lubricant, glidant, controlled-release agent, enteric coating, film-forming agent, plasticizer, colorant, sweetener, flavoring agent, etc., or any combination thereof.

[0382] Suitable binders for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starch such as corn starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, Methocel, Wakocel HM, Luvitec, Luvicaparolactam, Avicel, SMCC, UNIPURE, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH101, AVICEL PH103, AVICEL RC581, AVICEL PH105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Suitable anhydrous or low-moisture excipients or additives include AVICEL PH 103 and starch 1500LM.

[0383] Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, salts such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starch, microcrystalline cellulose, powdered cellulose, cellulose-based materials such as methylcellulose, carboxymethylcellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0384] The one or more binders or fillers in the composition are typically present in about 10% to about 99% (wt / wt) of the composition or dosage form. In some embodiments, the binders and / or fillers in the composition comprise about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, or about 50% to 99% (wt / wt) of the composition.

[0385] Disintegrants can be used in compositions to provide tablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate during storage, while those that contain too little disintegrant may not disintegrate at the desired speed or under the desired conditions.Therefore, a sufficient amount of disintegrant should be used to form a solid oral dosage form, but not too much or too little, so as to adversely alter the release of active ingredient.In some embodiments, disintegrant is located deep in the oral solid dosage form to delay disintegration.The amount of disintegrant used varies based on the type of formulation, and can be easily recognized by those skilled in the art.

[0386] Typical compositions contain 0.5% to 15% (wt / wt) disintegrant. In some embodiments, the composition contains 1% to 5% (wt / wt) disintegrant in the composition. In other embodiments, the disintegrant is 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of the composition.

[0387] Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacritin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0388] Lubricants that may be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, magnesium stearate, or potassium stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200 manufactured by W.R. Grace Co. of Baltimore, Md.), coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), Q7-9120 (Dow Corning), and mixtures thereof. If used at all, lubricants are typically used in amounts of less than 1% (wt / wt) of the composition or dosage form into which they are incorporated. In yet another embodiment, the lubricant is 0.1% to 3%, e.g., 0.5% to 1% (wt / wt) of the composition.

[0389] Plasticizers can be added to control the softness or flexibility of the shell of an oral dosage form, such as a capsule, caplet, or tablet, and can thus improve the mechanical properties of pH-sensitive materials in coatings on the oral dosage form. Suitable plasticizers include, but are not limited to, petroleum oils (e.g., paraffinic process oils, naphthenic process oils, and aromatic process oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicon oil, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene and liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycol, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotamiton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical preparation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1% to 10%, for example, 3% to 5% (wt / wt) of the composition.

[0390] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate (di- or tribasic), and the like.

[0391] Examples of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like.

[0392] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry, and the like.

[0393] The compositions disclosed herein, for example, tablets, caplets, and capsules formulated for oral delivery, can be coated with one or more enteric coating agents, controlled-release agents, or film-forming agents to control or delay the disintegration and absorption of the compositions comprising endoxifen or its salt in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time.Thus, in some embodiments, the tablets can be enteric-coated tablets, the caplets can be enteric-coated caplets, or the capsules can be enteric-coated capsules.The enteric-coated tablets, enteric-coated caplets, or enteric-coated capsules of the present disclosure can be prepared by techniques known in the art.

[0394] Pharmaceutical preparations disclosed herein can contain controlled release agent.The example of controlled release agent suitable for use includes but is not limited to pH-dependent polymer, acid-insoluble polymer, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, cellulose acetate trimellitate, sodium alginate, zein, synthetic wax, microcrystalline wax, paraffin wax, carnauba wax and wax, including beeswax; polyethoxylated castor oil derivative, hydrogenated oil, glyceryl mono-, di-, tribenate, glyceryl monostearate, glyceryl distearate, long-chain alcohol, for example, stearyl alcohol, cetyl alcohol and polyethylene glycol; and mixtures thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed, hi other embodiments, the controlled release agent is a digestible waxy substance, such as solid paraffin wax.

[0395] In some embodiments, the composition may include one or more pH-dependent polymers, such as acid-insoluble polymers. pH-dependent polymers become increasingly permeable above pH 5.0 but are impermeable below pH 5.0, while acid-insoluble polymers become soluble under neutral to slightly alkaline conditions. Such controlled-release polymers target the upper small intestine and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, alginates such as sodium or potassium alginate, shellac, pectin, and acrylic acid-methylacrylic acid copolymers (commercially available under the trade names EUDRAGIT® L and EUDRAGIT® S (as powder or a 30% aqueous dispersion) from Rohm America Inc., Piscataway, NJ; or EASTACRYL® (as a 30% dispersion) from Eastman Chemical Co., Kingsport, TN). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12.5, EUDRAGIT® S100, EUDRAGIT® S12.5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12.5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL and EUDRAGIT® NE and NM are also useful polymers for purposes of the present disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the preparation comprises EUDRAGIT® FS 30D. Those skilled in the art will recognize that at least some of the acid-insoluble polymers listed herein will also be biodegradable.

[0396] For time-delay or delayed-release pharmaceutical preparations of oral dosage forms, coatings based on glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, such as polymethacrylate pH-sensitive polymers, can be used (e.g., as enteric coatings for capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available (e.g., DRCAPS™ made from hypromellose (HPMC) from CAPSUGEL®, USA). Such delayed-release oral dosage forms are acid-resistant and can withstand acidity such as that found in the stomach for at least 30 minutes, e.g., at least 1 hour, at least 1.5 hours, or at least 2 hours. Such delayed-release oral dosage forms can release at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of endoxifen or its salt in the intestine (small intestine, large intestine / colon, etc.).

[0397] In one aspect of the present disclosure, enteric-coated tablets, enteric-coated caplets, and enteric-coated capsules may be uncoated. Uncoated hard capsules with enteric capabilities that use inherently enteric capsule technology (e.g., ENTRINSIC™ drug delivery available from CAPSUGEL®) are suitable for purposes of the present disclosure.

[0398] In various embodiments, the enteric-coated tablet is a hard tablet made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric-coated capsule is a hard capsule made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric-coated tablet is a hard tablet made with a free-flowing powder of endoxifen or a polymorph thereof. In various embodiments, the enteric-coated capsule is a hard capsule made with a free-flowing powder of endoxifen or a polymorph thereof.

[0399] In some embodiments, the enteric-coated capsule is a non-animal-based capsule, such as a hypromellose capsule (e.g., commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, Xcellodose, ENCODE colony delivery technology, and other enteric-coated capsules made using ENTRINSIC™ drug delivery technology from CAPSUGEL®). Other technologies known in the art and commercially available (e.g., QUALICAPS®, USA, Nutrascience, USA, etc.) for formulating enteric-coated oral solid dosage forms may also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that (Z)-endoxifen free base or a salt thereof is filled directly into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or a salt thereof, can be a free-flowing powder or a micronized powder. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a striped capsule.

[0400] Rapid absorption and bioavailability of anti-cancer therapeutics such as endoxifen, which can further reduce cancer growth rates, is highly desirable. In one aspect, the present disclosure provides that the compositions are formulated for predetermined pharmacokinetic (PK) properties.

[0401] In one aspect, rapid achievement of maximum and steady-state plasma levels of endoxifen is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve maximum plasma levels of endoxifen within 2 to 30 hours, 3 to 20 hours, 2 to 10 hours, or 4 to 8 hours after administration of the composition. Thus, in some embodiments, the time to maximum (peak) plasma levels of endoxifen is within 2 to 10 hours after administration of the composition. In some embodiments, the time to maximum plasma levels of endoxifen is within 4 to 8 hours after administration of a composition disclosed herein.

[0402] Rapid attainment of steady-state plasma levels of endoxifen is also highly desirable, and the compositions of the present disclosure can provide plasma levels of endoxifen in subjects administered compositions containing the polymorphic form of endoxifen, (Z)-endoxifen, or a salt thereof, that rapidly attain steady state. Steady-state plasma levels can be achieved between days 7 and 21. In some embodiments, steady-state plasma levels can be achieved by day 7 following daily administration of the compositions disclosed herein.

[0403] In one aspect, the present disclosure provides that circulating endoxifen released from the compositions disclosed herein can be eliminated faster than tamoxifen. The terminal elimination half-life of tamoxifen can be 5 to 7 days (Jordan C. Steroids. 2007 Nov;72(13):829-842), and the time to peak concentration of tamoxifen can be approximately 5 hours after administration. Endoxifen released from the compositions disclosed herein can have a terminal elimination half-life in the range of 30 to 60 hours, which is significantly shorter than that of tamoxifen. In some embodiments, the mean half-life is in the range of 40 to 53 hours. AUC 24時間 (Day 21) / AUC 0-inf The mean ratio (Day 1) typically ranges from 0.7 to 1.2 for compositions containing 1 mg to 4 mg of (Z)-endoxifen, or a salt thereof. Thus, the accumulation of endoxifen released from the compositions disclosed herein does not change significantly over time.

[0404] In another aspect, the compositions described herein achieve therapeutically effective absorption of endoxifen.

[0405] Area under the curve AUC (0-24時間) ("AUC 24時間 ") represents a subject's total exposure to the drug from the time of dosing (hour 0) over a 24-hour period. Compositions containing (Z)-endoxifen or a salt thereof typically have a mean AUC of 150 h*ng / mL to 600 h*ng / mL on Day 1 for an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. 24時間Compositions containing (Z)-endoxifen or a salt thereof typically achieve a mean AUC of 400 h*ng / mL to 2500 h*ng / mL on Day 21 following an initial (first) dose of a composition containing 1 mg to 4 mg of (Z)-endoxifen. 24時間 Achieve this.

[0406] AUC, the time-averaged concentration of a drug circulating in the body fluid being analyzed (usually plasma, blood, or serum) 0-inf ("AUC 0-inf ") represents a subject's total exposure to the drug. The present disclosure provides a measure of a subject's exposure to endoxifen (AUC 0-inf ) can be dose-proportional. In some embodiments, the AUC 0-inf In another embodiment, AUC 0-inf is in the range of 300 h*ng / mL to 8000 h*ng / mL. In certain embodiments, AUC 0-inf is 400 h*ng / mL to 6000 h*ng / mL over the dosage range of 1 mg to 4 mg of (Z)-endoxifen.

[0407] The dissolution of the oral dosage forms disclosed herein is tested by dissolution testing according to the current method of USP 711. In some embodiments, the oral dosage forms disclosed herein are protected from the acidic environment of the stomach and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours, or at least 8 hours. In at least one embodiment, the oral dosage form does not release endoxifen for at least 6 hours. In another embodiment, the oral dosage form does not release endoxifen or a salt thereof for at least 2 hours.

[0408] In other embodiments, when tested by the method of USP 711, less than 10% of (Z)-endoxifen in a composition comprising endoxifen or a salt thereof disclosed herein is released in the stomach 2 hours after administration; or less than 40% of (Z)-endoxifen is released in the stomach 4 hours after administration; or less than 50% of (Z)-endoxifen is released in the stomach 6 hours after administration.

[0409] In another embodiment, the compositions disclosed herein release less than 10% of the (Z)-endoxifen in the stomach at 2 hours after administration, less than 40% of the (Z)-endoxifen at 4 hours after administration, and less than 50% of the (Z)-endoxifen at 6 hours after administration when tested by the method of USP711.

[0410] In yet another embodiment, the composition is formulated for release in the small intestine such that, when tested by the method of USP 711, at least 10% of endoxifen is released after 4 hours after administration; or at least 30% of endoxifen is released after 6 hours after administration; or at least 40% of endoxifen is released after 7 hours after administration; or at least 50% of endoxifen is released after 8 hours after administration.

[0411] In a further embodiment, the composition is formulated to release at least 50% of the endoxifen in the colon 8 hours after administration as determined by the method of USP 711.

[0412] In still further embodiments, the composition is formulated to release at least 20% of the endoxifen in the colon after 4 hours following administration; at least 40% of the endoxifen after 6 hours following administration; at least 60% of the endoxifen after 7 hours following administration; or at least 80% of the endoxifen after 8 hours following administration.

[0413] Oral dosage forms can be of any shape suitable for oral administration, e.g., spherical (0.05-5 mL), oval (0.05-7 mL), elliptical, pear-shaped (0.3-5 mL), cylindrical, cubic, regular and / or irregular shapes. Oral dosage forms can be of any size suitable for oral administration, e.g., size 0, size 2, etc.

[0414] Those skilled in the art will further recognize that the compositions disclosed herein can contain one or more of the excipients known in the art and disclosed herein in any combination suitable for the desired formulation or preparation. Additional excipients can be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. Those skilled in the art will be able to select suitable excipients necessary for the preparation of a formulation compatible with the administration route and an appropriate dosage form ...

Claims

1. A method for purifying a compound of formula (IV), comprising: 【Chemistry 21】 The method comprises: (i) providing a compound of formula (III) comprising the compound of formula (IV); 【Chemistry 22】 (ii) performing fractional crystallization of the compound of formula (III) in ethyl acetate to produce a filtrate containing the compound of formula (IV); and (iii) using the filtrate to perform acetone and isopropyl alcohol recrystallization to purify the compound of formula (IV) to a purity of at least 94% (w / w); The method comprising:

2. The method, (iv) performing tetrahydrofuran recrystallization further comprising 2. The method of claim 1, wherein optionally, the tetrahydrofuran crystallization comprises contacting the compound of formula (IV) with tetrahydrofuran, and further optionally, the tetrahydrofuran crystallization further comprises contacting the compound of formula (IV) and the tetrahydrofuran with isopropyl alcohol (2-propanol).

3. Providing the compound of formula (III) comprises: providing a compound of formula (II); 【Chemistry 23】 and carrying out a McMurry reaction on the compound of formula (II) and propiophenone to produce the compound of formula (III). The method of claim 1 , comprising:

4. 4. The method of claim 3, wherein the McMurry reaction comprises contacting the compound of formula (II) and the propiophenone with zinc and titanium (IV) chloride. (a) the McMurry reaction further comprises maintaining a temperature of 60°C or greater for 8 hours or more; (b) the zinc, the titanium(IV) chloride, or both are dissolved or suspended in tetrahydrofuran; (c) the zinc and the titanium(IV) chloride are mixed at a temperature of 60° C. or greater for 2 hours or more before contacting with the compound of formula (II); (d) the compound of formula (II) is in suspension with the propiophenone and is one of the following: The suspension is suspended in an organic solvent selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof; The suspension is suspended in tetrahydrofuran; The suspension is mixed at a temperature of 60°C or greater before contacting the zinc and titanium(IV) chloride; or (e) any combination thereof; The method of claim 4.

6. 4. The method of claim 3, wherein the McMurry reaction further comprises extracting the product produced by the contacting of the compound of formula (II) with the zinc and the titanium(IV) chloride with an organic solvent. (a) the organic solvent is selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof; or 2-methyltetrahydrofuran; (b) the product produced by contacting the compound of formula (II) with the zinc and titanium(IV) chloride is carbonate, a carbonate selected from the group consisting of potassium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, and calcium carbonate, or potassium carbonate further extracted with a solution containing; (c) the product produced by contacting the compound of formula (II) with the zinc and titanium(IV) chloride is Arrhenius bases, an Arrhenius base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide; Sodium hydroxide further extracted with a solution containing; (d) the product produced by contacting the compound of formula (II) with the zinc and titanium(IV) chloride is Neutral salt, a neutral salt selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, potassium chlorate, sodium chlorate, potassium perchlorate, and sodium perchlorate, or Sodium chloride or (e) or any combination thereof; The method of claim 6.

8. Providing the compound of formula (III) comprises: (a) concentrating the product produced by the McMurry reaction in acetone, acetonitrile, or both; (b) washing the product produced by the McMurry reaction in acetone, acetonitrile, or both; or (c) Combinations thereof The method of claim 3 further comprising:

9. Providing the compound of formula (II) comprises: providing a compound of formula (I); 【Chemistry 24】 and carrying out a demethylation reaction on the compound of formula (I) to produce the compound of formula (II); The method of claim 3, comprising:

10. The demethylation reaction is carried out by reacting the compound of formula (I) with (a) N-ethyldiisopropylamine and one of the following: The compound of formula (I), the N-ethyldiisopropylamine, or both, are dissolved in an organic solvent; the compound of formula (I), the N-ethyldiisopropylamine, or both, are dissolved in an organic solvent selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, diglyme, nitromethane, 1,2-dimethoxyethane, pyridine, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, decane, and combinations thereof; or The compound of formula (I), the N-ethyldiisopropylamine, or both, are dissolved in tetrahydrofuran; (b) 1-chloroethyl chloroformate and one of the following: The compound of formula (I) and the 1-chloroethyl chloroformate are heated to reflux; or The compound of formula (I) and the 1-chloroethyl chloroformate are mixed at 60°C or higher for 12 hours or more; (c) a solution comprising an Arrhenius acid and one or more of the following: the Arrhenius acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrosulfic acid, acetic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, chloric acid, perchloric acid, chlorous acid, phosphoric acid, phosphorous acid, and carbonic acid; or the Arrhenius acid is hydrochloric acid; or (d) any combination thereof 10. The method of claim 9, comprising contacting the 11. The method comprising: (a) increasing the pH of the demethylation reaction to at least about 13 or at least about 13.4, and one of the following: increasing the pH comprises adding a solution comprising an Arrhenius base to the demethylation reaction; increasing the pH comprises adding to the demethylation reaction a solution comprising an Arrhenius base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide; increasing the pH comprises adding a solution comprising sodium hydroxide to the demethylation reaction; (b) extracting the compound of formula (II) with ethyl acetate; or (c) Combinations thereof 10. The method of claim 9, further comprising:

12. The ethyl acetate fractional recrystallization comprises contacting the compound of formula (III) with ethyl acetate and an Arrhenius acid to extract the compound of formula (IV), and one or more of the following: (a) the Arrhenius acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrosulfic acid, acetic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, chloric acid, perchloric acid, chlorous acid, phosphoric acid, phosphorous acid, and carbonic acid; (b) the Arrhenius acid is hydrochloric acid; (c) the compound of formula (III), the ethyl acetate, and the Arrhenius acid are mixed at 50°C to 70°C, or 55°C to 65°C, for 6 hours or more; or (d) combinations thereof; The method of claim 1 , comprising:

13. The ethyl acetate fractional recrystallization is (a) adjusting the pH of a solution containing the compound of formula (III) adding an Arrhenius base; adding an Arrhenius base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, and lithium hydroxide; or Adding sodium hydroxide Raising to 12 or higher by (b) adding ethyl acetate to extract the compound of formula (IV); (c) reacting the compound of formula (IV) Neutral salt; a neutral salt selected from the group consisting of sodium chloride, potassium chloride, potassium sulfate, sodium sulfate, potassium nitrate, sodium nitrate, potassium chlorate, sodium chlorate, potassium perchlorate, and sodium perchlorate; or Sodium chloride washing with a solution containing; (d) filtering the compound of formula (IV); or (e) any combination thereof The method of claim 1 further comprising:

14. 2. The method of claim 1, wherein the isopropyl alcohol and acetone crystallization comprises contacting the compound of formula (IV) with acetone, and optionally, the isopropyl alcohol and acetone crystallization further comprises contacting the compound of formula (IV) and the acetone with isopropyl alcohol (2-propanol).

15. 15. The method of any one of claims 1-14, wherein the ethyl acetate fractional recrystallization, the isopropyl alcohol and acetone crystallization, the tetrahydrofuran crystallization, or a combination thereof reduces the level of (E)-endoxifen in the compound of formula (III) or the compound of formula (IV), and the level of (E)-endoxifen in the compound of formula (III) or the compound of formula (IV) is reduced by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 45%, 40%, 30%, 20%, 10%, or 5%, as measured by HPLC.

16. 15. The method of any one of claims 1 to 14, wherein the ethyl acetate fractional recrystallization, the isopropyl alcohol and acetone crystallization, the tetrahydrofuran crystallization, or a combination thereof reduces the level of mesityl oxide in the compound of formula (III) or the compound of formula (IV), and the level of mesityl oxide in the compound of formula (III) or the compound of formula (IV) is reduced by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1%, as measured by HPLC.

17. The ethyl acetate fractional recrystallization, the isopropyl alcohol and acetone crystallization, the tetrahydrofuran crystallization, or a combination thereof reduces the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, or the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol in the compound of formula (III) or the compound of formula (IV), and one or more of the following: (a) the level of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol is reduced by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1% as measured by HPLC; (b) the level of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol is reduced by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1% as measured by HPLC; (c) the level of 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol is reduced by at least about 99.9%, 99%, 97%, 75%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, or 1% as measured by HPLC; (d) the level of the 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol is the level of (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; Levels of (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; Levels of (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; levels of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or a combination thereof; or (e) any combination thereof; The method according to any one of claims 1 to 14.

18. The method of any one of claims 1 to 14, wherein the compound of formula (IV) is purified to a purity of at least 96% (w / w).

19. 1. A composition comprising: at least 96% w / w of a compound of formula (IV), 【Chemistry 25】 and impurities of 4% w / w or less, said impurities including 25 ppm or less of mesityl oxide, 0.5% or less by weight of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol, and 3% (w / w) or less of (E)-endoxifen, based on the total weight of said composition. The composition comprising:

20. The composition comprising: (a) no more than 2.5%, 2%, 1.5%, or 1% by weight of (E)-endoxifen; (b) greater than 97%, 97.5%, 98%, 98.5%, or 99% by weight of (Z)-endoxifen; (c) mesityl oxide at or below 5 ppm, 10 ppm, 15 ppm, 20 ppm, or 25 ppm; (d) not more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, or 0.4% by weight of 4-(1-(4-methoxyphenyl)-2-phenylbut-1-en-1-yl)phenol; (e) no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, or 0.4% by weight of 4-(1-(4-isopropoxyphenyl)-2-phenylbut-1-en-1-yl)phenol; (f) 1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol at 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% by weight or less; (g) no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1S,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (h) no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1R,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (i) no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1S,2S)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; (j) no more than 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by weight of (1R,2R)-1-(4-(2-hydroxyethoxy)phenyl)-1,2-bis(4-hydroxyphenyl)-2-(4-(2-(methylamino)ethoxy)phenyl)ethane-1,2-diol; or (k) any combination thereof 20. The composition of claim 19, comprising:

21. The composition comprising: (a) ethanol not exceeding 5000 ppm; (b) 3000 ppm or less of methanol; (c) acetone not exceeding 5000 ppm; (d) 5000 ppm or less of isopropyl alcohol (2-propanol); (e) 410 ppm or less of acetonitrile; (f) ethyl acetate not exceeding 5000 ppm; (g) 720 ppm or less of tetrahydrofuran; (h) 520 ppm or less of 2-methyltetrahydrofuran; (i) n-heptane at or below 5000 ppm; (j) not more than 130 ppm zinc; (k) 2 ppm or less of benzene; or (l) any combination thereof 20. The composition of claim 19, comprising:

22. A composition comprising a compound of formula (IV) produced by the method of claim 1.

23. The compound of formula (IV) is a solid form of a compound of formula (III): 【Chemistry 26】 The solid form may be (i) (a) Form IV, characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3°2θ, 23.3±0.3°2θ, and 13.6±0.3°2θ; (b) Form V, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°2θ, 19.6±0.3°2θ, and 8.9±0.3°2θ; (c) Form VI, characterized by an X-ray powder diffraction pattern containing major peaks at 9.9±0.3°2θ, 13.4±0.3°2θ, and 13.7±0.3°2θ; (d) Form VII, characterized by an X-ray powder diffraction pattern containing major peaks at 20.0±0.3°2θ, 22.6±0.3°2θ, and 10.6±0.3°2θ; (e) Form VIII, characterized by an X-ray powder diffraction pattern containing major peaks at 4.8±0.3°2θ, 18.9±0.3°2θ, and 9.5±0.3°2θ; (f) Form IX, characterized by an X-ray powder diffraction pattern containing major peaks at 19.0±0.3°2θ, 12.9±0.3°2θ, and 15.9±0.3°2θ; (g) Form X, characterized by an X-ray powder diffraction pattern containing major peaks at 7.2±0.3°2θ, 14.3±0.3°2θ, 18.7±0.3°2θ, 21.5±0.3°2θ, and 22.7±0.3°2θ; (h) Form XI, characterized by an X-ray powder diffraction pattern containing major peaks at 14.0±0.3°2θ, 17.7±0.3°2θ, 11.9±0.3°2θ, 18.4±0.3°2θ, 23.9±0.3°2θ, 17.3±0.3°2θ, 21.8±0.3°2θ, 20.8±0.3°2θ, and 23.0±0.3°2θ; (i) Form XII, characterized by an X-ray powder diffraction pattern containing major peaks at 12.5±0.3°2θ, 15.6±0.3°2θ, and 19.0±0.3°2θ; (j) Form XIV, characterized by an X-ray powder diffraction pattern containing major peaks at 11.6±0.3°2θ, 21.3±0.3°2θ, and 19.3±0.3°2θ; (k) Form XV, characterized by an X-ray powder diffraction pattern containing major peaks at 9.8±0.3°2θ, 4.7±0.3°2θ, and 14.0±0.3°2θ; (l) Form XIX, characterized by an X-ray powder diffraction pattern containing major peaks at 4.7±0.3°2θ, 23.6±0.3°2θ, and 18.9±0.3°2θ; and (m) Combinations thereof A crystalline form of the compound of formula (III) selected from the group consisting of: (ii) an amorphous form of the compound of formula (III); or (iii) combinations thereof 23. The composition of claim 19 or claim 22, comprising:

24. 24. The composition of claim 23, wherein at least about 95%, at least about 98%, or at least about 99% by weight of the compound of Formula (III) in the composition is the (Z)-isomer.

25. 24. The composition of claim 23, wherein the crystalline form of the compound of formula (III) is stable at ambient temperature for at least 1 day, at least 3 days, at least 7 days, at least 14 days, at least 21 days, at least 30 days, at least 60 days, or at least 90 days at ambient temperature.

26. 24. The composition of claim 23, wherein the crystalline form of the compound of formula (III) is Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIV, Form XV, or Form XIX.

27. ​​The composition of claim 23, further comprising Form I characterized by an X-ray powder diffraction pattern including major peaks at 17.2±0.3°2θ, 21.8±0.3°2θ, and 24.4±0.3°2θ.

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