Composition comprising endoxifen with a defined amount of impurities, its use in therapy and its synthesis

Abstract

The present disclosure provides industrially scalable methods of making (Z)-endoxifen or a pharmaceutically acceptable salt thereof having improved safety and scalability compared to previous methods in terms of gas evolution, thermal stability, reaction calorimetry, and solvent safety. The methods and uses disclosed herein are for, but not limited to, treating tamoxifen-refractory hormone-dependent breast disorder, tamoxifen-refractory hormone-dependent reproductive tract disorder, or a combination thereof. Additional methods and uses include, but not limited to, treating prostate cancer, gynecomastia, or a combination thereof. Additional methods and uses include, but not limited to, treating a cancer, a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, and any combinations thereof. Additional methods and uses include, but not limited to, a method of treating an PKCβ1-mediated disease or disorder, a method of inhibiting PKCβ1, a method of treating an ERα-mediated disease or disorder, and a method of inhibiting estrogen receptor alpha (ERα).

Description

COMPOSITION COMPRISING ENDOXIFEN WITH A DEFINED AMOUNT OF IMPURITIES, ITS USE IN THERAPY AND ITS SYNTHESIS

[0001] This application claims benefit of priority under 35 U. S. C. § 119(e) of U. S. Provisional Patent Application No. 63 / 746,088 filed on January 16, 2025. The disclosure of the prior application is considered part of and is herein incorporated by reference in the disclosure of this application in its entirety’.BACKGROUND OF THE DISCLOSURE

[0002] Breast cancer is by far the most common form of cancer in women, and it is the second leading cause of cancer death in humans. Despite advances in diagnosing and treating breast cancer, the prevalence of this disease has been steadily rising at a rate of about 1% per year since 1940. Today, the likelihood that a woman living in North America will develop breast cancer during her lifetime is one in eight. In addition to breast cancers, other breast disorders affecting a large number of women include benign but often precancerous lesions, such as ductal hyperplasia, lobular hyperplasia, atypical ductal hyperplasia, and atypical lobular hyperplasia.

[0003] While hydrochloride and citrate salts of (Z)-endoxifen are known in the art and currently under evaluation for metastatic cancer, there remains unmet medical need for new compositions and methods for the treatment and / or prevention of hormone-dependent breast and reproductive tract (gynecologic) disorders. In addition, there remains a need for safe and scalable methods of preparing (Z)-endoxifen free base to meet the therapeutic need for this important drug.BRIEF SUMMARY OF THE DISCLOSURE

[0004] In some aspects, the techniques described herein relate to a sustainable and scalable method of preparing a compound of Formula (IV):including: (a) subjecting a compound of Formula (III):KTS Docket No.: 116771-1539925-823WO1to a first crystallization in an environmentally optimal amount of ethyl acetate to form a first solid and a first mother liquor; (b) concentrating the first mother liquor to form a first concentrated mother liquor; (c) subjecting the concentrated mother liquor to a second crystallization in an environmentally optimal amount of isopropyl alcohol and acetone to form a second solid and a second mother liquor; and (d) collecting the second solid, wherein the second solid includes the compound of Formula (IV).

[0005] In some aspects, the techniques described herein relate to a method, wherein the first crystallization includes heating the compound of Formula (III) in the environmentally optimal amount of ethyl acetate to a temperature of about 45 °C to about 55 °C.

[0006] In some aspects, the techniques described herein relate to a method, wherein the first crystallization further includes cooling the compound of Formula (III) in the environmentally optimal amount of ethyl acetate to a temperature of about -5 °C to about 5 °C.

[0007] In some aspects, the techniques described herein relate to a method, further including filtering the first mother liquor.

[0008] In some aspects, the techniques described herein relate to a method, further including concentrating the first mother liquor.

[0009] In some aspects, the techniques described herein relate to a method, wherein the second crystallization includes heating the concentrated mother liquor in the environmentally optimal amount of isopropyl alcohol and acetone to a temperature of about 45 °C to about 55 °C.

[0010] In some aspects, the techniques described herein relate to a method, wherein the second crystallization further includes cooling the concentrated mother liquor in the environmentally optimal amount of isopropyl alcohol and acetone to a temperature of about -5 °C to about 5 °C.

[0011] In some aspects, the techniques described herein relate to a method, wherein collecting the second solid includes filtering the second solid from the second mother liquor.

[0012] In some aspects, the techniques described herein relate to a method, wherein collecting the second solid includes drying the second solid at a temperature of not more than 80 °C.KTS Docket No.: 116771-1539925-823WO1

[0013] In some aspects, the techniques described herein relate to a method, further including suspending the compound of Formula (III) in an environmentally optimal amount of aqueous hydrochloric acid at a temperature of about 55 °C to about 70 °C prior to the first crystallization.

[0014] In some aspects, the techniques described herein relate to a method, further including suspending the compound of Formula (III) in an environmentally optimal amount of aqueous sodium hydroxide prior to the first crystallization.

[0015] In some aspects, the techniques described herein relate to a method, further including a preparative step including: (i) suspending the compound of Formula (III) in an environmentally optimal amount of aqueous hydrochloric acid and heating to a temperature of about 55 °C to about 70 °C; (ii) cooling the compound of Formula (III) in an environmentally optimal amount of aqueous hydrochloric acid to a temperature of about 0 °C to about 10 °C; (iii) adding an environmentally optimal amount of aqueous sodium hydroxide to the compound of Formula (III); (iv) adding an environmentally optimal amount of ethyl acetate to the compound of Formula (III); (v) adding aqueous sodium chloride to the compound of Formula (III) to yield an organic layer including the compound of Formula (III) and an aqueous layer; (vi) concentrating the organic layer to yield a concentrated organic layer; and (vii) adding an environmentally optimal amount of ethyl acetate to the concentrated organic layer; wherein steps (i) through (vii) are performed prior to the first crystallization.

[0016] In some aspects, the techniques described herein relate to a method, including: (a) subjecting the compound of Formula (III) to a first crystallization in an environmentally optimal amount of ethyl acetate to form a first solid and a first mother liquor, wherein the first crystallization includes heating the compound of Formula (III) in the environmentally optimal amount of ethyl acetate to a temperature of about 45 °C to about 55 °C followed by cooling the compound of Formula (III) in the environmentally optimal amount of ethyl acetate to a temperature of about -5 °C to about 5 °C; (b) filtering the first mother liquor and concentrating the first mother liquor to form a concentrated mother liquor; (c) subjecting the concentrated mother liquor to a second crystallization in an environmentally optimal amount of isopropyl alcohol and acetone to form a second solid and a second mother liquor, wherein the second crystallization includes cooling the concentrated mother liquor in the environmentally optimal amount of isopropyl alcohol and acetone to a temperature of about -5 °C to about 5 °C; and (d) collecting the second solid, wherein collecting the second solid includes filtering the second solid from the second mother liquor and drying the second solid at a temperature of not more than 80 °C. wherein the second solid includes the compound of Formula (IV).3KTS Docket No.: 116771-1539925-823WO1

[0017] In some aspects, the techniques described herein relate to a method, further including slurrying the compound of Formula (IV) in an environmentally optimal amount of ethyl acetate to yield Crystalline Form I of the compound of Formula (IV).

[0018] In some aspects, the techniques described herein relate to a method, wherein less than 25 ppm or less than 0.1 % of mesityl oxide is formed.

[0019] In some aspects, the techniques described herein relate to a method, wherein the compound of Formula (III) is prepared by subjecting a compound of Formula (II):(II);and propiophenone to a McMurry reaction, thereby preparing the compound of Formula (III); wherein the method does not result in an exothermic event having an enthalpy of greater than 540 J / g as measured by differential scanning calorimetry.

[0020] In some aspects, the techniques described herein relate to a method, wherein the McMurry reaction includes contacting the compound of Formula (II) and the propiophenone with zinc and titanium (IV) chloride.

[0021] In some aspects, the techniques described herein relate to a method, wherein the zinc, the titanium (IV) chloride, or a combination thereof are dissolved or suspended in an environmentally optimal amount of tetrahydrofuran.

[0022] In some aspects, the techniques described herein relate to a method, wherein the zinc is dissolved or suspended in an environmentally optimal amount of tetrahydrofuran at a temperature of about -5 °C to about 5 °C.

[0023] In some aspects, the techniques described herein relate to a method, wherein the titanium (IV) chloride is added to the zinc dissolved or suspended in an environmentally optimal amount of tetrahydrofuran.

[0024] In some aspects, the techniques described herein relate to a method, wherein the zinc and the titanium (IV) chloride are heated to a temperature of about 55 °C to about 75 °C.

[0025] In some aspects, the techniques described herein relate to a method, wherein the McMurry reaction includes heating a suspension including the compound of Formula (II), propiophenone, zinc, and titanium (IV) chloride to a temperature of not less than 60 °C.KTS Docket No.: 116771-1539925-823WO1

[0026] In some aspects, the techniques described herein relate to a method, further including performing one or more phase separations with an environmentally optimal amount of aqueous acid, aqueous base, or a combination thereof to form an organic layer.

[0027] In some aspects, the techniques described herein relate to a method, further including performing one or more phase separations in an environmentally optimal amount of aqueous hydrochloric acid and one or more phase separations in an environmentally optimal amount of aqueous sodium hydroxide.

[0028] In some aspects, the techniques described herein relate to a method, further including performing one or more phase separations with an environmentally optimal amount of aqueous acid, aqueous base, or a combination thereof to form an organic layer and washing the organic layer with an environmentally optimal amount of aqueous sodium hydroxide, aqueous sodium chloride, or a combination thereof.

[0029] In some aspects, the techniques described herein relate to a method, wherein the McMurry reaction includes: (a) dissolving or suspending zinc in an environmentally optimal amount of tetrahydrofuran at a temperature of about -5 °C to about 5 °C; (b) adding titanium (IV) chloride to the zinc; (c) heating the zinc and titanium (IV) chloride to a temperature of about 55 °C to about 75 °C; (d) adding the compound of Formula (II) and propiophenone to the zinc and titanium (IV) chloride to form a suspension; (e) heating the suspension to a temperature of not less than 60 °C; (f) distilling the suspension and adding an environmentally optimal amount of methyl tetrahydrofuran; (g) cooling the suspension to a temperature of about 5 °C to about 15 °C; (h) performing one or more phase separations with an environmentally optimal amount of aqueous acid, aqueous base, or a combination thereof to form an organic layer; (i) washing the organic layer with an environmentally optimal amount of aqueous sodium hydroxide, aqueous sodium chloride, or a combination thereof; (j) concentrating the organic layer to form a concentrated organic layer; (k) adding an environmentally optimal amount of acetonitrile, acetone, or a combination thereof to the concentrated organic layer; and (1) filtering the concentrated organic layer to yield a solid including the compound of Formula (III)..

[0030] In some aspects, the techniques described herein relate to a method, wherein the compound of Formula (II) is prepared by subjecting a compound of Formula (I):O5KTS Docket No.: 116771-1539925-823WO1to a demethylation reaction, thereby producing the compound of Formula (II); wherein the demethylation reaction is performed inside a suitable reactor to normalize heat flow.

[0031] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction includes suspending the compound of Formula (I) in an environmentally optimal amount of anhydrous tetrahydrofuran.

[0032] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction includes contacting the compound of Formula (I) with diisopropylethylamine.

[0033] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction includes contacting the compound of Formula (I) with 1 -chloroethyl chloroformate.

[0034] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction includes heating the compound of Formula (I) and diisopropylethylamine to a temperature of about 60 °C to about 70 °C.

[0035] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction includes heating the compound of Formula (I), 1 -chloroethyl chloroformate, and diisopropylethylamine to a temperature of about 60 °C to about 70 °C.

[0036] In some aspects, the techniques described herein relate to a method, including: (a) suspending the compound of Formula (I) in an environmentally optimal amount of anhydrous tetrahydrofuran; (b) adding diisopropylethylamine to the compound of Formula (I) in the environmentally optimal amount of anhydrous tetrahydrofuran and heating to a temperature of 60 °C; (c) adding 1-chloroethyl chloroformate to the compound of Formula (I) and the diisopropylethylamine; (d) adding an environmentally optimal amount of methanol to the compound of Formula (I), the 1-chloroethyl chloroformate, and the diisopropylethylamine over a time of not less than 2 hours at a temperature of about 60 °C to about 70 °C; (e) adding an environmentally optimal amount of aqueous hydrochloric acid over a time of not less than two hours, followed by adding an environmentally optimal amount of aqueous sodium hydroxide; (f) extracting with an environmentally optimal amount of ethyl acetate to form an organic layer and an aqueous layer; (g) slurrying the aqueous layer with an environmentally optimal amount of water, isopropyl alcohol, or a combination thereof; (h) washing the aqueous layer with an environmentally optimal amount of ethyl acetate to form a solid including the compound of Formula (II); and (i) drying the solid including the compound of Formula (II) at a temperature of not more than 60 °C.6KTS Docket No.: 116771-1539925-823WO1

[0037] In some aspects, the techniques described herein relate to a method, wherein the demethylation reaction results in a normalized heat flow of not more than about 100 W / kg.

[0038] In some aspects, the techniques described herein relate to a compound 1-34.

[0039] In some aspects, the techniques described herein relate to a compound, including less than 25 ppm or less than 0.10% of mesityl oxide.

[0040] In some aspects, the techniques described herein relate to a compound, having an aerobic bacterial plate count of not more than about 20,000 cfu / g.

[0041] In some aspects, the techniques described herein relate to a compound, having a water content of not more than 1.0% as tested by Method Ic of USP 921.

[0042] In some aspects, the techniques described herein relate to a compound, having a water activity (Aw) of less than 0.9.

[0043] In some aspects, the techniques described herein relate to a compound, having a residue on ignition of not more than 0.1% as tested by a method of USP 281.

[0044] In some aspects, the techniques described herein relate to a compound, including not more than 20 ppm of heavy metals as tested by Method II of USP 231.

[0045] In some aspects, the techniques described herein relate to a compound, including not more than 130 ppm zinc.

[0046] In some aspects, the techniques described herein relate to a compound, including not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, not more than 5000 ppm ethanol, not more than 5000 ppm acetone, not more than 401 ppm acetonitrile, not more than 520 ppm methyltetrahydrofuran, not more than 3 ppm benzene, or any combination thereof, as measured by gas chromatography.

[0047] In some aspects, the techniques described herein relate to a compound, including not more than 0.10% of an impurity having m / z of 402.

[0048] In some aspects, the techniques described herein relate to a compound, including not more than 0.15% of an impurity having m / z of 416.

[0049] In some aspects, the techniques described herein relate to a compound, including not more than 3% of (E)-endoxifen.

[0050] In some aspects, the techniques described herein relate to a compound 16-34.

[0051] In some aspects, the techniques described herein relate to a compound, including less than about 0.6% of an impurity having m / z of 511.

[0052] In some aspects, the techniques described herein relate to a compound 27-34.7KTS Docket No.: 116771-1539925-823WO1

[0053] In some aspects, the techniques described herein relate to a compound, including less than about 1.0% of an impurity having m / z of 569.

[0054] In some aspects, the techniques described herein relate to a compound, including less than about 0.5% of an impurity having m / z of 300.

[0055] In some aspects, the techniques described herein relate to a compound, including less than about 0.4% of an impurity having m / z of 512.

[0056] In some aspects, the techniques described herein relate to a compound, including less than about 1% of an impurity having m / z of 330.INCORPORATION BY REFERENCE

[0057] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also ■‘Figure” and “FIG.” herein), of which:

[0059] FIG. 1A is an X-ray powder diffraction (XRPD) pattern of Crystalline Form I of (Z)-endoxifen, according to an embodiment of the present disclosure;

[0060] FIG. IB is an XRPD pattern of Crystalline Form I of (Z)-endoxifen after 0, 7, and 42 days of storage, according to embodiments of the present disclosure;

[0061] FIG. 1C is a DSC profile of Cry stal line Form I of (Z)-endoxifen, according to an embodiment of the present disclosure;

[0062] FIG. ID shows a TGA profile of Crystalline Form I of (Z)-endoxifen in the top panel, a heat flow profile of Crystalline Form I of (Z)-endoxifen in the middle panel, and a first derivative of the TGA profile of Crystalline Form I of (Z)-endoxifen in bottom panel, according to embodiments of the present disclosure;

[0063] FIG. 2 shows the reaction calorimetry trends of Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0064] FIG. 3 shows the normalized heat flow of Step 1 of making (Z)-endoxifen according to a method of the present disclosure;8KTS Docket No.: 116771-1539925-823WO1

[0065] FIG.4 shows the release profile of methyl chloride, according to an embodiment of the present disclosure;

[0066] FIG. 5 shows the gas flow rate of ACE-CL, carbamate, and carbonate methanolysis as measured using a Ritter volumetric flow meter, according to an embodiment of the present disclosure;

[0067] FIG. 6 shows the gas flow rate as a function of distillation temperature of Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0068] FIG. 7 is a DSC profile of unreacted ACE-CI during Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0069] FIG. 8 is a DSC profile showing the decomposition of unreacted ACE-CI during Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0070] FIG. 9 is a DSC profile of the second distillation showing the decomposition of unreacted ACE-CI during Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0071] FIG. 10 is a DSC of the wet reaction product of Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0072] FIG. 11 is a dynamic DSC of the third distillation during Step 1 of making (Z)-endoxifen according to a method of the present disclosure;

[0073] FIG. 12 shows the self-healing rate (SHR) profile of THF / Methyl THF Residue and Solvent Switch, according to an embodiment of the present disclosure;

[0074] FIG. 13 is a Pareto chart, which tabulates the statistical test T (the ratio between the coefficient of the linear model and the standard error of the coefficient) and confirms that the parameters evaluated for Step 1 are well below a p-value of 0.05, according to an embodiment of the present disclosure;

[0075] FIG. 14 is a Pareto chart showing that increasing the reaction time prior may reduce the formation of an impurity having m / z of 330, according to an embodiment of the present disclosure;

[0076] FIG. 15 is a Pareto chart regarding the formation of the compound of formula (II), according to embodiments of the present disclosure;

[0077] FIG. 16 is a Pareto chart regarding the formation of the compound of formula (III), according to embodiments of the present disclosure;9KTS Docket No.: 116771-1539925-823WO1

[0078] FIG. 17 is a Pareto chart regarding the amount of zinc and the time of ketone mixture addition in relation to the formation of the compound of formula (III), according to an embodiment of the present disclosure;

[0079] FIG. 18 is a Pareto chart regarding the amount of tin chloride in relation to the formation of an impurity having m / z of 511, according to an embodiment of the present disclosure;

[0080] FIG. 19 is a contour plot showing the relationship between temperature and time in the isomerization of (E)-endoxifen to (Z)-endoxifen, according to an embodiment of the present disclosure;

[0081] FIG. 20 is a contour plot showing the proven acceptable range (PAR) for temperature and time in the formation of (Z)-endoxifen, according to an embodiment of the present disclosure;

[0082] FIG. 21 shows a contour plot showing the normal operating range (NOR) for temperature and time in the formation of (Z)-endoxifen, according to an embodiment of the present disclosure;

[0083] FIG. 22 shows aXRPD pattern of crystalline Form II as measured by Cu Ka radiation; and

[0084] FIG. 23 displays shows a XRPD pattern of crystalline Form V as measured by Cu Ka radiation.DETAILED DESCRIPTION OF THE DISCLOSURE

[0085] This present disclosure relates compositions comprising (Z)-endoxifen, pharmaceutical compositions comprising (Z)-endoxifen, their preparation as well as their use in the treatment of a cancer, a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, and any combinations thereof. Their use in the treatment of a mood disorder, a mental disorder, or a combination thereof are also disclosed. The compositions and the pharmaceutical composition have improved impurity profiles, containing less endoxifen-related impurities.

[0086] Breast cancer is by far the most common form of cancer in women, and it is the second leading cause of cancer death in humans. Selective estrogen receptor modulators, such as Tamoxifen, are used for the treatment of women with endocrine responsive breast cancer, e.g., hormone dependent or hormone-sensitive breast cancer. Endoxifen is a potent selective estrogen receptor modulator (SERM). Endoxifen (a mixture of (Z)-endoxifen and (E)-endoxifen) and its therapeutically effective isomer. (Z)-endoxifen. have limited solubility in aqueous media and their solubility is strongly pH dependent with increased solubility in acidic 10KTS Docket No.: 116771-1539925-823WO1conditions and decreased solubility in basic conditions. Unfortunately, in acidic conditions (Z)-endoxifen isomerizes to generate the (E)-isomer that is not therapeutically effective so releasing (Z)-endoxifen in the stomach is undesirable as the gastric pH is about 1 to about 2. However, releasing (Z)-endoxifen in the intestines where the pH is about 5 to about 7 decreases the bioavailability of (Z)-endoxifen, but prevents the isomerization of (Z)-endoxifen.

[0087] While not intending to be bound by any particular theory, (Z)-endoxifen binds estrogen receptor alpha (ERa) with high affinity, inhibits estrogen-induced transcription, and promotes receptor degradation, effectively reducing estrogen-driven proliferation. These effects translate into potent anti-proliferative activity in cancer cell lines, such as ER+ breast cancer cell lines. The anti-tumor activity of (Z)-endoxifen extends to in vivo animal models. Beyond ERa antagonism, (Z)-endoxifen also targets alternative oncogenic pathways. Notably, it inhibits the β1 variant of protein kinase C (PKCβ1), a kinase implicated in breast cancer cell survival and proliferation (Ali, S. M., et al. (2010). Endoxifen is a new potent inhibitor ofPKC: a potential therapeutic agent for bipolar disorder. Bioorganic & Medicinal Chemistry Letters, 20(8), 2665-2667. DOI: 10.1016 / j.bmcl.2010.02.024). Moreover, while notintending to be bound by any particular theory, it is thought that binding of endoxifen to PKCβ1 destabilizes the protein, promoting its degradation. Loss of PKCβ1 leads to marked reductions in ER protein expression, depletion of key cell cycle regulators such as cyclin DI and E2F1, and further suppression of tumor growth. It has been reported that, PKC i was identified as a target for (Z)-endoxifen with IC₅₀ value of 360 nM, compared with nearly 5 μM for tamoxifen (Jayaraman et al., 2023). No other kinases were identified as endoxifen targets. Notably, (Z)-endoxifen did not interact with PKCβ2, the other isoform encoded by the PRKCB gene (Jayaraman, A., et al. (2023). Endoxifen downregulates AKT phosphorylation through protein kinase C beta 1 inhibition in ERa+ breast cancer. NPJ Breast Cancer, 9(1), 101. DOI: 10.1038 / s4523-023-00606-2). Therefore, no significant off-target pharmacology would be anticipated.

[0088] The present disclosure sets forth numerous exemplary' configurations, methods, parameters, and the like. It should be recognized, however, that such disclosure is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary' embodiments.

[0089] Throughout the text and the follow description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details.11KTS Docket No.: 116771-1539925-823WO1Definitions

[0090] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0091] As used herein and in the claims, the terms "‘comprising," “containing," “having,” and “including" are inclusive, open-ended and do not exclude additional unrecited elements, compositional components or method steps. Accordingly, the terms “comprising" and “including” encompass the more restrictive terms “consisting of’ and “consisting essentially of.

[0092] As used herein and unless otherwise specified, the term “consisting essentially of’ when used herein in connection with a compound, composition, use, or method, denotes that additional elements, method steps or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method, or use functions.

[0093] As used herein and unless otherwise specified, the term “consisting of’ when used herein in connection with a compound, composition, use, or method, excludes the presence of additional elements and / or method steps.

[0094] As used herein and in the appended claims, the singular forms “a," “an," and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent" includes a plurality of such agents, and reference to “the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof know n to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0095] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary up to 10% of the stated number or numerical range. For example, an XRPD peak (e.g., about 5.00° 2-Theta, about 10.00° 2-Theta, about 15.00° 2-Theta) can vary within a range of ±0.1 °2-Theta, ±0.2° 2-Theta, ±0.3 °2-Theta, ±0.4° 2-Theta, or ±0.5° 2-Theta. In some embodiments of XRPD peaks, about means ± 0.5 ° 2-Theta. For example, a temperature (e.g., about 80.0 °C, about 100.0 °C, about 120.0 °C) associated with a feature in a TGA pattern 12KTS Docket No.: 116771-1539925-823WO1or a DSC thermogram can vary within a range of ±1.0 °C, ±2.0 °C, ±3.0 °C, ±4.0 °C, or ±5.0 °C.

[0096] Whenever the term ‘'about,” “at least,” “greater than,” or '‘greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “about,” “at least,” “greater than,"’ or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, “greater than or equal to 1, 2, or 3" is equivalent to “greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3”.

[0097] Whenever the term “no more than,” “at most,” '‘less than,” or '‘less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than." “at most,” “less than." or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, “less than or equal to 3, 2, or 1” is equivalent to “less than or equal to 3, less than or equal to 2, or less than or equal to 1”.

[0098] As used herein, the terms “weight percent,” “wt%,” and “percent by weight” are used interchangeably to refer to the concentration of a substance as the weight of that substance divided by the total weight of the composition or of the mixture and multiplied by 100.

[0099] The term “substantially as shown in” or “substantially the same” when referring, for example, to an XRPD pattern, DSC thermogram, or TGA thermogram, resembles the reference spectrum to a great degree in both the peak locations and peak intensity but is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-Theta (20) values. Accordingly, when a specified 2-Theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5° 2-Theta, such as ± 0.4° 2-Theta, ± 0.3° 2-Theta, ± 0.2° 2-Theta, or ± 0.1° 2-Theta. As used herein, “major peak” can refer to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Alternatively, or in addition thereto, “major peak” can refer to an XRPD peak which is among the ten most intense XRPD peaks w ithin an XRPD pattern. Relative intensity is calculated as a ratio of the peak intensity of the peak of interest versus the peak intensity of the largest peak in the XRPD pattern.

[0100] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3. 4, 5, 6. 7, 8, 9. 10. 11. 12, 13, 14,13KTS Docket No.: 116771-1539925-823WO115, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, ‘’nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. For example, if a concentration range or beneficial range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% etc., are expressly enumerated in this specification. It is also to be understood that if a concentration or dose is stated as a specific value such as 1 mg or 10 mg, it is intended that to include 10% variation. As another example, a stated concentration of 20% is intended to include values ± 10%. Y et another example, if a ratio of 1: 10 to 10: 1 is stated, then it is intended that ratios such as 1:9 to 9:1, from 1:8 to 8:1, from 1:7 to 7:1, from 1:6 to 6:1, from 1:5 to 5:1, from 1:4 to 4:1, from 1:3 to 3:1, from 1:2 to 2:1, from 1:1 to 2:1 or from 2:5 to 3:5 etc. are specifically intended.

[0101] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may' not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0102] The term “modulate,” “modulating,” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the G protein-coupled receptor.

[0103] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0104] The term “agonist” as used herein refers to a modulator that binds to a receptor or target enzy me and activates the receptor or enzyme to produce a biological response. By way of example, “GPR40 agonist” can be used to refer to a compound that exhibits an EC 50 with respect to GPR40 activity of no more than about 100 pM, as measured in the as measured in the inositol phosphate accumulation assay. In some embodiments, the term “agonist” includes full agonists or partial agonists.

[0105] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an agonist can elicit at the receptor or enzyme.14KTS Docket No.: 116771-1539925-823WO1

[0106] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.

[0107] The terms “inhibit,” “block,” “suppress,” and grammatical variants thereof are used interchangeably herein and refer to any statistically significant decrease in biological activity', including full blocking of the activity. In some embodiments, “inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% in biological activity. Accordingly, when the terms “inhibition” or “suppression” are applied to describe, e.g., an effect on the enzymatic activity of a target, the term refers to the ability of a compound disclosed herein to statistically significantly decrease the activity of the target.

[0108] The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0109] As used herein, the term “tamoxifen refractory ” refers to a subject that has been dosed daily with tamoxifen for at least 2 days and has a level of plasma endoxifen of less than 30 nM (e g., less than 20 nM, less than 25 nM, or less than 30 nM). As used herein, the term “tamoxifen resistance” refers to two classes of resistance: (a) de novo resistance, i.e., non-responsiveness to tamoxifen therapy from the beginning of the treatment, or (b) acquired resistance, i.e.. non-responsiveness to tamoxifen therapy after initial responsiveness or tamoxifen-dependent growth / stimulated growth while continuing to express estrogen receptors (Minsun Chang. Biomol. Ther. 20(3), 256-267 (2012)). The acquired resistance to tamoxifen may develop as early as 3 m to 1 year to as late as 5 to 10 years. As used herein, the term “reference plasma endoxifen level” refers to a value of 30 nM.

[0110] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.[OHl] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity', irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments, the phrase “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not 15KTS Docket No.: 116771-1539925-823WO1abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0112] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0113] In some embodiments, the composition described herein is a “pharmaceutical composition”. A pharmaceutical composition comprises at least one active agent (e.g., at least one active pharmaceutical compound or ingredient, API or salt thereof) with an excipient. Excipients include carriers, inerts or actives (e.g., a phospholipid), making the compositions suitable for at least diagnostic or therapeutic uses in vitro, in vivo, or ex vivo.

[0114] The term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art, such as organic and inorganic counter ions derived from inorganic or organic acids and bases. The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation that is physiologically tolerated in a subject (e.g., a mammal, and / or in vivo, ex vivo, in vitro cells, tissues, or organs). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic 16KTS Docket No.: 116771-1539925-823WO1acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. Typically, pharmaceutical salts are more soluble and more rapidly soluble in stomach and intestinal juices than non-iomc species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this cap ability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0115] For the purposes of this application, the salts of the compounds of the present disclosure are pharmaceutically acceptable for therapeutic uses. However, salts of acids and bases that are non-pharmaceutically acceptable are also useful; for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0116] Examples of anion salts of endoxifen include arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / di phosphate, poly gal acuronate, salicylate, stearate, sulfate, tannate, Teoclate, and triethiodide. Examples of cation salts of (Z)-endoxifen selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium,17KTS Docket No.: 116771-1539925-823WO1magnesium, potassium, and zinc, and the like. In some embodiments, the present disclosure provides that embodiments include salts made with acids that are not pharmaceutically acceptable.

[0117] The term “solvate,” as used herein, means a molecular complex between compounds of the disclosed herein and solvent molecules. Examples of solvates include, but are not limited to, compounds disclosed herein in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term “hydrate” can be used when said solvent is water. In some embodiments, one solvent molecule can be associated with one molecule of the compounds disclosed herein, such as a hydrate. In some embodiments, more than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a dihydrate. In some embodiments, less than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a hemihydrate. In some embodiments, solvates of compounds of disclosed herein retain the biological effectiveness of the non-hydrate form of the compounds (referred to as pharmaceutically acceptable solvates).

[0118] The term “prevent” or “preventing”, as used herein, as related to a disease or disorder may refer to a compound or a pharmaceutically acceptable salt thereof that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. In some embodiments, the terms “prevent,” “preventing,” or “prevention” are used interchangeably refer to prevention of a particular disorder or the occurrence or onset of one or more symptoms associated with the particular disease or disorder and does not necessarily mean the complete prevention of the disease or disorder. For example, the term “prevent,” “preventing,” and “prevention” means the administration of therapy on a prophylactic or preventative basis to a subject in need thereof who may ultimately manifest at least one symptom of a disease or disorder but who has not yet done so. Such a subject in need thereof can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.

[0119] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human 18KTS Docket No.: 116771-1539925-823WO1primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. In one aspect, the subject is a human. In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject displays one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a mammal with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, the human is an infant, a child, an adult, or a senior citizen (i.e.. the subject is of advanced age, such as older than 50). In some embodiments, a child refers to a human that is between 0 and 2 years of age. In some embodiments, a child refers to a human that is between 2 and 18 years of age. In some embodiments, an adult refers to a human that is from 18 to 50 years of age.

[0120] As used herein, the phrase "a subject in need thereof’ and “in need of treatment” are used interchangeably to refer to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof described herein. In some embodiments, the phrase “a subject in need thereof’ and “in need of treatment” are used interchangeably when referring to treatment refer to a judgment made by a caregiver (e g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety’ of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit, or ameliorate the disease, condition or disorder.

[0121] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary’ depending upon the intended application (in vitro or in vivo), or the subject 19KTS Docket No.: 116771-1539925-823WO1and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. The term an “effective amount” or “therapeutically effective” amount can also refer to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect benefit and / or a prophylactic benefit. The term an “effective amount” or “therapeutically effective” amount can also refer any amount which results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0122] The terms “treat,” "treating,” or “treatment,” as used herein, may include alleviating, preventing, abating, or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, preventing the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. In some embodiments, the terms “treat,” “treating,” or “treatment,” may refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include the eradication, prevention, or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing,20KTS Docket No.: 116771-1539925-823WO1delaying, preventing, or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment, prevention, or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0123] A "therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes preventing, delaying, or eliminating the appearance of a disease or condition, preventing, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, preventing, or reversing the progression of a disease or condition, or any combination thereof.

[0124] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0125] As used herein, the terms “active pharmaceutical ingredient” (API), “active ingredient,” “drug,” and “therapeutic agent” are used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition and are intended for use in diagnosis, cure, mitigation, treatment, and / or prevention of disease in a human or another mammal. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. The therapeutic agent as used herein includes the active compounds and their salts, isomers, polymorphs, prodrugs, and metabolites.

[0126] As used herein, the terms “dose form” or “dosage form” refers to physically discrete unit suitable for unitary’ dosages for a subj ect, each unit containing a predetermined quantity’ of active material calculated to produce the desired therapeutic effect. In some embodiments, the dosage form comprises one or more suitable pharmaceutical excipients. Pharmaceutical compositions may be prepared in a variety’ of dosage forms suitable for a variety of routes and methods of administration. By way of example only, a pharmaceutical composition may be prepared in a liquid dosage form selected from emulsions, microemulsions, nanoemulsions,21KTS Docket No.: 116771-1539925-823WO1solutions, suspensions, syrups, and elixirs; an injectable dosage form; a solid dosage form selected from capsules, tablets, pills, powders, and granules; and a dosage form for topical and / or transdermal administration selected from ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches.

[0127] As used herein, the terms “unit dose'’ or “unit dosage” refers to is discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient calculated to produce the desired therapeutic effect. In some embodiments, the unit dose comprises one or more suitable pharmaceutically acceptable excipients. A unit dose a single dose that is capable of being administered to a subject and which can be readily handled and packaged. A “unit dose” is a dose of any therapeutic or active agent administered in one dose / at one time / single route / single point of contact, i.e., one administration event. As used herein, “split dose” refers to (1) dosing regimens in which one or more active agents are administered to a patient at least twice daily; (2) once daily administration of a pharmaceutical composition containing one or more active agent in which a portion of the active agent is formulated for immediate release and a portion of the active agent is formulated for delayed or pulsatile release; and (3) once daily administration of a pharmaceutical composition containing an active agent formulated for controlled or sustained release.

[0128] As used herein "primary therapy” refers to a first line of treatment upon initial diagnosis of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both in a subject. Exemplary primary therapies may involve surgery, a wide range of chemotherapies, and radiotherapy.

[0129] As used herein, the terms “preventive treatment” and “preventive therapy” refer to a treatment or therapy that is administered to a healthy subj ect in need thereof who is at increased risk of a disease or disorder and to decrease the risk of being diagnosed with the disease or disorder is administered the preventive treatment or preventive therapy. For example, to decrease the risk of being diagnosed with breast cancer a healthy subject in need thereof that has an increased risk of breast cancer is administered the preventive treatment or treatment therapy.

[0130] As used herein, the term “adjuvant therapy” refers to a therapy that is administered to a subject in need thereof, that has undergone a primary therapy for a disease or disorder and is at increased risk of relapse or recurrence of the disease or disorder. The goal of an adjuvant therapy is to decrease the risk of the subject experiencing a relapse or recurrence of the disease or disorder. For example, to decrease the risk of relapse in breast cancer, a subject in need thereof 22KTS Docket No.: 116771-1539925-823WO1that has undergone a primary therapy for breast cancer and is at increased risk of relapse is administered an adjuvant therapy.

[0131] As used herein, the term “neo-adjuvant therapy” refers to a therapy that is administered to a subject in need thereof that has an increased risk of one or more adverse outcomes of a disease or disorder (i.e., progression of the disease or disorder) prior to a primary therapy for the disease or disorder. The purpose of the neo-adjuvant therapy is to decrease a burden of the disease or disorder, thereby improving the effectiveness of the primary therapy. For example, to decrease tumor burden in breast cancer, a subject in need thereof that has an increased risk of one or more adverse outcomes is administered the neo-adjuvant therapy prior to surgery for breast cancer.

[0132] As used herein, "‘breast cancer” refers to any malignant tumor of breast cells. Breast cancer may be at any stage of breast cancer, including stages of a pre-cancer, an early-stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, and a metastatic cancer. Breast cancer can be invasive breast cancer or in situ breast cancer. There are several types of breast cancer. Exemplary’ breast cancers include, but are not limited to, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), invasive (or infiltrating) lobular carcinoma (ILC), invasive (or infiltrating) ductal carcinoma (IDC), microinvasive breast carcinoma (MIC), inflammatory’ breast cancer, ER-positive (ER+) breast cancer, ERnegative (ER-) breast cancer, HER2+ breast cancer, triple negative breast cancer (TNBC), adenoid cystic (adenocystic) carcinoma, low-grade adenosquamatous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary’ carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. A single breast cancer tumor can be a combination of these types or be a mixture of invasive and in situ cancer.

[0133] As used herein, the terms “hormone-dependent breast disorder.” “hormone-dependent reproductive tract disorder,” “hormone-dependent breast and reproductive tract disorder” each and collectively include, without limitation, any’ breast or reproductive tract (gynecologic) disorder that is related to or is sensitive to high estrogen or normal estrogen levels that need to be reduced, disorders with estrogen-receptor positive (ER+) and / or progesterone-receptor positive (PR+) disorders, for example, breast disorders, endometriosis, uterine fibroids (also called leiomyomas) etc. Reproductive tract disorders include endometrial, ovarian, cervical, uterus, vaginal, and vulvar cancers. The terms “estrogen-related disorder” and “estrogen-receptor related disorder” may be used interchangeably to refer to the foregoing hormone dependent disorders. The disorders may be presented primarily or secondarily to an underlying 23KTS Docket No.: 116771-1539925-823WO1disease, for example, prostate cancer or other disorders such as liver diseases. Hormonedependent breast and reproductive tract disorder include, for example, McCune- Albright syndrome, which is a disorder caused by a mutation in the GNAS gene affecting bones, skin, and several hormone-producing (endocrine) tissues, often resulting in abnormal scar-like (fibrous) tissue in their bones, a condition called polyostotic fibrous dysplasia, hyperthyroidism in individuals carrying such mutations, and in girls often resulting in precocious puberty.

[0134] As used herein, "breast disorder” means any aberration or a constellation of aberrations in the breast. Such aberration may be proliferative, non-proliferative, benign or malignant. Breast disorders include benign lesions of the breast (e.g., hyperplasia), increased breast density, gynecomastia, mastalgia, and breast cancer. Benign breast lesions include, but are not limited to. hyperplasia, atypia, ductal hyperplasia, lobular hyperplasia, atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH). While not cancerous, ADH and ALH may be indicative of a predisposition for breast cancer.

[0135] As used herein, the term “combination therapy” refers to the use of a composition described herein in combination with one or more additional treatment. Treatment in combination therapy can be any treatment such as any prophylactic agent, therapeutic agent (such as chemotherapy), radiotherapy, surgery and the like. The combination can refer to inclusion of a therapeutic or prophylactic agent in a same composition as a composition disclosed herein (for example, in the same capsule, tablet, ointment, etc.) or in separate compositions (for example, in 2 separate capsules). The separate compositions may be in a different dosage form. The use of the terms “combination therapy” and “in combination with” does not restrict the order in which a composition described herein and prophylactic and / or therapeutic agent and / or treatment are administered to a subject in need thereof. Compositions of the present disclosure can be administered prior to (e.g., 1 minute (min), 5 min, 15 min, 30 min, 45 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 1 week (wk), 2 wk, 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or 1 year before), concomitant with, or subsequent to (e.g., 1 minute (min), 5 min, 15 min, 30 min, 45 min, 1 hour (h), 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h. 72 h, 96 h, 1 week (wk), 2 wk. 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or 1 year after) administration of one or more prophylactic and / or therapeutic agent and / or treatment to a subject in thereof. Combination therapy as used herein can also refer to treatment of a subject having a single disease or multiple diseases, for example, prostate cancer in men and gynecomastia.24KTS Docket No.: 116771-1539925-823WO1

[0136] As used herein, the term “pharmaceutically acceptable carrier” or “carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting one or more of the compounds of the present disclosure from one tissue, organ, or portion of the body or across the skin.

[0137] As used herein, the term “tamoxifen” refers to 2-[4-(1.2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethanamine, which has two isomeric forms: (Z)-tamoxifen ((Z)-2-[4-(l,2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethanamine) and (E)-tamoxifen ((E)-2-[4-(l,2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethanamine). Unless otherwise specified, “tamoxifen” refers to a mixture of (E)-tamoxifen and (Z)-tamoxifen. Furthermore, unless otherwise specified, "tamoxifen" refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “tamoxifen” and “tamoxifen free base” are equivalent terms.

[0138] As used herein, the terms “4-hydroxy tamoxifen”, “afimoxifene”, and “4-OHT” used interchangeably refer to 4-l-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-l-enyl]phenol, and constitutes an active metabolite of tamoxifen. 4-OHT has two isomeric forms: (Z)-4-OHT and (E)-4-OHT. Unless specified, “4-OHT” refers to a mixture of (E)-4-OHT and (Z)-4-OHT. Furthermore, unless otherwise specified, “4-OHT” refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “4-OHT” and “4-OHT free base” are equivalent terms.

[0139] As used herein, the term “endoxifen” refers to 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol) (also known as 4-hydroxy-N-desmethyl-tamoxifen or desmethylhydroxy tamoxifen). Endoxifen has two isomeric forms: (E)-endoxifen ( (E)-4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol ) and (Z)-endoxifen ( (Z)-4-(l -(4-(2-(methy lamino)ethoxy )phenyl)-2-pheny Ibut- 1 -en- 1 -yl)phenol). Unless otherwise specified, “endoxifen”, also referred to as “(Z / E)-endoxifen”. is a mixture of (Z)-endoxifen and (E)-endoxifen with a Z: E ratio of 1: 1. By way of example only:“(95:5) endoxifen”, “endoxifen (95:5)”, “endoxifen (Z: E = 95:5)”, “(Z: E = 95:5)”, “endoxifen (Z / E = 95:5)”, and “(Z / E = 95:5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio of 95:5;“(95>5) endoxifen”, “endoxifen (95>5)”, “endoxifen (Z: E = 95>5)”, “(Z: E = 95>5)”, “endoxifen (Z / E = 95>5)”, and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio greater than 95:5;25KTS Docket No.: 116771-1539925-823WO1“(95>5) endoxifen”, “endoxifen (95>5)”, "endoxifen (Z: E = 95>5)”, “(Z. E = 95>5)”, “endoxifen (Z / E = 95>5)". and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio greater than or equal to 95:5;“(95<5) endoxifen”, “endoxifen (95<5)”, “endoxifen (Z: E = 95<5)”, “(Z: E = 95<5)”, “endoxifen (Z< E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio less than 95:5; and“(95<5) endoxifen”, “endoxifen (95<5)”, “endoxifen (Z: E = 95<5)”, “(Z: E = 95<5)”, “endoxifen (Z< E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio less than or equal to 95:5.

[0140] As used herein, unless otherwise specified, “endoxifen” refers to the free base (i.e., not a salt) of endoxifen. Therefore, “endoxifen”. “endoxifen free base”, “(Z / E)-endoxifen”, and “(ZZE)-endoxifen free base” are all equivalent terms. By way of example only:HNrepresents (Z)-endoxifen ((Z)-endoxifen free base);HNrepresents (E)-endoxifen ((E)-endoxifen free base); andI (E / Z)H H N Nrepresent endoxifen ((Z / E)-endoxifen).

[0141] As used herein, the term “(Z)-endoxifen” is isomeric pure (100% of one alkene isomer)HN(Z)-endoxifen. (Z)-endoxifen is represented by the structureHOKTS Docket No.: 116771-1539925-823WO1

[0142] As used herein, the term "(E)-endoxifen" is isomeric pure (100% of one alkene isomer)(E)-endoxifen. (E)-endoxifen is represented by the structureHO

[0143] As used throughout the present disclosure, the wiggly line (n' ') attached to the tetrasubstituted alkene bond of endoxifen or thewritten adjacent to the tetrasubstituted alkene bond of endoxifen denotes a mixture of (E)-endoxifen and (Z)-endoxifen:(E)-endoxifen

[0144] Furthermore, salts of endoxifen, (Z)-endoxifen, and / or (E)-endoxifen are disclosed herein. By way of example only, below are representations of salts of (Z)-endoxifen:the following structures are equivalent representations of (Z)-endoxifen citrate (as referred toequivalent representations of (Z)-endoxifen hydrochloride (also referred to as (Z)-endoxifen27KTS Docket No.: 116771-1539925-823WO1.hci 0CIhydrochloride): HO XJ CL ° w and ^0 X? O ^ -J ©2.. In some embodiments, the salt is a pharmaceutically acceptable salt.

[0145] As used herein, unless otherwise specified, the term “endoxifen-related impurity” is an impurity that arises from the synthesis of endoxifen, specifically (Z)-endoxifen, as outlined in the present disclosure. By way of example only, an endoxifen-related impurity is selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and a pharmaceutically acceptable salt of any one thereof. In some embodiments, an endoxifen-related impurity is selected from an impurity having m / z 512, an impurity having m / z 716, and a pharmaceutically acceptable salt of any one thereof. In some embodiments, an endoxifen-related impurity is (E)-endoxifen. In some embodiments, an endoxifen-related impurity is mesityl oxide. In some embodiments, an endoxifen-related impurity is a starting material or a reagent from any one of the synthetic steps as outlined in the present disclosure. In some embodiments, an endoxifen-related impurity is a starting material or a reagent from any one of the synthetic steps of Improved Process 3 of the present disclosure.

[0146] As used herein, " In some embodiments,” and " In some cases,” are used interchangeably herein and mean that a particular feature, structure, characteristic, step, or element described in connection with the embodiment is included in at least one aspect of the present disclosure. Thus, the phrases An some embodiments” and “in some cases” in various places throughout this specification are not necessarily all referring to the same embodiment or the same aspect of the present disclosure, but they could be referring to the same embodiment or the same aspect of the present disclosure. Furthermore, the particular features, structures, characteristics, steps, or elements disclosed may be combined in any suitable manner or combination in one or more embodiments or aspects of the present disclosure. Such combinations of the features, structures, characteristics, steps, or elements are expressly and unambiguously contemplated in the present disclosure. Unless otherwise indicated, the features, structures, characteristics, steps, or elements described in relation to any aspect or embodiment of the present disclosure may be used in combination with the features, structures, characteristics, steps, or elements of any other aspect or embodiment. Unless the context clearly dictates otherwise, the features.28KTS Docket No.: 116771-1539925-823WO1structures, characteristics, or elements of any method or use disclosed herein are mutually compatible. Unless the context clearly dictates otherwise, the features, structures, characteristics, or elements of a compound or pharmaceutically acceptable salt of any Formula of the present disclosure, or a composition or a pharmaceutical composition thereof, are mutually compatible. For instance, if a Formula (Ill-alpha) or Formula (Ill-beta) comprises a R1and a R2and a paragraph exists in the specification for each R1and R2such as “In some embodiments, for a method of the present disclosure or for a compound or pharmaceutically acceptable salt of Formula (Ill-alpha) or Formula (Ill-beta),... ” then each and every one of the combinations of R1and R2are expressly and unambiguously contemplated in the present disclosure. By way of example only, if the following sentences exist: “In some embodiments, R1is selected from halogen.”, “In some embodiments, R2is selected from -CN, -OH, C1-3 alkyl, and C3-6 cycloalkyl.”, and “In some embodiments, R2is selected from -CN, -OH, and C1-3 alkyl” then the following is expressly and unambiguously contemplated: “In some embodiments, R1is selected from halogen; and R2is selected from -CN, -OH, C1-3 alkyl, and C3-6 cycloalkyl.” and “In some embodiments, R1is selected from halogen; and R2is selected from -CN, -OH, and C1-3 alkyl”. This logic regarding R1and R2applies to other features, structures, characteristics, or elements that a Formula, a composition, or a pharmaceutical composition may comprise. Furthermore, this logic applies to “In some embodiments, for a method or a use of the present disclosure....” As used herein, the phrases “In some embodiments, for a method or a use of the present disclosure,...” and “In some embodiments, for a method of the present disclosure,...” are used interchangeably. Unless indicated otherwise, any aspect or embodiment of the present disclosure can be combined with any other aspect or embodiment of the present disclosure.

[0147] As used herein, the term “test sample” means sample of blood obtained from a subject. It is to be understood that when blood sample is obtained from a subject, subject's blood is used for determining the subject's endoxifen levels and / or other biomarkers that may be measured or tested. As used herein “plasma endoxifen” is used to refer to endoxifen levels in the subject's test sample, whether the test is conducted on whole blood, plasma, or serum.

[0148] As used herein, the term “an environmentally optimal amount” of a solvent or ingredient is the minimum amount of a solvent or ingredient that, together with other variable input parameters, result in maximizing output parameters. An environmentally optimal amount of a solvent or ingredient may vary from a non-environmentally optimal amount by 1%, 2%, 5%, 10%, 20%, or more. Identifying the environmentally optimal amount of a solvent or 29KTS Docket No.: 116771-1539925-823WO1ingredient by the methods described herein can lead to the use of substantially smaller amounts of solvents or ingredients, which can minimize waste and reduce the recycling or disposal needs during the process, as well as reduce costs.

[0149] The input parameters are the variables that affect the quality, efficiency, and cost of production of active pharmaceutical ingredients or pharmaceutical compositions. The input parameters include environmentally optimal amounts as described herein, along with temperature, pressure, speed, and time. Careful control of input parameters, including environmentally optimal amounts of solvents or ingredients, can lead to increased output parameters.

[0150] Output parameters are the results that are measured to evaluate the performance of the production process. The output parameters include yield, defect rate, customer satisfaction, and profitability.

[0151] Critical process parameters (CPPs) are important variables that are monitored to ensure the quality and efficacy of pharmaceutical products. CPPs include blending time, number of blender revolutions, kneading time, impeller and chopper speed, binder addition time, inlet air temperature, fluidization air volume, dew point, and product temperature.

[0152] Following identification of environmentally optimal amounts of solvents or ingredients according to the methods disclosed herein, manufacturers of pharmaceutical compositions may further establish upper and lower tolerances around a midpoint for each CPP to ensure acceptable output parameters.

[0153] Embodiments that reference throughout this specification to “a compound”, such as compounds of Formula (I), Formula (II), Formula (III) and Formula (IV), include the polymorphic, salt, free base, co-crystal, and solvate forms of the formulas and / or compounds disclosed herein. Thus, the appearances of the phrases “a compound”, “compound of Formula (I)”, “compound of Formula (II)”, “compounds of Formula (III)” and “compound of Formula (IV)” include Form I of the compound of Formula (IV), Forms IV -XIX of the compounds of Formula (III), the free base of the compound of Formula (IV), the free base of the compounds of Formula (III), and / or the gluconate salts as described herein.

[0154] Abbreviations Used HereinACE-CL: Ethyl chloroformatesCAN or MeCN: AcetonitrileACT: AcetoneBuOAc: Butyl acetate30KTS Docket No.: 116771-1539925-823WO1BME: Butyl methyl etherDCM: DicholoromethaneDIPEA: DiisopropylethylamineDMF: DimethylformamideEtOAc: Ethyl acetateEtOH: EthanolGC: Gas chromatographyHCl: Hydrochloric acidHPLC: High-performance liquid chromatographyH2O: WaterdH2O: Deionized waterHep: HeptaneICP-MS: Inductively-coupled plasma mass spectrometryIPA: Isopropyl alcohol; isopropanolMeOH: Methanol2-MeTHF: 2-MethyltetrahydrofuranMIBK: Methyl isobutyl ketone (4-methyl-2-pentanone)NaCl: Sodium chlorideNaHCO3: Sodium hydrocarbonateNaOH: Sodium hydroxideNMR: Nuclear magnetic resonancePPW: Process Purified WaterTCA: Trichloroacetic acidTFA: Trifluoroacetic acidTHF: Tetrahydrofuran2-MeTHF: 2-MethyltetrahydrofuranTol: TolueneCV: Coefficient of VarianceTmax: time to maximum concentrationCmax: maximum concentration,AUCo-24h: (“AUC24hf’) area under the concentration-time curve from time 0 to 24 hours following drug administrationAUCo-inf: (“AUCo-inf”) Area under the concentration-time curve from time 0 to infinity 31KTS Docket No.: 116771-1539925-823WO1Kel: terminal elimination rate constant, and volume oft1 / 2: terminal half-lifeCL / F: terminal clearanceVd / F: distribution.DSC: differential scanning calorimetryEGA: evolved gas analysisEVHT: evaporation at high temperatureEVRT: evaporation at room temperatureGRAD: gradient precipitationHT: high temperatureNOR: Normal operating rangePAD: precipitation by antisolvent addition to a saturated solutionPAI: precipitation by saturated solution addition to an antisolventPAR: Proven acceptable rangeSLRT: slurry experiment at room temperatureSLHT: slurry experiment at high temperatureTGA: thermogravimetric analysisXRPD: X-ray powder diffractionIPC: In-process control

[0155] All methods and uses described herein can be performed in any suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as,” “the like,” “for example,” “for instance,” “by way of example only,” etc.) is intended merely to illustrate the matter of the present disclosure and does not pose a limitation on the scope of the matter of the present disclosure unless otherwise claimed. No language in the present disclosure should be construed as any indicating any non-claimed element as essential to practice of the invention as used herein.

[0156] In some aspects, the present disclosure provides industrially scalable methods of making (Z)-endoxifen free base, mixtures of (E)-endoxifen and (Z)-endoxifen (E / Z-mix), and salts thereof. In an aspect, the industrially scalable methods are synthetic methods of making stable (Z)-endoxifen free base, E / Z-mix, and salts thereof. In another aspect, the present disclosure provides methods of making compositions comprising stable (Z)-endoxifen free base, E / Z-mix, and salts thereof. The methods of the present disclosure may, in some embodiments, provide improved safety and scalability compared to other methods.32KTS Docket No.: 116771-1539925-823WO1

[0157] Current best practice for the treatment of breast cancer is to diagnose breast cancer with mammography and then treat the patient with surgery, radiation therapy, and chemotherapy. The current widespread use of mammography has resulted in improved detection of breast cancer. Although breast cancer is about 100 times less common among men than among women, the lifetime risk of men getting breast cancer is about 1 in 1,000. About 2,470 new cases of invasive breast cancer will be diagnosed in men and about 460 men will die from breast cancer. American Cancer Society estimates that in 2017, 255,180 new cases of breast cancer will be diagnosed in both men and women combined and 41,070 subjects will die of breast cancer. Nonetheless, the death rate due to breast cancer has remained relatively unchanged at about 21 deaths per 100,000 women and 0.4 deaths per 100,000 men. All too often, breast cancer is discovered at a stage that is too far advanced, when therapeutic options and survival rates are severely limited.

[0158] Breast density is a breast disorder identified by visual techniques such as mammography and reflects increased fibroglandular tissue within the breast, i.e., overgrowth of stromal and epithelial cells in the breast. Breast density is classified in 4 classes — Class A, B, C and D — based on the degree of severity of the density. It is an independent risk factor for breast cancer. At least 23 states in the USA require physicians to inform subjects if they have dense breast(s). There is currently no treatment for dense breasts, although subjects are reminded to make healthy lifestyle choices and undergo regular mammograms to monitor changes in breast.

[0159] Gynecomastia is a common male breast condition reflecting increased hyperplasia of the breast tissue, including epithelial hyperplasia, with prevalence of asymptomatic gynecomastia of 60% to 90% in neonates, 50% to 60% in adolescents, and up to 70% in men aged 50 to 69 years (Therapeutics and Clinical Risk Management 2011:7, 145 - 148). Newborn gynecomastia usually resolves itself within 4 weeks of birth and at least half of adolescent males experience gynecomastia with typical onset of 13 to 14 years of age (Tanner stage 3 or 4). Gynecomastia has been proposed to be a risk factor for male breast cancer.

[0160] Further, gynecomastia often presents itself secondarily to an underlying disorder such as prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure and in patients undergoing hemodialysis, Type I diabetes mellitis, etc. Further, medications, such as anti-androgen medications or certain anti-psychotics, themselves have been reported to cause up to 25% of cases of gynecomastia and can be categorized by their hormone-like action. For example, the most common side effects attributed to bicalutamide. a 33KTS Docket No.: 116771-1539925-823WO1nonsteroidal antiandrogen used for treatment of prostate cancer, are gy necomastia and breast pain.

[0161] DCIS is the most common non-invasive breast cancer. It involves the cell lining of the breast ducts. In DCIS, the cells have not spread beyond the walls of the duct into the surrounding breast tissue. About 1 in 5 new breast cancer cases will be DCIS. LCIS is a pre-cancerous neoplasia. It may be indicative of a predisposition for invasive cancer. LCIS only accounts for about 15% of the in situ (ductal or lobular) breast cancers.

[0162] IDC is the most invasive breast cancer. As the name applies, it is a carcinoma that begins in the breast ducts and then invades the surrounding fatty tissue. About 8 to 10 invasive breast cancers are infdtrating ductal carcinomas. IDC is often treated by surgery to excise the cancerous tissue, and radiation therapy. In addition, chemotherapy combined with immunotherapy (e.g., tamoxifen and trastuzumab) is often used to treat IDC. If the tumor is larger than 4 cm, then a radical mastectomy may be performed.

[0163] ILC is a cancer that develops in the lobules of the breast and has invaded the surrounding tissue. About 1 in 10 invasive breast cancer is an ILC. ILC is treated by surgery to excise the cancerous tissue, and radiation therapy. In addition, chemotherapy and immunotherapy combination (e.g., tamoxifen and trastuzumab) is often used as an adjuvant therapy to treat ILC.

[0164] Inflammatory breast cancer accounts for about 1% to 3% of all breast cancers. In inflammatory’ breast cancer, cancer cells block lymph vessels in the skin, resulting in the beast turning red and feeling warm. The affected breast may become larger or firmer, tender, or itchy. Inflammatory' breast cancer is treated with chemotherapy, immunotherapy, radiation therapy and in some cases, surgery.

[0165] Estrogen Receptor positive (ER+) breast cancer is characterized by the presence of estrogen receptors on the surface of the cancerous cells. Growth of ER+ cancer cells is associated with the availability of estrogen (hormone-dependent or hormone sensitive breast cancer). Approximately, 80% of all breast cancers are ER+ breast cancers. Treatment options for ER+ breast cancer include chemotherapeutic agents that block estrogen (e.g., tamoxifen).

[0166] Tamoxifen is a selective estrogen receptor modulator that is used for the treatment of women 'ith endocrine responsive breast cancer, i.e., hormone-dependent or hormone-sensitive breast cancer. Adjuvant therapy primarily via oral delivery' of tamoxifen is known to have severe side effects such as vasomotor symptoms, for example hot flashes, and reproductive tract (gynecologic) cancers. Patient compliance remains a problem with tamoxifen therapy.34KTS Docket No.: 116771-1539925-823WO1Further, the majority of the individuals on adjuvant tamoxifen therapy do not respond to the drug and 30 - 50% of the patients subsequently die of their disease.

[0167] Several cytochrome P450 (CYP) mutations have been proposed to cause reduced conversion of tamoxifen to its active metabolite, endoxifen, and reduce tamoxifen efficacy and increase resistance to the drug. So far, over 140 allelic variants of CYP2D6 have been described and a substantial part of these are associated with reduced or absent activity of the encoded enzyme. Based on the combination of the carried alleles, each individual subject can be classified into one of four phenotypic groups: poor metabolizer (PM) with plasma endoxifen levels less than 30 nM, intermediate metabolizer (IM), extensive metabolizer (EM) and ultrarapid metabolizer (UM), reflecting variations in levels of serum endoxifen. However, changes in the CYP genotype do not fully explain the tamoxifen resistance and the reduced endoxifen levels observed in some subjects.

[0168] Therefore, several alternatives to tamoxifen are being developed for the treatment of breast cancer, which include low dose-tamoxifen and tamoxifen's active metabolites, afimoxifene, endoxifen, and their derivatives. It is widely accepted that (Z)-endoxifen is the main active metabolite responsible for the clinical efficacy of tamoxifen.

[0169] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Further Forms

[0170] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherw ise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0171] ’‘Isomers” are different compounds that have the same molecular formula. “Stereoisomers”' are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can 35KTS Docket No.: 116771-1539925-823WO1be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Compounds described herein may contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0172] The carbon-carbon or carbon-heteroatom bonds of the compounds of the present disclosure may7be depicted herein using a solid line), a solid wedge (or a hashed wedge (••*'' ). The use of a solid line to depict bonds to asymmetric center is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or hashed wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. Compounds of the present disclosure may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds disclosed herein can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or hashed wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity7of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry7, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0173] When stereochemistry is not specified, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for 36KTS Docket No.: 116771-1539925-823WO1example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0174] In certain embodiments, compositions of the disclosure may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers.

[0175] Methods of producing substantially pure enantiomers are known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel. NicGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for sen ice basis.

[0176] A 'tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:KTS Docket No.: 116771-1539925-823WO1NHN HN" N, N NH NZ

[0177] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0178] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0179] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F.15F,16F,17F,18F.33S,34S,35S,36S.35C1,37C1,79Br,81Br. and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0180] In certain embodiments, the compounds disclosed herein have some or all of the 'H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds38KTS Docket No.: 116771-1539925-823WO1are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0181] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000. 110 pp; George W.; Varma, Raj ender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0182] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co..

[0183] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0184] The compounds, compositions, and methods described herein include amorphous forms as well as crystalline forms, including crystalline polymorph forms where applicable. The compounds described herein may be in the form of a pharmaceutically acceptable salt, salt, free base, or free acid. The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In some embodiments, the unsolvate form is referred to as an anhydrous form or anhydrate form. In some embodiments, the solvate form comprises water and is referred to as a hydrate form. In some embodiments, the solvate form is referred to as a pseudopolymorph. In some embodiments, the hydrate form is referred to as a pseudopolymorph. Both unsolvate and solvate forms of the compounds presented herein are also considered to be disclosed herein.39KTS Docket No.: 116771-1539925-823WO1

[0185] The term “form’" refers to a solid-state form of a particular compound (e.g., the free base, the free acid, a salt or a pharmaceutically acceptable salt). The term 'form" includes crystalline polymorphs, hydrates and solvates (pseudopolymorphs), amorphous forms, and mixtures thereof, unless a particular cry stalline, polymorph, pseudopolymorph, or amorphous form is expressly referred to. The term “polymorph” refers to a crystalline form of a given chemical species that differs from another crystalline form of that same molecular formula solely in crystal packing and / or molecular conformation within the lattice and, unless otherwise specified, excludes hydrates and solvates. If more than one polymorph, hydrate, or solvate exists, they will be designated for clarity (e.g., Form I, Form II; monohydrate, dihydrate; ethanol solvate, methanol solvate).

[0186] The terms “amorphous” and “amorphous form” are used interchangeably herein to refer to a solid having no long range order in the position of its atoms. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement and no long range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. An amorphous solid is a solid that is characterized as having no sharp peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). An XRPD pattern of an amorphous form may one or several broad peaks (e.g., halos). Broad peaks (e.g., halos) are characteristic of an amorphous solid. An amorphous solid system may be composed of a single chemical entity or may be a multi-component system containing, e.g., an API, polymer, and other excipients, without stoichiometric composition. Amorphous solids may possess cry stal like short range molecular arrangement, but no long-range order of molecular packing.

[0187] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.40KTS Docket No.: 116771-1539925-823WO1

[0188] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may. for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0189] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J Pharmaceutics, 47, 103 (1988); Sinkula et al., J Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the abovedefined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0190] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).CompoundsEndoxifen, a Potent Selective Estrogen Receptor Modulator

[0191] Endoxifen is an active metabolite of tamoxifen that is broken down in the liver into active compounds, or metabolites. One of the active tamoxifen metabolites is endoxifen, also referred to as 4-hydroxy-N-desmethyltamoxifen. Endoxifen, particularly the active isomer (Z)- 41KTS Docket No.: 116771-1539925-823WO1endoxifen, is a selective estrogen receptor modulator (SERM) that functions as a competitive partial agonist of estrogen receptor in a tissue-specific manner. (Z)-endoxifen has robust antitumor and anti-estrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. (Z)-endoxifen is beneficial in treating cancers in patients that are resistant to other hormone therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, in part because endoxifen functions independently of metabolic enzymes such as CYP2D6.

[0192] In some embodiments, the compositions described herein include endoxifen, which may comprise (Z)-endoxifen, (E)-endoxifen, or a combination thereof.

[0193] In one aspect, the present disclosure provides a compound of Formula (III):or a pharmaceutically acceptable salt thereof.

[0194] In another aspect, the present disclosure provides a compound of Formula (IV):HOor a pharmaceutically acceptable salt thereof.

[0195] In one aspect, the present disclosure provides a compound of Formula (I-E):HO' O Formula (V),or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III), Formula (III) is represented by Formula (IV). In some embodiments, Formula (III) is represented by Formula (V).KTS Docket No.: 116771-1539925-823WO1

[0197] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), the compound is crystalline Form I of (Z)-endoxifen. In some embodiments, the crystalline Form I is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 16.8±0.3° 2-Theta, about 17.1±0.3° 2-Theta, and about 21.8±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 16.0±0.3° 2-Theta, about 18.8±0.3° 2-Theta, and about 26.5±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 12.3±0.3° 2-Theta, about 28.0±0.3° 2-Theta, and about 29.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having peaks at 12.3±0.3° 2-Theta, 16.0±0.3° 2-Theta, 18.8±0.3°, 26.5±0.3° 2-Theta, 28.0±0.3° 2-Theta, and 29.0±0.3° 2-Theta as measured by Cu Ka radiation.

[0198] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), the compound is crystalline Form II of (Z)-endoxifen. In some embodiments, the crystalline Form II is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 7.0±0.3° 2-Theta, about 11.9±0.3° 2-Theta. and about 14.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 6.6±0.3° 2-Theta, 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3 ± 0.3° 2-Theta, about 20.0±0.3° 2-Theta, and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation.

[0199] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). the compound is crystalline Form V of (Z)-endoxifen. In some 43KTS Docket No.: 116771-1539925-823WO1embodiments, the crystalline Form V is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 8.9± 0.3° 2-Theta, 12.5± 0.3° 2-Theta, and 19.6± 0.3° 2-Theta, as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 21.7± 0.3° 2-Theta. 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having three additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, or 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having four additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, 16.0± 0.3° 2-Theta, 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation.

[0200] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). the compound is a crystalline Form selected from Form I, Form II, Form V, and any combinations thereof. In some embodiments, the compound is a crystalline Form selected from Form I, Form II, and a combination thereof. In some embodiments, the compound is a crystalline Form selected from Form I, Form V, and a combination thereof. In some embodiments, the crystalline Form I is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 16.8±0.3° 2-Theta, about 17.1±0.3° 2-Theta, and about 21.8±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 16.0±0.3° 2-Theta, about 18.8±0.3° 2-Theta, and about 26.5±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 12.3±0.3° 2-Theta, about 28.0±0.3° 2-Theta, and about 29.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having peaks at 12.3±0.3° 2-Theta, 16.0±0.3° 2-Theta, 18.8±0.3°, 26.5±0.3° 2-Theta, 28.0±0.3° 2-Theta, and 29.0±0.3° 2-Theta as measured by Cu Ka radiation.44KTS Docket No.: 116771-1539925-823WO1In some embodiments, the crystalline Form II is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 7.0±0.3° 2-Theta, about 11.9±0.3° 2-Theta, and about 14.0±0.3° 2-Theta as measured by Cu Kot radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 6.6±0.3° 2-Theta, 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3 ± 0.3° 2-Theta, about 20.0±0.3° 2-Theta, and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form V is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 8.9± 0.3° 2-Theta, 12.5± 0.3° 2-Theta, and 19.6± 0.3° 2-Theta, as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, cry stal 1 ine Form V is further characterized as having two additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta. and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having three additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, or 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having four additional peak selected from 21.7±45KTS Docket No.: 116771-1539925-823WO10.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, 16.0± 0.3° 2-Theta, 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation.

[0201] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the salt is selected from the acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy napthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, or any combination thereof. In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (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. In some embodiments, the salt is D-gluconate, L-gluconate, or a combination thereof. In some embodiments, the salt is hydrochloride. In some embodiments, the salt is citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is selected from (Z)-endoxifen hydrochloride and (Z)-endoxifen citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate. In some embodiments, the salt is (Z)-endoxifen L-gluconate. In some embodiments, the salt is (Z)-endoxifen hydrochloride. In some embodiments, the salt is (Z)-endoxifen citrate. In some embodiments, the salt is (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is (E)-endoxifen D-gluconate. In some embodiments, the salt is (E)-endoxifen L-gluconate. In some embodiments, the salt is (E)- 46KTS Docket No.: 116771-1539925-823WO1endoxifen hydrochloride. In some embodiments, the salt is (E)-endoxifen citrate. In some embodiments, the salt is endoxifen D-gluconate. In some embodiments, the salt is endoxifen L-gluconate. In some embodiments, the salt is endoxifen hydrochloride. In some embodiments, the salt is endoxifen citrate.

[0202] In some embodiments, the compound or a pharmaceutically acceptable salt of Formula (III) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)-endoxifen citrate, or any combination thereof. In some embodiments, the compound of Formula (III) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)-endoxifen citrate, or a combination thereof. In some embodiments, the compound of Formula (III) is (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the compound of Formula (III) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or any combinations thereof. In some embodiments, the compound of Formula (III) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen citrate, (E)-endoxifen citrate, or any combinations thereof. In some embodiments, the compound of Formula (III) is (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or a combination thereof. In some embodiments, the compound or salt of Formula (III) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (III) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (III) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (III) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (III) is (Z)-endoxifen. In some embodiments, the compound or salt of Formula (III) is (E)-endoxifen.

[0203] In some embodiments, the compound or a pharmaceutically acceptable salt of Formula (IV) is (Z)-endoxifen, (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (IV) is (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (IV) is (Z)-endoxifen hydrochloride. In some embodiments, the compound of Formula (IV) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (IV) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (IV) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (IV) is (Z)-endoxifen.

[0204] In some embodiments, the compound or a pharmaceutically acceptable salt of Formula (V) is (E)-endoxifen. (E)-endoxifen hydrochloride, (E)-endoxifen hydrochloride or (E)- 47KTS Docket No.: 116771-1539925-823WO1endoxifen citrate. In some embodiments, the compound of Formula (V) is (E)-endoxifen. In some embodiments, the compound of Formula (V) is (E)-endoxifen hydrochloride or (E)-endoxifen citrate. In some embodiments, the compound of Formula (V) is (E)-endoxifen hydrochloride. In some embodiments, the compound of Formula (V) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (V) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (V) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (V) is (E)-endoxifen.

[0205] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the compound or salt of Formula (III), Formula (IV), or Formula (V) is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the compound or salt is a crystalline form. In some embodiments, the compound or salt is a solvate form. In some embodiments, the compound or salt is a polymorph form. In some embodiments, the compound or salt is an amorphous form. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0206] In some embodiments, endoxifen or a pharmaceutically acceptable salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some 48KTS Docket No.: 116771-1539925-823WO1embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0207] In some embodiments, (Z)-endoxifen or a pharmaceutically acceptable salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (Z)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0208] In some embodiments, (E)-endoxifen or a pharmaceutically acceptable salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (E)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, endoxifen is a solvated form. In some embodiments, the solvated form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvated form is an ethanol solvate form. In some embodiments, the solvated form is a methanol solvate form. In some embodiments, the solvated form is an isopropanol solvate form. In some embodiments, the solvated form is a hydrate.49KTS Docket No.: 116771-1539925-823WO1Compositions and Pharmaceutical Formulations / Compositions

[0209] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity.

[0210] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity.

[0211] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity.

[0212] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity.KTS Docket No.: 116771-1539925-823WO1

[0213] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):Formula (III)or a pharmaceutically acceptable salt thereof; and(ii) less than 0.09 wt% of an endoxifen-related impurity.

[0214] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):HO Formula (IV)or a pharmaceutically acceptable salt thereof; and(ii) less than 0.09 wt% of an endoxifen-related impurity.

[0215] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):HhkFormula (III); and(ii) less than 0.09 wt% of an endoxifen-related impurity.

[0216] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):HNHO Formula (IV); and(ii) less than 0.09 wt% of an endoxifen-related impurity.

[0217] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):KTS Docket No.: 116771-1539925-823WO1or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0218] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0219] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0220] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):52KTS Docket No.: 116771-1539925-823WO1(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0221] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (III):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0222] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0223] In one aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (111):KTS Docket No.: 116771-1539925-823WO1(ii) less than or equal to 0.2 wt% of an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0224] In another aspect, the present disclosure provides a composition comprising:(i) a compound of Formula (IV):HHO' O Formula (IV); and(ii) less than or equal to 0.2 wt% of an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

[0225] In one aspect, the present disclosure provides a composition comprising(i) a compound of Formula (III):HHO' ON\xFormula (III)or a pharmaceutically acceptable salt thereof;(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof; and (iii) less than 0.09 wt% of an endoxifen-related impurity’ selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

[0226] In another aspect, the present disclosure provides a composition comprising(i) a compound of Formula (IV):HHO O Formula (IV)or a pharmaceutically acceptable salt thereof;54KTS Docket No.: 116771-1539925-823WO1(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512. an impurity having m / z 716. a pharmaceutically acceptable salt of any one thereof, and any combination thereof; and (iii) less than 0.09 wt% of an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

[0227] In one aspect, the present disclosure provides a composition comprising(i) a compound of Formula (III):(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716. a pharmaceutically acceptable salt of any one thereof, and any combination thereof; and (iii) less than 0.09 wt% of an endoxifen-related impurity7selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

[0228] In another aspect, the present disclosure provides a composition comprising(i) a compound of Formula (IV):(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716. a pharmaceutically acceptable salt of any one thereof, and any combination thereof; and (iii) less than 0.09 \\1% of an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 55KTS Docket No.: 116771-1539925-823WO1416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

[0229] In one aspect, the present disclosure provides a composition comprising a compound of Formula (III):HO'wherein the compound of Formula (III) is prepared by a method or a process of the present disclosure.

[0230] In another aspect, the present disclosure provides a composition comprising a compound of Formula (II):HNFormula (II),wherein the compound of Formula (II) is prepared by a method or a process of the present disclosure.

[0231] In one aspect, the present disclosure provides a composition comprising a compound of Formula (IV):HO O ^Formula (IV), wherein the compound of Formula (IV) is prepared by a method or a process of the present disclosure.

[0232] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises an impurity. In some embodiments, the impurity is an endoxifen-related impurity. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity havingKTS Docket No.: 116771-1539925-823WO1m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, and any combinations thereof. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and a combination thereof. In some embodiments, the endoxifen-related impurity is selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof. In some embodiments, the impurity having m / z 512 isembodiments, the impurity having m / z 512 isKTS Docket No.: 116771-1539925-823WO1composition further comprises: (iii) less than 0.09 wt% of an endoxifen-related impurity selected from an impurity having m / z 300, an impurity’ having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises less than 0.06 wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises less than 0.04 wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises less than 0.04 wt% of an impurity’ having m / z 300. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 330. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 402. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 416. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 511. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 569. In some embodiments, the composition comprises less than 0.04 wt% of an impurity having m / z 512. In some embodiments, the composition comprises less than 0.03 wt% of the endoxifen-related impurity selected from an impurity’ having m / z 300, an impurity’ having m / z 330, an impurity having m / z 402, an impurity’ having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises a wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity’ having m / z 330, an impurity’ having m / z 402, an impurity’ having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises less than 0.03 wt% of an impurity having m / z 300. In some embodiments, the composition comprises less than 0.03 wt% of an impurity having m / z 330. In some embodiments, the composition comprises less than 0.03 wt% of an impurity’ having m / z 402. In some embodiments, the composition comprises less than 0.03 wt% of an impurity having m / z 416. In some embodiments, the composition comprises less than 0.03 wt% of an 58KTS Docket No.: 116771-1539925-823WO1impurity having m / z 511. In some embodiments, the composition comprises less than 0.03 wt% of an impurity having m / z 569. In some embodiments, the composition comprises less than 0.03 wt% of an impurity having m / z 512. In some embodiments, the composition comprises less than 0.01 wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises a wt% of the endoxifen-related impurity’ selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof that is below detection limits as determined by HPLC. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 300. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 330. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 416. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 511. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 569. In some embodiments, the composition comprises less than 0.01 wt% of an impurity having m / z 512. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 300. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 330. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 402. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 416. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 511. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 569. In some embodiments, the composition comprises a wt% that is below detection limits as determined by HPLC of an impurity having m / z 512. In some embodiments, the impurity 59KTS Docket No.: 116771-1539925-823WO1having m / z 300 isHO; the impurity having m / z 402 is selectedfrom; the impurity having m / z 416 is selected fromHO; the impurity having m / z 511 is selected fromm / z 569 isO. In some embodiments,Othe impurity having m / z 300 isHO. In some embodiments, theimpurity having m / z 402 is selected fromHO. In someembodiments, the impurity’ having m / z 416 is selected fromHO In some embodiments, the impurity having m / z 511 is selected fromKTS Docket No.: 116771-1539925-823WO1

[0233] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises: (i)pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of an impuritysalt of any one thereof, and any combinations thereof. In some embodiments, the composition 61KTS Docket No.: 116771-1539925-823WO1comprises: (i) a compound of Formula(III): HO Formula (III) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.1 wt% of ansalt of any one thereof, and any combinations thereof. In some embodiments, the compositioncomprises: (i) a compound of Formula (IV): HO Formula (IV) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of animpurity selected fromKTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations thereof. . In some embodiments, the composition comprises: (i) a compound of Formula (IV): HO Formula (IV) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.1 wt% of ansalt of any one thereof, and any combinations thereof.

[0234] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises: (i)KTS Docket No.: 116771-1539925-823WO1pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of an impuritysalt of any one thereof, and any combinations thereof; (iii) less than 0.04 wt% of an endoxifen-related impurity selected fromKTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations. In some embodiments, the compositionor a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of ansalt of any one thereof, and any combinations thereof; (iii) less than 0.04 wt% of an endoxifen-related impurity selected from65KTS Docket No.: 116771-1539925-823WO1acceptable salt of any one thereof, and any combinations. In some embodiments, thecomposition comprises: (i) a compound of Formula(III): HO Formula (III) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.166KTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations thereof; (iii) less than 0.04 wt% of an endoxifen-related impurity selected fromKTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations. In some embodiments, the compositionor a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.1 wt% of ansalt of any one thereof, and any combinations thereof; (iii) less than 0.04 wt% of an endoxifen-related impurity selected from68KTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations. In some embodiments, the compositioncomprises: (i) a compound of Formula(III): HO Formula (III) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of anKTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations thereof; (iii) a wt% of an impurity selected fromKTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations thereof that is below detection limits as determined by HPLC. In some embodiments, the composition comprises: (i) a compound ofFormula (IV) or a pharmaceutically acceptable salt thereof; and (ii) less than or equal to 0.16 wt% of an i mpuri ty selected fromsalt of any one thereof, and any combinations thereof; (iii) a wt% of an impurity selected from 71KTS Docket No.: 116771-1539925-823WO1salt of any one thereof, and any combinations thereof that is below detection limits as determined by HPLC. In some embodiments, the composition comprises less than 25 ppm of mesityl oxide. In some embodiments, the composition comprises less than 15 ppm of mesityl oxide. In some embodiments, the composition comprises less than 10 ppm of mesityl oxide.

[0236] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the compound of Formula (III) comprises (Z)-endoxifen. In some embodiments, the compound of Formula (III) comprises greater than or equal to 95 wt%, greater than or equal to 96 wt%, greater than or equal to 9772KTS Docket No.: 116771-1539925-823WO1wt%, greater than or equal to 98 wt%, or greater than or equal to 98.5 wt% of (Z)-endoxifen. In some embodiments, the compound of Formula (III) comprises greater than or equal to 95 wt% of (Z)-endoxifen. In some embodiments, the compound of Formula (III) comprises greater than or equal to 96 wt% of (Z)-endoxifen. In some embodiments, the compound of Formula (III) comprises greater than or equal to 97 wt% of (Z)-endoxifen. In some embodiments, the compound of Formula (III) comprises greater than or equal to 98.5 wt% of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is crystalline Form I of (Z)-endoxifen that is characterized as having X-ray composition diffraction (XRPD) pattern with peaks at about 16.8 ± 0.3° 2-Theta, about 17.1 ± 0.3° 2-Theta, and about 21.8 ± 0.3° 2-Theta as measured using Cu Kα radiation. In some embodiments, the crystalline Form I of (Z)-endoxifen is further characterized as having one additional XRPD peak selected from about 12.3 ± 0.3° 2-Theta, about 16.0 ± 0.3° 2-Theta, about 18.8 ± 0.3° 2-Theta, about 26.5 ± 0.3° 2-Theta, about 28.0 ± 0.3° 2-Theta, and about 29.0 ± 0.3° 2-Theta as measured using Cu Ka radiation. In some embodiments, the pharmaceutically acceptable salt of (Z)-endoxifen is selected from acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the pharmaceutically acceptable salt of (Z)-endoxifen is selected from citrate, gluconate, and hydrochloride. In some embodiments, the pharmaceutically acceptable salt of (Z)-endoxifen is citrate. In some embodiments, the pharmaceutically acceptable salt of (Z)-endoxifen is gluconate. In some embodiments, the pharmaceutically acceptable salt of (Z)-endoxifen is hydrochloride. In some embodiments, the compound of Formula (III) comprises less than 5 wt% of (E)-endoxifen. In some embodiments, the compound of Formula (III) comprises less than 4 wt% of (E)-endoxifen. In some embodiments, the compound of Formula (III) comprises less than 3.5 wt% of (E)-endoxifen. In some embodiments, the compound of Formula (III)73KTS Docket No.: 116771-1539925-823WO1comprises less than 3 wt% of (E)-endoxifen. In some embodiments, the compound of Formula (III) comprises less than 2.5 wt% of (E)-endoxifen.

[0237] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises (E)-endoxifen. In some embodiments, the composition comprises less than or equal to 3 wt% of (E)-endoxifen. In some embodiments, the composition comprises less than or equal to 2.5 wt% of (E)-endoxifen. In some embodiments, the composition comprises less than or equal to 2 wt% of (E)-endoxifen.

[0238] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises (Z)-endoxifen. In some embodiments, the composition comprises greater than or equal to 95 wt%, greater than or equal to 96 wt%, greater than or equal to 97 wt%, greater than or equal to 98 wt%, or greater than or equal to 98.5 wt% of (Z)-endoxifen. In some embodiments, the composition comprises greater than or equal to 95 wt% of (Z)-endoxifen. In some embodiments, the composition comprises greater than or equal to 96 wt% of (Z)-endoxifen. In some embodiments, the composition comprises greater than or equal to 97 wt% of (Z)-endoxifen. In some embodiments, the composition comprises greater than or equal to 98.5 wt% of (Z)-endoxifen.

[0239] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the compound of Formula (IV) is (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is greater than or equal to 95 wt%, greater than or equal to 96 wt%, greater than or equal to 97 wt%, greater than or equal to 98 wt%, or greater than or equal to 98.5 wt% (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is greater than or equal to 95 wt% (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is greater than or equal to 96 wt% (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is greater than or equal to 97 wt% (Z)-endoxifen. In some embodiments, the compound of Formula (IV) comprises greater than or equal to 98.5 wt% of (Z)-endoxifen. In some embodiments, the compound of Formula (IV) is crystalline Form I of (Z)-endoxifen that is characterized as having X-ray composition diffraction (XRPD) pattern with peaks at about 16.8 ± 0.3° 2-Theta, about 17.1 ± 0.3° 2-Theta, and about 21.8 ± 0.3° 2-Theta as measured using Cu Ka radiation. In some embodiments, the crystalline Form I of (Z)-endoxifen is further characterized as having one additional XRPD peak selected from about 12.3 ± 0.3° 2-Theta, about 16.0 ± 0.3° 2-Theta, about 18.8 ± 0.3° 2- 74KTS Docket No.: 116771-1539925-823WO1Theta, about 26.5 ± 0.3° 2-Theta, about 28.0 ± 0.3° 2-Theta, and about 29.0 ± 0.3° 2-Theta as measured using Cu Ka radiation. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IV) is selected from acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IV) is selected from citrate, gluconate, and hydrochloride. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IV) is citrate. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IV) is gluconate. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (IV) is hydrochloride.

[0240] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition comprises residual solvent, residual metal, or a combination thereof. In some embodiments, the composition comprises less than 3000 ppm methanol, less than 5000 ppm of ethanol, less than 5000 ppm of acetone, less than 5000 ppm of isopropanol, less than 410 ppm of acetonitrile, less than 3000 ppm of ethyl acetate, less than 720 ppm of tetrahydrofuran, less than 520 ppm of 2-methyltetrahydrofuran, less than 5000 ppm of n-heptane, or any combinations thereof. In some embodiments, composition comprises residual solvent. In some embodiments, the composition comprises less than 200 ppm methanol, less than 200 ppm of ethanol, less than 1000 ppm of acetone, less than 4000 ppm of isopropanol, less than 50 ppm of acetonitrile, less than 1000 ppm of ethyl acetate, less than 200 ppm of tetrahydrofuran, less than 200 ppm of 2-methyltetrahydrofuran, less than 10 ppm of n-heptane, or any combinations thereof. In some embodiments, the composition comprises less than 50 ppm methanol, less than 60 ppm of ethanol, less than 600 ppm of acetone, less than 3000 ppm of isopropanol, less than 30 ppm of acetonitrile, less than 2500 ppm of ethyl acetate, less than 500 ppm of tetrahydrofuran, less 75KTS Docket No.: 116771-1539925-823WO1than 100 ppm of 2-methyltetrahydrofuran, less than 10 ppm of n-heptane, or any combinations thereof. In some embodiments, the composition comprises less than 50 ppm methanol, less than 60 ppm of ethanol, less than 600 ppm of acetone, less than 3000 ppm of isopropanol, less than 30 ppm of acetonitrile, less than 2500 ppm of ethyl acetate, less than 500 ppm of tetrahydrofuran, less than 100 ppm of 2-methyltetrahydrofuran, and less than 10 ppm of n-heptane. In some embodiments, the composition comprises less than 50 ppm methanol, less than 50 ppm of ethanol, less than 1000 ppm of acetone, less than 3000 ppm of isopropanol, less than 10 ppm of acetonitrile, less than 500 ppm of ethyl acetate, less than 100 ppm of tetrahydrofuran, less than 100 ppm of 2-methyltetrahydrofuran, less than 10 ppm of n-heptane, or any combinations thereof. In some embodiments, the composition comprises less than 50 ppm methanol, less than 50 ppm of ethanol, less than 1000 ppm of acetone, less than 3000 ppm of isopropanol, less than 10 ppm of acetonitrile, less than 500 ppm of ethyl acetate, less than 100 ppm of tetrahydrofuran, less than 100 ppm of 2-methyltetrahydrofuran, and less than 10 ppm of n-heptane. In some embodiments, the composition comprises less than 200 ppm of titanium, less than 130 ppm of zinc, or a combination thereof. In some embodiments, the composition comprises less than 200 ppm of titanium and less than 130 ppm of zinc. In some embodiments, the composition comprises less than 150 ppm of titanium, less than 10 ppm of zinc, or a combination thereof. In some embodiments, the composition comprises less than 150 ppm of titanium and less than 10 ppm of zinc. In some embodiments, the composition comprises less than 150 ppm of titanium. In some embodiments, the composition comprises less than 10 ppm of zinc. In some embodiments, the composition comprises less than 32 ppm of titanium, less than 130 ppm of zinc, or a combination thereof. In some embodiments, the composition comprises less than 20 ppm of titanium, less than 20 ppm of zinc, or a combination thereof. In some embodiments, the composition comprises less than 10 ppm of titanium, less than 10 ppm of zinc, or a combination thereof.

[0241] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition is stable composition. In some embodiments, composition is a storage stable composition. In some embodiments, the composition is a stable composition at 25°C / 60% RH. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 3% relative to 76KTS Docket No.: 116771-1539925-823WO1day 0. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 3% relative to day 0. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 1% relative to day 0. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 1% relative to day 0. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 0.5% relative to day 0. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 0.5% relative to day 0. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in water content (wt%) of no more than 1% relative to day 0 as determined by Karl Fischer titration. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in water content (wt%) of no more than 1% relative to day 0 as determined by Karl Fischer titration. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is 77KTS Docket No.: 116771-1539925-823WO1characterized by an increase in water content (wt%) of no more than 0.5% relative to day 0 as determined by Karl Fischer titration. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in water content (wt%) of no more than 0.5% relative to day 0 as determined by Karl Fischer titration. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300. an impurity having m / z 330, an impurity having m / z 402. an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH. wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 78KTS Docket No.: 116771-1539925-823WO1569, an impurity having m / z 716, or any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH,79KTS Docket No.: 116771-1539925-823WO1wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity’ having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569. an impurity having m / z 716, and any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or 80KTS Docket No.: 116771-1539925-823WO1equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH. wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512. an impurity having m / z 716, and a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months at 81KTS Docket No.: 116771-1539925-823WO125°C / 60% RH. wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity’ having m / z 716, or a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC.

[0242] In some embodiments, for a composition comprising a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), the composition is stable composition. In some embodiments, the composition is a storage stable composition. In some embodiments, the composition is a stable composition at 25°C / 60% RH. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 3% relative to day 0. In some embodiments, the composition is storage stable for or less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 1% relative to day 0. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 0.5% relative to day 0. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by’ an increase in water content (wt%) of no more than 1% relative to day 0 as determined by Karl Fischer titration. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in water content (wt%) of no more than 0.5% relative to day 0 as determined by’ Karl Fischer titration. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity’ having m / z 716, and any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 82KTS Docket No.: 116771-1539925-823WO125°C / 60% RH. wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity’ having m / z 716, or any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some 83KTS Docket No.: 116771-1539925-823WO1embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH. wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity7having m / z 416, an impurity7having m / z 511, an impurity having m / z 512, an impurity7having m / z 569, an impurity having m / z 716. or any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, or any combinations thereof, of no more than 0.1 \\1% relative to day70 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512. an impurity having m / z 716, and a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, or less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.5 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.584KTS Docket No.: 116771-1539925-823WO1wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, and a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC. In some embodiments, the composition is storage stable for less than or equal to 18 months, at 25°C / 60% RH, wherein a storage composition is characterized by an increase in an impurity having m / z 512, an impurity having m / z 716, or a combination thereof, of no more than 0.2 wt% relative to day 0 as determined by HPLC.

[0243] In one aspect, the present disclosure provides a pharmaceutical composition comprising a composition of the present disclosure, and at least one pharmaceutical acceptable excipient

[0244] In certain embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the composition is a pharmaceutical composition.

[0245] In certain embodiments, a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V) is formulated into pharmaceutical composition.

[0246] In some embodiments, a compound or a pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), or a pharmaceutical composition of the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V) is useful for the treatment of a disease or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder. In some embodiments, the compound is effective at treating a disease or disorder. In some embodiments, the pharmaceutical acceptable salt is effective at treating a disease or disorder.

[0247] Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active 85KTS Docket No.: 116771-1539925-823WO1compounds into preparations that are used pharmaceutically. Pharmaceutical compositions may be formulated using one or more physiologically acceptable excipients including carriers and auxiliaries. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman. L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999), herein incorporated by reference for such disclosure.

[0248] In some embodiments, a compound or a pharmaceutically acceptable salt thereof disclosed herein is administered either alone or in combination with pharmaceutically acceptable excipients, including carriers and auxiliaries, in a pharmaceutical composition. In some embodiments the compound or the pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition. Administration of the compounds, the pharmaceutically acceptable salts, and pharmaceutical compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. In some embodiments, these methods include oral administration.

[0249] The compounds or the pharmaceutically acceptable salts thereof disclosed herein, the pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof disclosed herein, and the methods disclosed herein may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human. In some embodiments, the subject is a non-human mammal. When administered to a mammal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable excipient (excipients include carriers and auxiliaries). Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The pharmaceutical composition can be in dosage 86KTS Docket No.: 116771-1539925-823WO1unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository’, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. The composition can also be suitable for nasal delivery. The composition can also be suitable for inhalation.

[0250] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units (also referred to as "dosage unit forms7’) such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. The predetermined amount can be in the form of a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

[0251] Pharmaceutical compositions which can be used orally include tablets, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0252] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular deliver}', intraperitoneal delivery, inhalation, nasal delivery, or other method, may be in the form of a liquid. A liquid pharmaceutical composition 87KTS Docket No.: 116771-1539925-823WO1may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline. Ringer's solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity7such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. A liquid pharmaceutical composition may be delivered / administered orally.

[0253] For oral formulations, at least one of the compounds or pharmaceutically acceptable salts thereof described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e g., in a liquid, solid or semi-solid formulation.

[0254] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0255] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.

[0256] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for 88KTS Docket No.: 116771-1539925-823WO1example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0257] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject's condition, that is. stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. Dosage amount and interval / regimen can be adjusted individually to provide levels that are sufficient to maintain the desired therapeutic effects. It is possible that the interval / regimen may comprise an infrequent administration (e.g. monthly, as opposed to daily) to achieve the desired therapeutic effect.

[0258] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed.. 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro. 21st Ed. Mack Pub. Co., Easton. PA (2005)), herein incorporated by reference for such disclosure.. Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s).

[0259] Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and any combinations thereof..

[0260] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the 89KTS Docket No.: 116771-1539925-823WO1compound of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is a therapeutic composition.

[0261] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%. less than 5%, less than 6%, less than 7%. less than 8%, less than 9%, or less than 10% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, or less than 9% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, or less than 8% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, or less than 7% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, or less than 6% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, or less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1% (E)-endoxifen by 90KTS Docket No.: 116771-1539925-823WO1weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 2% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 3% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 4% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 0.5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0262] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 50:50, at least 60:40, at least 64:36, at least 70:30, at least 80:30, at least 82:18, at least 85:15, at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 85: 15, at least 90: 10. at least 94:6, at least 95:5, at least 96:4, at least 97:3. at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 90:10. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 94:6. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 95:5. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 95:5. In 91KTS Docket No.: 116771-1539925-823WO1some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 96:4. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 97:3. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 98:2, at least 99:1. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is 100:0. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0263] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition may comprise one or more crystalline forms of a compound or salt of Formula (III), Formula (IV), or Formula (V). A crystalline form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.92KTS Docket No.: 116771-1539925-823WO1

[0264] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of a compound or salt of Formula (III), Formula (IV), or Formula (V). A polymorphic form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0265] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%. at least 80%. at least 90%. at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80%, at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the 93KTS Docket No.: 116771-1539925-823WO1pharmaceutical composition comprises at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%, crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 95% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0266] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), Formula (V). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 4 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to 40 mg crystalline 94KTS Docket No.: 116771-1539925-823WO1Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0267] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 4 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical 95KTS Docket No.: 116771-1539925-823WO1composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0268] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 30% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen citrate in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)-endoxifen hydrochloride 96KTS Docket No.: 116771-1539925-823WO1on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 30% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0269] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is an oral formulation. In some embodiments, the pharmaceutical composition comprises a tablet, a caplet, or a capsule. In some embodiments, the tablet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. The enteric coating agent, the control release agent and / or the film forming agent control or delay disintegration and absorption of the compositions including (Z)-endoxifen or salts thereof and elagolix or salts thereof in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. In some embodiments, the caplet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. In some embodiments, the capsule is coated with one or more of an enteric coating agent, a control release agent or a film forming. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the caplet is an enteric caplet. In some embodiments, the capsule is an enteric capsule. In some embodiments, the capsule is an enteric coated capsule. The enteric tablets, enteric caplets, or enteric capsules of the present disclosure are prepared by techniques known in the art. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.97KTS Docket No.: 116771-1539925-823WO1

[0270] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient and at least one pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient and a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical acceptable excipients are selected from pharmaceutical acceptable disintegrants, pharmaceutical acceptable fillers, pharmaceutical acceptable lubricants, and pharmaceutical acceptable binders. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or any combinations thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric caplet. In some embodiments, the pharmaceutical composition further comprises an enteric tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, a caplet, or a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a caplet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises a capsule, a caplet, or a tablet. In some embodiments, the pharmaceutical composition further comprises a capsule. In some embodiments, the pharmaceutical composition further comprises a caplet. In some embodiments, the pharmaceutical composition further comprises a tablet. In some embodiments, the pharmaceutical composition further comprises a tablet-in-tablet, a tablet-in-capsules, a beads-in-capsule, or a spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises a tablet-in-tablet. In some embodiments, the 98KTS Docket No.: 116771-1539925-823WO1pharmaceutical composition further comprises a tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises a beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises a spheres-in capsule. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric caplet. In some embodiments, the capsule is an enteric capsule. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the tablet is a delayed-release tablet. In some embodiments, the caplet is a delayed-release caplet. In some embodiments, the capsule is a delayed-release capsule. In some embodiments, the tablet is an enteric coated delayed-release tablet. In some embodiments, the caplet is an enteric coated delayed-release caplet. In some embodiments, the capsule is an enteric coated delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is a delayed-release tablet. In some embodiments, the capsule of the tablet-in-capsule is a delayed-release capsule. In some embodiments, one of the tablets of the tablet-in-tablet is a delayed-release tablet. In some embodiments, both of the tablets of the tablet-in-tablet are a delayed-release tablet. In some embodiments, the capsule of the beads-in-capsule is a delayed-release capsule. In some embodiments, the capsule of the spheres-in-capsule is a delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric coated tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric coated capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric coated tablet. In some embodiments, both of the tablets of the tablet-in -tablet are an enteric coated tablet. In some embodiments, the capsule of the beads-in-capsule is an enteric coated capsule. In some embodiments, the capsule of the spheres-in-capsule is an enteric coated capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric tablet. In some embodiments, both of the tablets of the tablet-in-tablet are an enteric tablet. In some embodiments, the capsule of the beads-in-capsule is an enteric capsule. In some embodiments, the capsule of the spheres-in-capsule is an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated caplet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated delayed release capsule, an enteric coated delayed release tablet,99KTS Docket No.: 116771-1539925-823WO1an enteric coated delayed release tablet-in-tablet, an enteric coated delayed release tablet-in-capsule, an enteric coated delayed release beads-in-capsule, or an enteric coated delayed release spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule, an enteric coated tablet, an enteric coated tablet-in-tablet, an enteric coated tablet-in-capsule, an enteric coated beads-in-capsule, or an enteric coated spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet-in-tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated spheres-in capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral administration in a subject in need thereof.

[0271] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), the enteric capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV). or Formula (V), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0272] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), the enteric coated capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.100KTS Docket No.: 116771-1539925-823WO1

[0273] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a delayed-release capsule. In some embodiments, the enteric capsule is further coated with an enteric coating. In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0274] In some embodiments, for a pharmaceutical composition disclosed herein, the enteric capsule is selected from a non-animal-based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsicTM drug delivery technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience. USA, etc.) can also be utilized for formulating enteric forms of oral solid dosage forms. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or pharmaceutical composition thereof or elagolix or pharmaceutical composition thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or elagolix or pharmaceutical compositions thereof are free flowing powders or micronized powders. In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is an enteric capsule. In some embodiments, the dosage form is an enteric coated capsule. In some embodiments, the dosage form is an enteric capsule, wherein the enteric capsule is further coated an enteric coating. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is a banded capsule. In some embodiments, the capsule is an enteric, seamless capsule. In some embodiments, the capsule is an enteric, banded capsule. In some embodiments, the capsule is an enteric coated, seamless capsule. In some embodiments, the capsule is an enteric coated, banded capsule. In some embodiments, the capsule is a Capsugel Enprotect capsule. In some embodiments, the Capsugel Enprotect capsule comprises HMPC-AS. In some embodiments, the Capsugel Enprotect capsule comprises HMPC. In some embodiments, the Capsugel Enprotect capsule comprises HMPC and HPMC-AS. In some embodiments, the capsule is an Eudracap enteric capsule. In some embodiments, the Eudracap enteric capsule comprises a methacrylic acid and ethyl acrylate copolymer. In some embodiments, the 101KTS Docket No.: 116771-1539925-823WO1Eudracap enteric capsule comprises EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D and EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC, EUDRAGIT® NM 30 D, EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC. In some embodiments, the pharmaceutical composition is a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a delay ed-release pharmaceutical composition.

[0275] In some embodiments, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability using intrinsically enteric capsule technology (for example, ENTRINSICT® Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.

[0276] In some embodiments, the enteric tablet is a hard tablet made with free-flowing powder of (Z)-endoxifen or a salt thereof In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of (Z)-endoxifen or a polymorph thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a polymorph thereof.

[0277] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition comprises a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes, including synthetic waxes, microcrystalline waxes, 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, and polyethylene glycol, and any combinations thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. In some embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose 102KTS Docket No.: 116771-1539925-823WO1acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, glyceryl mono-, di-tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylatemethacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylatemethacrylic acid copolymers, shellac, and cellulose acetate. In some embodiments, the pharmaceutical composition is a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a delayed-release pharmaceutical composition.

[0278] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises a sustained release agent. In some embodiments, the pharmaceutical composition is a sustained release pharmaceutical composition. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, protein-derived compounds, and any combinations thereof. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, and any combinations thereof. Examples of cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (HPMCP or Hypromellose phthalate), carboxyalkyl 103KTS Docket No.: 116771-1539925-823WO1celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (HPMCP or Hypromellose phthalate), carboxyalky l celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxy alkyl celluloses, hydroxy ethyl celluloses, hydroxypropyl celluloses, and hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos.2208, 2906, 2910). In some embodiments, the sustained release agent is selected from HPMC. In some embodiments, the sustained release agent is a pH sustained release agent. Examples of pH sustained release agents include, but are not limited to, acid insoluble polymers which become increasingly soluble and permeable above pH 5.0 but remaining impermeable below pH 5.0. Such controlled release polymers target upper small intestines and / or colon. Nonlimiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate buty rate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, including those available commercially from EVONIK® or ROHM® (e.g., EUDRAGIT® sustained release polymers EUDRAGIT® RL (high permeability), EUDRAGIT® RS (low permeability) and EUDRAGIT® NM 30D (low permeability )), and any combinations thereof. In some embodiments, the pH sustained release agent is selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, and acrylic acid-methylacrylic acid copolymers such as EUDRAGIT® sustained release polymers EUDRAGIT® RL, EUDRAGIT® RS, and EUDRAGIT® NM 30D. In some embodiments, the acid-insoluble polymers are selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®, from Eastman Chemical Co., Kingsport, TN, as a 30% dispersion). In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® L 100-55, EUDRAGIT® L30 D-55, EUDRAGIT® L 100, EUDRAGIT® L 100 12,5, EUDRAGIT® S100, EUDRAGIT® S 12, 5, EUDRAGIT® FS 30D, EUDRAGIT® E 100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® L 100-55, EUDRAGIT® RS, EUDRAGIT® RL,104KTS Docket No.: 116771-1539925-823WO1EUDRAGIT® NE, EUDRAGIT® NM 30 D, EUDRAGIT® S, EUDRAGIT® L and any combinations thereof. In some embodiments, the acid-insoluble polymers is selected from EUDRAGIT® S, EUDRAGIT® L, and a combination thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® L 100-55, EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combinations thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® L 100-55. EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combination thereof. In some embodiments, the pH sustained release agent is EUDRAGIT® L30 D-55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable. In some embodiments, the pharmaceutical composition is a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a sustained-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a delayed-release pharmaceutical composition. In some embodiments, the sustained release agent further comprises a delayed-release agent. In some embodiments, the sustained release agent is also a delayed-release agent. In some embodiments, the sustained release agent is also a delayed-release agent. In some embodiments, the pharmaceutical composition comprises a sustained release agent and a delayed-release agent.

[0279] In some embodiments, a pharmaceutical composition of the present disclosure may comprise one or more of pH-dependent polymers such as acid insoluble polymers. The pH-dependent polymers become increasingly permeable above pH 5.0, but are impermeable at a pH below 5.0. In contrast, acid insoluble polymers become soluble in neutral to weakly alkaline conditions. Such control release polymers target upper small intestines and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®, from Eastman Chemical Co., Kingsport, TN, as a 30% dispersion). Additional examples include EUDRAGIT® L 100-55, EUDRAGIT® L30 D-55, EUDRAGIT® L 100, EUDRAGIT® L 100 12,5, EUDRAGIT® S 100, EUDRAGIT® S 12,5, EUDRAGIT® FS 30 D, EUDRAGIT® E 100. EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L 100-55. EUDRAGIT® RS, EUDRAGIT® RL,105KTS Docket No.: 116771-1539925-823WO1EUDRAGIT® NE, and EUDRAGIT® NM are also useful polymers for the purpose of pharmaceutical compositions of the present disclosure. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® L30 D-55. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® FS 30 D. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® FS 30 D and EUDRAGIT® L30 D-55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable. In some embodiments, the pharmaceutical composition is a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a delay ed-release pharmaceutical composition.

[0280] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition further comprises a delayed-release agent. Examples of delayed-release agents include glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, are used, (e.g., as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available, for example DRCap (from Capsugel, USA) or Eudracap capsule. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours. Such delayed release oral dosage forms release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen or salts thereof or elagolix or salts thereof in the intestines (small intestines, large intestine / colon etc.). In some embodiments, the capsule is an Eudracap enteric capsule. In some embodiments, the Eudracap enteric capsule comprises a methacrylic acid and ethyl acrylate copolymer. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D and EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC, EUDRAGIT® NM 30 D, EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC. In some embodiments, the DRCap comprises HMPC. In some embodiments, the pharmaceutical composition is a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a delayed-release 106KTS Docket No.: 116771-1539925-823WO1pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a sustained release agent and a delay ed-release agent.

[0281] Commercially available delayed release capsules such as those available from Capsugel (e.g., VCAPS® Plus enteric capsules), can be used to prepared delayed release capsules. In some embodiments, the enteric delayed release capsules can be non-animal-based capsules, such as a hypromellose capsule (for example, commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, other enteric capsules made using XCELLODOSE®, DRCAPS®, Encap Colonic Delivery (ENCODE), and ENTRINSICTMdrug delivery technology from CAPSUGEL®). Other technologies known in the art and available commercially (for example, QUALICAPS®, USA, NutraScience, USA, etc.) for the formulating enteric forms of oral solid dosage forms can also be utilized. In some embodiments, the pharmaceutical compositions of the present disclosure may be encapsulated in a DRCAPS® enteric-resistant delayed release capsule. In some embodiments, the pharmaceutical compositions of the present disclosure may be encapsulated in a EudraCap® capsule. In some embodiments, the capsule is an enteric coated Eudracap capsule. In some embodiments, the capsule is an Eudracap capsule. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or salts thereof can be free flowing powders or micronized powders. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0282] In some embodiments, the enteric capsule is a non-animal based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsic™ drug delivery technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience, USA, etc.) for the formulating enteric forms of oral solid dosage forms are also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or a pharmaceutically acceptable salt thereof is filled neat into the capsule.

[0283] In some embodiments, for a pharmaceutical composition disclosed herein, a pharmaceutical composition comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition comprises an enteric capsule. In some embodiments, the pharmaceutical composition comprises an enteric capsule with an enteric coating. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising 107KTS Docket No.: 116771-1539925-823WO1from 10 mg to 80 mg (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 10 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 20 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 30 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 40 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 50 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 60 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 70 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 80 mg of (Z)-endoxifen per capsule.

[0284] For a modified-released pharmaceutical composition, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, may be used, (e.g., as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available, for example DRCaps made of hypromellose (HPMC) from Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours. In some embodiments, the modified-released pharmaceutical composition is a delayed-release pharmaceutical composition.

[0285] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition further comprises one or more excipients from 1% to 99%, 5% to 95%, from 5% to 90%, from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 50% to 60%, from 60% to 70%, from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the 108KTS Docket No.: 116771-1539925-823WO1composition comprises one or more excipients from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the composition comprises one or more excipient from 40% to 60% or from 60% to 80% by weight of the total composition. In some embodiments, the excipients are selected from bulking agents, binders, fillers, disintegrating agents, lubricants, glidants, control release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, or any combination thereof.

[0286] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a binder. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as com starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, methocel, WALOCEL® HM, LUVITEC®, caparolactam, AVICEL®, SMCC, UNI-PURE®, 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, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL® PH 101. AVICEL® PH 103 AVICEL® RC 581. AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, pharmaceutical composition further comprises a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH 103 and Starch 1500 LM.

[0287] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a filler. In some embodiments, the filler is selected from microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, a salt such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and any combinations thereof.109KTS Docket No.: 116771-1539925-823WO1

[0288] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III), Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises one or more fillers from 1% to 99%, 5% to 95%, from 5% to 90%, from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 50% to 60%, from 60% to 70%, from 70% to 80%, or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 70% to 80%, or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 40% to 60% or from 60% to 80% by weight of the total composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10% or from 10% to 20% by weight of the total pharmaceutical composition. In some embodiments, the fillers are selected from dextrose, sucrose, lactose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and any combination thereof. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0289] In some embodiments, for a pharmaceutical composition disclosed herein, one or more of a binder or a filler is present from 10% to 99% wt / wt of the pharmaceutical composition or the dosage form. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 99%, from 20% to 60%, from 25% to 55%, from 30% to 50%, from 35% to 60%, from 50% to 99% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 30% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 5% to 10% wt / wt of the total pharmaceutical 110KTS Docket No.: 116771-1539925-823WO1composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 30% to 60% wt / wt of the total pharmaceutical composition.

[0290] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a disintegrant. Disintegrants are used in the pharmaceutical composition to provide tablets that disintegrate when exposed to an aqueous environment. In some embodiments, disintegrants are selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum, xanthan gum, and resins. In some embodiments, the disintegrant is a superdisintegrant. In some embodiments, the superdisintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and any combinations thereof. In some embodiments, the superdisintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate. In some embodiments, the superdisintegrant is croscarmellose sodium. In some embodiments, the superdisintegrant is crospovidone. In some embodiments, the superdisintegrant is sodium starch glycolate. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. In some embodiments, the disintegrant is deep in the oral solid dosage form to delay disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[0291] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.1% to 10%, from 1.0% to 10%, from 1.5% to 10%, from 2.0% to 10%, from 2.5% to 10%, from 2.6% to 10%, from 2.8% to 10%, or from 2.9% to 10% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the formulation comprises a disintegrant from 0.1% to 8.0%, from 1.0% to 8.0%, from 1.5% to 8.0%, from 2.0% to 8.0%, from 2.5% to 8.0%, from 2.6% to 8.0%, from 2.8% to 8.0%, from 2.9% to 8.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.1% to 1.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical 111KTS Docket No.: 116771-1539925-823WO1composition comprises a disintegrant from 1% to 8% by weight of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 4% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.5% to 15% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 3% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 5% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 5% to 10% wt / wt of the pharmaceutical composition. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum, and xanthan gum, and any combination thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and any combinations thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, and any combination thereof. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and any combinations thereof. In some embodiments, the disintegrant is a superdisintegrant. In some embodiments, the superdisintegrant is selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and any combinations thereof. In some embodiments, the superdisintegrant is selected from croscarmellose sodium, crospovidone, and sodium starch glycolate. In some embodiments, the superdisintegrant is croscarmellose sodium. In some112KTS Docket No.: 116771-1539925-823WO1embodiments, the superdisintegrant is crospovidone. In some embodiments, the superdisintegrant is sodium starch glycolate.

[0292] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a lubricant. Lubricant that are 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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a SYLOID silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore. Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CABOSIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), silicon dioxide, Q7-9120 (Dow Coming), and any combination thereof. If used at all, lubricants are typically used in an amount of less than 1% wt / wt of the formulation, composition, or dosage forms into which they are incorporated. In some embodiments, the lubricant is from 0.1% to 1% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 0.5% to 2% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 1% to 3% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is selected from zinc stearate, magnesium stearate, potassium stearate, and any combinations thereof. In some embodiments, the lubricant is selected from zinc stearate, magnesium stearate, and potassium stearate.

[0293] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a plasticizer. Plasticizers may be added to control the softness or pliability of oral dosage forms such as shell of a capsule, caplet, or a tablet and thus, may improve the mechanical properties of the pH-sensitive materials of the capsules or coatings on the oral dosage forms. Suitable plasticizers, include, without limitation, petroleum oils (for e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates,113KTS Docket No.: 116771-1539925-823WO1sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In some embodiments, plasticizer is sorbitol, dimethyl isosorbide, or a glycerol. In some embodiments, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the pharmaceutical composition. In some embodiments, the plasticizer is triethyl citrate. In some embodiments, the plasticizer is triethyl citrate and the pharmaceutical composition comprises from about 1 wt% to about 10 wt% of tri ethyl citrate. In some embodiments, the plasticizer is triethyl citrate and the pharmaceutical composition comprises from about 1 wt% to about 5 wt% of triethyl citrate. In some embodiments, the plasticizer is triethyl citrate and the pharmaceutical composition comprises from about 5 wt% to about 10 wt% of tri ethyl citrate. In some embodiments, the plasticizer is triethyl citrate and the pharmaceutical composition comprises less than or equal to 5 wt% of triethyl citrate.

[0294] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic and the like. As an example, sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like. Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry', strawberry', pineapple, orange, cherry' and the like.

[0295] In some embodiments, for a pharmaceutical composition of the present disclosure, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients is selected from a bulking agent, a binder, a filler, a disintegrating agent, a lubricant, a glidant, a control release agent, an enteric coating, a film-forming agent, a plasticizer, a colorant, a sweetener, a flavoring agent, and any combinations thereof.

[0296] In some embodiments, for a pharmaceutical composition of the present disclosure, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipients. In some embodiments, the at least one pharmaceutically acceptable excipients is selected from a bulking agent, a binder, a filler, a disintegrating agent, a lubricant, a glidant, a control release agent, an enteric coating, a film-forming agent, a plasticizer, a colorant, a sweetener, a flavoring agent, and any combinations thereof.

[0297] Rapid achievement of steady-state plasma levels of (Z)-endoxifen is also highly desirable. In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV). a pharmaceutical composition is provided comprising the 114KTS Docket No.: 116771-1539925-823WO1compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition provides a plasma level of (Z)-endoxifen in a subject administered the composition or formulation. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen, a polymorph of (Z)-endoxifen, a solvate of (Z)-endoxifen, or is amorphous (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen or a polymorph of (Z)-endoxifen. In various aspects, steady state plasma levels are achieved from day 7 to day 21. In some aspects, the steady state plasma levels are achieved by day 7 upon daily administration of a composition disclosed herein.

[0298] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). Area under Curve AUC(0-24hr) ('‘AUC24hr”) describes the total exposure of the subject in need thereof to a drug from time of dosing (0 hr) over a 24-hour period. The pharmaceutical composition achieves mean (AUC24hr) of 150 hr*ng / mL to 600 hr*ng / mL of (Z)-endoxifen on Day 1 of initial (first) dose of the pharmaceutical composition including 1 mg to 4 mg of (Z)-endoxifen. In some embodiments, the compositions achieves mean AUC24hr of 400 hr*ng / mL to 2500 hr*ng / mL of (Z)-endoxifen on Day 21 of initial (first) dose of compositions including 1 mg to 4 mg of (Z)-endoxifen.

[0299] AUCo-inf is a time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum), describes the total exposure of the subject to a drug. The present disclosure provides that the exposure of a subject to endoxifen (AUCO-inf) is dose proportional. In some embodiments, AUCo-inf ranges from 200 hr*ng / mL to 10000 hr*ng / mL. In other embodiments, the AUCo-inf ranges from 300 hr*ng / mL to 8000 hr*ng / mL. In certain embodiments, the AUCo-inf ranges from 400 hr*ng / mL to 6000 hr*ng / mL over the dosing range of 1 mg to 4 mg of (Z)-endoxifen.

[0300] Dissolution of a formulated pharmaceutical composition disclosed herein is tested by the dissolution tests. In some embodiments, the dissolutions tests are dissolution tests of USP 711. In some embodiments, the formulated pharmaceutical composition is 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 some embodiments, the formulated pharmaceutical composition do not release endoxifen for at least 6 hours. In some embodiments, the formulated pharmaceutical composition do not release endoxifen or a salt thereof for at least 2 hours. In some embodiments, the formulated pharmaceutical 115KTS Docket No.: 116771-1539925-823WO1composition releases less than 10% of (Z)-endoxifen in the stomach after 2 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 40% of (Z)-endoxifen in the stomach after 4 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 50% of (Z)-endoxifen in the stomach after 6 hours after administration.

[0301] In some embodiments, for a formulated pharmaceutical composition disclosed herein, the formulated pharmaceutical composition provides that circulating (Z)-endoxifen released from the formulated pharmaceutical composition is cleared faster than tamoxifen. In some embodiments,, terminal elimination half-life of tamoxifen is 5-7 days, and peak concentration time of tamoxifen is approximately 5 hours post-dose. (Z)-endoxifen released from a formulated pharmaceutical composition disclosed herein provides a terminal elimination halflife ranging from 30 to 60 hours. This is significantly lower than tamoxifen. In some embodiments, the mean half-life ranges from 40 to 53 hours. The mean ratio of AUC24hr(Day 21) / AUC0-inf (Day 1) typically ranges from 0.7 to 1.2 for compositions including 1 mg to 4 mg (Z)-endoxifen, or a salt thereof. Thus, accumulation of (Z)-endoxifen released from a composition disclosed herein does not significantly vary over continued treatment.

[0302] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical releases at least 10% of endoxifen in the small intestine after 4 hours after administration. In some embodiments, the pharmaceutical composition releases at least 30% of endoxifen after 6 hours after administration. In some embodiments, the pharmaceutical composition releases at least 40% of endoxifen after 7 hours after administration. In some embodiments, the pharmaceutical composition releases at least 50% of endoxifen after 8 hours after administration. In some embodiments, the pharmaceutical composition releases at least 20% of endoxifen in the colon after 4 hours after administration. In some embodiments, the pharmaceutical composition releases at least 40% of endoxifen in the colon after 6 hours after administration. In some embodiments, the pharmaceutical composition releases at least 80% of endoxifen in the colon after 8 hours after administration.

[0303] Rapid absorption and bioavailability of the active agent are highly desirable. In an aspect, the present disclosure provides that the pharmaceutical compositions are formulated for certain pharmacokinetic (PK) properties. In some aspects, (Z)-endoxifen is released predominantly in the intestines (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of (Z)-endoxifen in the stomach for at least 6 hours as tested by a method of USP 711.116KTS Docket No.: 116771-1539925-823WO1In one aspect, rapid achievement of maximal and steady state plasma levels of (Z)-endoxifen is a particular aspect of the present disclosure. The present disclosure provides pharmaceutical compositions that achieve a maximal plasma level of (Z)-endoxifen ranging from 2 to 30 hours, from 3 to 20 hours, from 2 to 10 hours, or from 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of (Z)-endoxifen ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 6 to 8 hours after administration of a pharmaceutical composition disclosed herein.

[0304] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some aspects, the pharmaceutical compositions intended for oral use are prepared in solid or fluid unit dosage forms. In at least some embodiments, the pharmaceutical compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, and the like.

[0305] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.9. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.8. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.75. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.4 to 0.6. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.2 to 0.4. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.25 to 0.5. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.05 to 0.1. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. When the water activity (Aw) is less than 0.75, testing Total Aerobic Plate Count (TAC) and USP indicator organism is typically not necessary for solid formulations (see “Microbial Bioburden on Oral Solid Dosage Form,’" by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70). For other formulations, such as liquid or fluid formulations 117KTS Docket No.: 116771-1539925-823WO1with water activity of less than 0.75, Tests for Specified Microorganisms (S. aureus, Ps. aeruginosa, Salmonella, C. albicans, Clostridia, E. coli and Bile Tolerant Gram negative bacteria) in compliance with USP Guidelines Chapter 62 may not need to be performed. In some embodiments, pharmaceutical composition is formulated as a solid dosage. In some embodiments, the solid dosage is an oral solid dosage. In some embodiments, the solid dosage is a tablet or a capsule. In some embodiments, the solid dosage is a capsule. In some embodiments, the solid dosage is an enteric capsule. In some embodiments, the solid dosage is an enteric capsule with an enteric coating. An enteric capsule with an enteric coating is a capsule that is made of enteric materials that further comprises an enteric coating on the surface of the enteric capsule.

[0306] A (Z)-endoxifen composition of the present disclosure may be formulated as a pharmaceutical composition for topical or transdermal delivery. In some embodiments, a (Z)-endoxifen composition for topical or transdermal del i very may be formulated as a cream, a gel, a cream, an emulsion, a lotion, an ointment, a solution, a paste, a patch, or an oil. A (Z)-endoxifen composition for topical or transdermal delivery may be applied to the skin of a subject to treat a cancer (e.g., melanoma, esophageal cancer, or breast cancer). The topical or transdermal composition may be applied to a region of skin at or near a location of a caner. For example, a topical (Z)-endoxifen composition may be applied at the site of a cancerous skin growth in a subject with melanoma, thereby treating the melanoma. In another example, a topical (Z)-endoxifen composition may be applied to the skin around the throat of a subject with esophageal cancer, thereby treating the esophageal cancer. In some embodiments, a pharmaceutical composition for topical or transdermal administration may comprise (Z)-endoxifen, 2-(2-ethoxyethoxy)ethanol (e.g., TRANSCUTOL®), isopropanol, a fully saturated emollient triester (e.g.. CRODAMOL™ GTCC), and mineral oil.

[0307] In some embodiments, a pharmaceutical composition comprising (Z)-endoxifen (e.g., (Z)-endoxifen) may be formulated as a modified-release pharmaceutical composition. In some embodiments, the modified-release pharmaceutical composition is a sustained-release pharmaceutical composition. Sustained release agent present in a sustained release composition of the present disclosure may be any sustained release agent known in the art to slow the release of a hydrophobic drug such as (Z)-endoxifen or a polymorph or a salt thereof. Examples of sustained release agents include cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, and combinations thereof, polyvinyl pyrrolidine, and protein-derived compounds. Examples of 118KTS Docket No.: 116771-1539925-823WO1cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl celluloses (HPMC or hypromellose, for example Nos. 2208, 2906, 2910), carboxy alkyl celluloses, and carboxymethyl celluloses. In some embodiments, the at least one sustained release agent is a pH sustained release agent such as acid insoluble polymers which become increasingly soluble and permeable above pH 5.0 but remaining impermeable below pH 5.0. Such controlled release polymers target upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, including those available commercially from Evonik or Rohm ((EUDRAGIT® sustained release polymers, EUDRAGIT® RL (high permeability), Eudragit® RS (low permeability) and EUDRAGIT® NM 30D (low permeability)) - alone or in any combination thereof to achieve the desired permeability for sustained release. The viscosity of sustained release agents may be any viscosity suitable for sustained release of (Z)-endoxifen or a polymorph or a salt thereof. In some embodiments, the viscosity of the at least sustained release agent ranges from 1000 mPa.s to 150,000 mPa.s. In some embodiments, the sustained release delivery system includes one or more SR / release rate controlling agents with viscosity ranging from 1000 mPa.s to 10,000 mPa.s, from 10,000 mPa.s to 70,000 mPa.s, from 70,000 mPa.s to 150,000 mPa.s. or a combination thereof. In some embodiments, the present disclosure provides that the sustained release delivery system includes two or more sustained release agents. Each sustained release agent may have the same viscosity or a differing viscosity, for example one sustained release agent may have a viscosity ranging from 1000 mPa.s to 10,000 mPa.s, while other sustained release agent may have a viscosity of 10,000 mPa.s to 70,000 mPa.s or 70,000 mPa.s to 150,000 mPa.s. In some embodiments, the sustained release agent is HPMC / hypromellose (e.g., Nos. 2208, 2906, 2910). Hypromellose to be used in the present disclosure has a weight molecular average of 20,000-500,000. In some embodiments, hypromellose has a molecular weight average of generally 20,000 - 250,000. Hypromellose is commercially available from Dow Chemicals under the trade name METHOCELL™, for example, METHOCELL™ KI 00 (average molecular weight 26,000, 2% viscosity; 75,000 -140,000 mPa.s); METHOCELL™ KL5M (average molecular weight 120,000, 2% viscosity; 15,000 cP, 13275 - 24,780 mPa.s); METHOCELL™ K4M (average molecular weight 86,000, 2% viscosity; 4,000 cP, 75,000 to 140,000 mPa.s). Hypromellose of one grade may be used alone or in combination with another grade. In some embodiments, the pharmaceutical 119KTS Docket No.: 116771-1539925-823WO1composition comprises a sustained release agent and a delayed-release agent. In some embodiments, the pharmaceutical composition comprises a sustained release agent. In some embodiments, the pharmaceutical composition comprises a delayed-release agent.

[0308] When a sustained release composition showing release of (Z)-endoxifen or a polymorph or a salt thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours is obtained, in some embodiments the sustained release agent, such as Hypromellose, has an average molecular weight generally ranging from 15,000 to 140,000 Daltons. In at least one embodiment, the average molecular weight of 15,000 Daltons.

[0309] The amount of sustained release agent in the composition may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for 2 hours post-dose to protect the therapeutic agent from the acidic environment of the stomach and allow passage of the therapeutic agent through the stomach into the intestines and prolong such release for a period of 2 hours to 72 hours. The amount of sustained release agent in the composition may be any amount effective to provide a slower rate of release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof as compared with the reference product. In some embodiments, the amount of sustained release agent in the composition may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for at least 1 hour, at least 1.1 hours, at least 1.2 hours, at least 1.3 hours, at least 1.4 hours, at least 1.5 hours, at least 1.6 hours, at least 1.7 hours, at least 1.8 hours, at least 1.9 hours, at least 2 hours, at least 2.1 hours, at least 2.2 hours, at least 2.3 hours, at least 2.4 hours, or at least 2.5 hours post-dose, as compared with the reference product.

[0310] When a modified-release pharmaceutical composition, a delayed-release pharmaceutical composition, or a sustained release pharmaceutical composition shows percentage dissolution ranging from 0% to 35% at 3 hours, from 35% to 55% at 12 hours, and from 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid as a test medium, at least one sustained release agent, such as Hypromellose (HPMC), may generally be present in a sustained release composition of the present disclosure in amounts from 0.1% to 99%, from 0.1% to 90%, from 5% to 90%, from 5% to 80%, from 5% to 70%, and from 5% to 60% w / w of the sustained release composition. In some embodiments, the sustained release agent (e.g., a gum, an acrylic resin, methacrylic 120KTS Docket No.: 116771-1539925-823WO1acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, a protein-derived compound, a hydroxyalkyl cellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl celluloses, a carboxyalkyl cellulose, or, a carboxymethyl cellulose) may be present in an amount of from 10% to 40%, from 10% to 50%, from 10% to 60%, from 20% to 40%, from 20% to 50%, from 20% to 60%. In some embodiments, the sustained release agent may be present in an amount of at least 10%, at least 20%, at least 30%, or at least 40%. Such sustained release compositions of the present disclosure as disclosed herein release (Z)-endoxifen or polymorphs or salts thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours.

[0311] A pharmaceutical composition of the present disclosure may be for treatment of various cancers (e.g., medulloblastoma or glioblastoma). In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises an anti-cancer agent. In some embodiments, the anticancer agent is selected from bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, an antineoplastic, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine. eribulin, ixabepilone, an immune checkpoint inhibitor, a PD 1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, or an ATP-cassette binding protein inhibitor. In some embodiments, the anti-cancer agent is selected from bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, an antineoplastic, capecitabine. carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, proteinbound paclitaxel, vinorelbine, eribulin, ixabepilone, an immune checkpoint inhibitor, a PD1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, or an ATP-cassette binding protein inhibitor, and any combinations thereof. In some embodiments, the additional therapeutic agent comprises a selective serotonin reuptake inhibitor. In some embodiments, the selective serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, paroxetine, sertraline, vilazodone, and any combinations thereof. In some embodiments, the selective serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.121KTS Docket No.: 116771-1539925-823WO1

[0312] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated for oral, topical, rectal, intravenous, intra-arterial, parenteral, or transdermal administration, or for administration via inhalation. In some embodiments, a (Z)-endoxifen composition may be formulated as a sustained-release composition or a delayed release composition. In some embodiments, a (Z)-endoxifen composition may be formulated as a capsule or a tablet. In some embodiments, a (Z)-endoxifen composition may be formulated as a cream, a gel, a cream, an emulsion, a lotion, an ointment, a solution, a paste, a patch, or an oil.

[0313] In come embodiments, a pharmaceutical composition provided herein comprises from 1% to 99.99%, 5% to 95%, 5% to 90%, 10% to 80%, 15% to 70%, 20% to 60%, from 30% to 95%. from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of one or more pharmaceutically acceptable excipients. In some embodiments, the composition provided herein comprises 99.99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% by weight of one or more pharmaceutically acceptable excipients. In some embodiments, the composition provided herein comprises 99.99%, 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%. 89%, 88%, 87%, 86%, or 85% by weight of one or more pharmaceutically acceptable excipients. In some embodiments, the composition provided herein comprises 85%, 84%, 83%, 82%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, or 65% by weight of one or more pharmaceutically acceptable excipients. In some embodiments, the composition provided herein comprises 55%, 54%, 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, or 45% by weight of one or more pharmaceutically acceptable excipients. In some embodiments, the composition provided herein comprises 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, or 20% by weight of one or more excipients.

[0314] A pharmaceutical composition disclosed herein may comprise a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes, including synthetic waxes, microcrystalline waxes, 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, and polyethylene glycol; and 122KTS Docket No.: 116771-1539925-823WO1mixtures thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. In other embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax.

[0315] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (III) or Formula (IV), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (III). Formula (IV), or Formula (V). In some embodiments, the pharmaceutical composition is administered at a dose of 0.01 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 0.1 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 5 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 5 mg to 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 10 mg to 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 20 mg to 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 40 mg to 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 120 mg to 140 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 140 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 5 mg to 10 mg, 10 mg to 20 mg. 20 mg to 40 mg, and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 10 mg to 20 mg, 20 mg to 40 mg, and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg, 60 mg to 80 mg, 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 40 mg of (Z)-endoxifen. In some embodiments, the 123KTS Docket No.: 116771-1539925-823WO1pharmaceutical composition is administered at a dose of about 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 90 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 25 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 35 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 45 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 55 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 65 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 75 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the (Z)-endoxifen is a pharmaceutically acceptable salt of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen citrate. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen hydrochloride. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a polymorph form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a solvate form of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is orally administered. In some embodiments, the pharmaceutical composition is administered once every’ 1, 2, 3, 4, 5, 6, 7. 8, 9, or 10 days. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered once every 1, 2, or 3 days. In some embodiments, the pharmaceu...

Claims

1. CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising:(i) a compound of Formula (III):u3HHO O Formula (III)or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.2 wt% of an endoxifen-related impurity selected from an impurity having m / z 512, an impurity having m / z 716, a pharmaceutically acceptable salt of any one thereof, and any combination thereof.

2. The composition of claim 1, wherein:the impurity having m / z 512 is3. The composition of claim 1 or claim 2, wherein the composition further comprises:(iii) less than 0.09 wt% of an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

4. The composition of claim 3, wherein the composition comprises less than 0.06 wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330,379KTS Docket No.: 116771-1539925-823WO1an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

5. The composition of claim 3 or claim 4, wherein the composition comprises less than 0.04 wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof.

6. The composition of any one of claims 3 to 5, wherein the composition comprises a wt% of the endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 569, a pharmaceutically acceptable salt of any one thereof, and any combinations thereof that is below detection limits as determined by HPLC.

7. The composition of claim any one of claims 3 to 6, wherein:the impurity having m / z 300 isHOthe impurity having m / z 402 is selected from HOand380KTS Docket No.: 116771-1539925-823WO1the impurity having m / z 569 isThe composition of any one of claims 1 to 7, wherein the composition comprises:(i) a compound of Formula (III):or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.16 wt% of an impurity selected fromacceptable salt of any one thereof, and any combinations thereof.

9. The composition of any one of claims 1 to 8, wherein the composition comprises:(i) a compound of Formula (III):381KTS Docket No.: 116771-1539925-823WO1or a pharmaceutically acceptable salt thereof; and(ii) less than or equal to 0.1 wt% of an impurity selected fromacceptable salt of any one thereof and any combinations thereof.The composition of any one of claims 1 to 8, wherein the composition comprises:(i) a compound of Formula (III):or a pharmaceutically acceptable salt thereof;(ii) less than or equal to 0.16 wt% of an impurity selected from382KTS Docket No.: 116771-1539925-823WO1acceptable salt of any one thereof, and any combinations thereof; and(iii) less than 0.04 wt% of an endoxifen-related impurity selected from383KTS Docket No.: 116771-1539925-823WO1acceptable salt of any one thereof, and any combinations thereof.

11. The composition of any one of claims 1 to 10, wherein the composition comprises:(i) a compound of Formula (III):or a pharmaceutically acceptable salt thereof;(ii) less than or equal to 0.1 wt% of an impurity selected fromacceptable salt of any one thereof, and any combinations thereof; and (iii) less than 0.04 wt% of an endoxifen-related impurity selected from384KTS Docket No.: 116771-1539925-823WO1acceptable salt of any one thereof, and any combinations thereof.

12. The composition of any one of claims 1 to 11, wherein the compound of Formula (III) comprises greater than or equal to 95 wt%, greater than or equal to 96 wt%, greater than or equal to 97 wt%, greater than or equal to 98 wt%, or greater than or equal to 98.5 wt% of (Z)-endoxifen.

13. The composition of claim 12, wherein the (Z)-endoxifen is crystalline Form I of (Z)-endoxifen that is characterized as having X-ray composition diffraction (XRPD) pattern with peaks at about 16.8 ± 0.3° 2-Theta, about 17.1 ± 0.3° 2-Theta, and about 21.8 ± 0.3° 2-Theta as measured using Cu Ka radiation.

14. The composition of claim 13, wherein the crystalline Form I of (Z)-endoxifen is further characterized as having one additional XRPD peak selected from about 12.3 ± 0.3° 2-Theta, about 16.0 ± 0.3° 2-Theta, about 18.8 ± 0.3° 2-Theta, about 26.5 ± 0.3° 2-Theta, about 28.0 ± 0.3° 2-Theta, and about 29.0 ± 0.3° 2-Theta as measured using Cu Ka radiation.385KTS Docket No.: 116771-1539925-823WO115. The composition of any one of claims 1 to 12, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is selected from acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole. chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, napsylate, nitric, nitrate, oxalate, pamaoate (Embonate), pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

16. The composition of any one of claims 1 to 15, wherein the compound of Formula (III) comprises less than 3 wt% of (E)-endoxifen.

17. The composition of any one of claims 1 to 16. wherein the composition comprises less than 3000 ppm methanol, less than 5000 ppm of ethanol, less than 5000 ppm of acetone, less than 5000 ppm of isopropanol, less than 410 ppm of acetonitrile, less than 3000 ppm of ethyl acetate, less than 720 ppm of tetrahydrofuran, less than 520 ppm of 2-methyltetrahydrofuran, less than 5000 ppm of n-heptane, or any combinations thereof.

18. The composition of any one of claims 1 to 17, wherein the composition comprises less than 50 ppm methanol, less than 60 ppm of ethanol, less than 600 ppm of acetone, less than 3000 ppm of isopropanol, less than 30 ppm of acetonitrile, less than 2500 ppm of ethyl acetate, less than 500 ppm of tetrahydrofuran, less than 100 ppm of 2-methyltetrahydrofuran, less than 10 ppm of n-heptane, or any combinations thereof.

19. The composition of any one of claims 1 to 18, wherein the composition comprises less than 200 ppm of titanium, less than 130 ppm of zinc, or a combination thereof.

20. The composition of any one of claims 1 to 17, wherein the composition comprises less than 150 ppm of titanium, less than 10 ppm of zinc, or a combination thereof.386KTS Docket No.: 116771-1539925-823WO121. The composition of any one of claims 1 to 20, wherein the composition comprises less than 25 ppm of mesityl oxide.

22. The composition of any one of claims 1 to 21, wherein the composition comprises less than 5 ppm of mesityl oxide.

23. The composition of any one of claims 1 to 22. wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 3% relative to day 0.

24. The composition of any one of claims 1 to 23, wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in (E)-Endoxifen content (wt%) of no more than 1% relative to day 0.

25. The composition of any one of claims 1 to 24, wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage composition is characterized by an increase in water content (wt%) of no more than 1% relative to day 0 as determined by Karl Fischer titration.

26. The composition of any one of claims 1 to 25. wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH, wherein a storage stable composition is characterized by an increase in water content (wt%) of no more than 0.5% relative to day 0 as determined by Karl Fischer titration.

27. The composition of any one of claims 3 to 26, wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH. wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an 387KTS Docket No.: 116771-1539925-823WO1impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 1 wt% relative to day 0 as determined by HPLC.

28. The composition of any one of claims 3 to 30, wherein the composition is storage stable for a period of time selected from less than or equal to 3 months, less than or equal to 6 months, less than or equal to 9 months, less than or equal to 12 months, and less than or equal to 18 months at 25°C / 60% RH. wherein a storage composition is characterized by an increase in an endoxifen-related impurity selected from an impurity having m / z 300, an impurity having m / z 330, an impurity having m / z 402, an impurity having m / z 416, an impurity having m / z 511, an impurity having m / z 512, an impurity having m / z 569, an impurity having m / z 716, and any combinations thereof, of no more than 0.1 wt% relative to day 0 as determined by HPLC.

29. The composition of any one of claims 1 to 28, wherein the composition is a stable composition.

30. The composition of any one of claims 1 to 29. wherein the composition is a stable composition at 25°C / 60% RH.

31. A pharmaceutical composition comprising the composition of any one of claims 1 to 30, and at least one pharmaceutical acceptable excipient.

32. The pharmaceutical composition of claim 31, wherein the at least one pharmaceutical acceptable excipient is selected from microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and any combinations thereof.

33. The pharmaceutical composition of claim 31 or claim 32. wherein the pharmaceutical composition is a solid dosage form.

34. The pharmaceutical composition of claim 33, wherein the solid dosage form is selected from a capsule and a tablet.

35. The pharmaceutical composition of claim 33 or claim 34, wherein the solid dosage form is selected from an enteric capsule, an enteric-coated capsule, an enteric-coated enteric capsule, an enteric tablet, an enteric-coated tablet, enteric-coated enteric tablet.388KTS Docket No.: 116771-1539925-823WO136. The pharmaceutical composition of any one of claims 33 to 35, wherein the solid dosage form is selected from an enteric capsule, an enteric-coated capsule, and an enteric-coated enteric capsule.

37. The pharmaceutical composition of any one of claims 33 to 36, wherein the solid dosage form is selected from an enteric capsule and an enteric-coated capsule.

38. The pharmaceutical composition of any one of claims 33 to 37, wherein the solid dosage form is enteric capsule.

39. The pharmaceutical composition of any one of claims 33 to 38, wherein the solid dosage form comprises an enteric material.

40. The pharmaceutical composition of any one of claims 33 to 39, wherein the solid dosage form comprises hypromellose.

41. The pharmaceutical composition of any one of claims 33 to 40, wherein the pharmaceutical composition comprises from about 1 mg to about 80 mg of (Z)-endoxifen.

42. The pharmaceutical composition of any one of claims 33 to 41, wherein the pharmaceutical composition comprises from about 10 mg to about 40 mg of (Z)-endoxifen.

43. The pharmaceutical composition of any one of claims 33 to 42, wherein the pharmaceutical composition releases less than 1% of (Z)-endoxifen after 60 minutes in an acid buffer as determined by a dissolution test in accordance with USP <711>.

44. The pharmaceutical composition of any one of claims 33 to 43, wherein the pharmaceutical composition releases less than 1% or less than 6% of (Z)-endoxifen after 90 minutes in an acid buffer as determined by a dissolution test in accordance with USP <711>.

45. The pharmaceutical composition of any one of claims 33 to 44, wherein the pharmaceutical composition releases less than 55% of (Z)-endoxifen after 30 minutes in a pH 7 buffer as determined by a dissolution test in accordance with USP <711>.389KTS Docket No.: 116771-1539925-823WO146. The pharmaceutical composition of any one of claims 33 to 45, wherein the pharmaceutical composition releases less than 91% of (Z)-endoxifen after 60 minutes in a pH 7 buffer as determined by a dissolution test in accordance with USP <711>.

47. The pharmaceutical composition of any one of claims 33 to 46, wherein the pharmaceutical composition releases greater than 50% of (Z)-endoxifen after 30 minutes in a pH 7 buffer as determined by a dissolution test in accordance with USP <711>.

48. The pharmaceutical composition of any one of claims 33 to 47. wherein the pharmaceutical composition releases greater than 80% of (Z)-endoxifen after 60 minutes in a pH 7 buffer as determined by a dissolution test in accordance with USP <711>.

49. The pharmaceutical composition of any one of claims 33 to 48, wherein the pharmaceutical composition releases greater than or equal to 90% of (Z)-endoxifen after 90 minutes in a pH 7 buffer as determined by a dissolution test in accordance with USP <711>.

50. The pharmaceutical composition of any one of claims 33 to 49. wherein the pharmaceutical composition is a modified-release composition.

51. The pharmaceutical composition of any one of claims 33 to 50, wherein the pharmaceutical composition is a delayed-release composition.

52. A sustainable and scalable method of preparing a compound of Formula (IV):comprising:(a) subjecting a compound of Formula (III):390KTS Docket No.: 116771-1539925-823WO1to a first crystallization in an environmentally optimal amount of ethyl acetate to form a first solid and a first mother liquor;(b) concentrating the first mother liquor to form a concentrated mother liquor; (c) subjecting the concentrated mother liquor to a second crystallization in an environmentally optimal amount of isopropyl alcohol and acetone to form a second solid and a second mother liquor; and(d) collecting the second solid, wherein the second solid comprises the compound of Formula (IV).

53. The method of claim 52, wherein the first crystallization comprises heating the compound of Formula (III) in the environmentally optimal amount of ethyl acetate to a temperature from about 45 °C to about 55 °C.

54. The method of claim 52 or claim 53, wherein the first crystallization comprises heating the compound of Formula (III) in about 11 wt to about 13 wt of ethyl acetate at a temperature from about 45°C to about 55°C.

55. The method of any one of claims 52 to 54, wherein the first crystallization comprises heating the compound of Formula (III) in about 11 wt to about 13 wt of ethyl acetate at atemperature from about 45°C to about 55°C for about 1 hour to about 1.5 hours.

56. The method of any one of claims 52 to 55, wherein the first crystallization further comprises cooling the compound of Formula (III) in the ethyl acetate to a temperature from about -5°C to about 0°C.

57. The method of any one of claims 52 to 56. wherein the first crystallization further comprises cooling the compound of Formula (III) in the ethyl acetate to a temperature from about -5°C to about 0°C for at least 4 hours.

58. The method of any one of claims 52 to 57, wherein the first crystallization comprises heating the compound of Formula (III) in about 11 wt to about 13 wt of ethyl acetate at atemperature from about 45°C to about 55°C for about 1 hour to about 1.5 hours and cooling the compound of Formula (III) in the ethyl acetate to a temperature from about -5 °C to about 0°C for at least 4 hours.391KTS Docket No.: 116771-1539925-823WO159. The method of any one of claims 52 to 58, wherein the method further comprises filtering the first mother liquor.

60. The method of claim 59, wherein the filtering removes (E)-endoxifen.

61. The method of any one of claims 52 to 60, wherein the concentrated mother liquor comprises about 3 wt of ethyl acetate.

62. The method of any one of claims 52 to 61, wherein the concentrated mother liquor comprises the compound of Formula (III) with an E / Z ratio of less than 0.25.

63. The method of any one of claims 52 to 62, wherein the concentrated mother liquor is subjected to a solvent swap comprising adding an environmentally optimal amount of isopropyl alcohol to the concentrated mother liquor to afford a diluted solution and concentrating the diluted solution.

64. The method of any one of claims 52 to 63, wherein the concentrated mother liquor is subj ected to a solvent swap comprising adding about 10 wt of isopropyl alcohol to the concentrated mother liquor to afford a diluted solution and concentrating the diluted solution until the diluted solution comprises less than 1 wt% of ethyl acetate.

65. The method of any one of claims 52 to 64, wherein the second crystallization comprises heating the concentrated mother liquor in the environmentally optimal amount of isopropyl alcohol and acetone to a temperature from about 45°C to about 55°C.

66. The method of any one of claims 52 to 65, wherein the second crystallization comprises heating the concentrated mother liquor in about 1.2 wt to about 2.4 wt of isopropyl alcohol and about 1.5 wt acetone to a temperature from about 45°C to about 55°C.

67. The method of any one of claims 52 to 66, wherein the second crystallization comprises dissolving the concentrated mother liquor in about 1.2 wt to about 2.4 wt of isopropyl alcohol and about 1.5 wt acetone to afford a diluted solution; heating the diluted solution to about 45°C to about 55°C over a period of time of at least 1 hour; and stirring the diluted solution at about 45°C to about 55°C for at least 2 hours.392KTS Docket No.: 116771-1539925-823WO168. The method of any one of claims 52 to 67, wherein the second crystallization further comprises cooling the concentrated mother liquor to about -5°C to about 5°C from about 45°C to about 55°C.

69. The method of any one of claims 52 to 68, wherein the second crystallization further comprises cooling the concentrated mother liquor in about 1.2 wt to about 2.4 wt of isopropyl alcohol and about 1.5 wt acetone to about -5°C to about 5°C from about 45°C to about 55°C.

70. The method of any one of claims 52 to 69, wherein the second crystallization further comprises cooling the concentrated mother liquor in about 1.2 wt to about 2.4 wt of isopropyl alcohol and about 1.5 wt acetone to to about -5°C to about 5°C from about 45°C to about 55°C over a period of time of at least 4 hours; and stirring the diluted solution at about -5°C to about 5°C for at least 6 hours.

71. The method of any one of claims 52 to 70, wherein the second crystallization comprises dissolving the concentrated mother liquor in about 2 wt of isopropyl alcohol and about 1.5 wt of acetone to afford a diluted mother liquor; heating the diluted mother liquor to a temperature from about 45°C to 55°C for at least 3 hours; and cooling the diluted mother liquor to -5°C to 5°C from about 45°C to 55°C for at least 10 hours.

72. The method of any one of claims 52 to 71. wherein collecting the second solid comprises filtering the second solid from the second mother liquor.

73. The method of any one of claims 52 to 72, wherein collecting the second solid comprises drying the second solid at a temperature of not more than 80 °C.

74. The method of any one of claims 52 to 73, wherein the second solid comprises less than or equal to 3 wt% (E)-endoxifen.

75. The method of any one of claims 52 to 74, wherein the second solid comprises greater than or equal to 96 wt% (Z)-endoxifen.

76. The method of any one of claims 52 to 75, wherein the second solid comprises crystalline Form I of (Z)-endoxifen. crystalline Form V of (Z)-endoxifen, or a combination thereof.393KTS Docket No.: 116771-1539925-823WO177. The method of claim 76, wherein the (Z)-endoxifen is crystalline Form I of (Z)-endoxifen that is characterized as having X-ray composition diffraction (XRPD) pattern with peaks at about 16.8 ± 0.3° 2-Theta, about 17.1 ± 0.3° 2-Theta, and about 21.8 ± 0.3° 2-Theta as measured using Cu Ka radiation.

78. The method of claim 77, wherein the crystalline Form I of (Z)-endoxifen is further characterized as having one additional XRPD peak selected from about 12.3 ± 0.3° 2-Theta, about 16.0 ± 0.3° 2-Theta, about 18.8 ± 0.3° 2-Theta. about 26.5 ± 0.3° 2-Theta, about 28.0 ± 0.3° 2-Theta, and about 29.0 ± 0.3° 2-Theta as measured using Cu Ka radiation.

79. The method of claim 76, wherein the (Z)-endoxifen is crystalline Form V of (Z)-endoxifen that is characterized as having X-ray composition diffraction (XRPD) pattern with peaks at about 8.9± 0.3° 2-Theta, 12.5± 0.3° 2-Theta, and 19.6± 0.3° 2-Theta, as measured by Cu Ka radiation.

80. The method of claim 79, wherein the crystalline Form V of (Z)-endoxifen is further characterized as having one additional XRPD peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Kot radiation.

81. The method of any one of claims 52 to 80, wherein the second solid comprises less than 25 ppm or less than 0.1% of mesityl oxide.

82. The method of any one of claims 52 to 81, wherein the second solid comprises less than or equal to 1 wt% of an impurity selected from an impurity having m / z of 300, an impurity having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 512, an impurity having m / z of 569, an impurity having m / z of 716, and any combinations thereof.

83. The method of any one of claims 52 to 82, wherein the second solid comprises less than or equal to 0.2 wt% of an impurity selected from an impurity’ having m / z of 300, an impurity having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 512, an impurity having m / z of 569, an impurity having m / z of 716, and any combinations thereof.

84. The method of any one of claims 52 to 83, wherein the second solid comprises less than or equal to 0.16 wt% of an impurity having m / z 716.394KTS Docket No.: 116771-1539925-823WO185. The method of any one of claims 52 to 84, wherein the second solid comprises less than or equal to 0.1 wt% of an impurity having m / z 716.

86. The method of any one of claims 52 to 85, wherein the second solid comprises:less than or equal to 0.1 wt% of an impurity selected from an impurity having m / z of 716, an impurity having m / z of 512, and a combination thereof; andless than 0.09 wt% of an impurity selected an impurity having m / z of 300, an impurity having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 569, an impurity having m / z of 716, and any combinations thereof.

87. The method of any one of claims 52 to 86, wherein the second solid comprises less than 0.09 wt% of an impurity selected from an impurity having m / z of 300, an impurity having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 512, an impurity having m / z of 569, and any combinations thereof.

88. The method of any one of claims 52 to 87, wherein the second solid comprises less than 0.04 wt% of an impurity selected from an impurity having m / z of 300, an impurity having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 512, an impurity having m / z of 569, and any combinations thereof.

89. The method of any one of claims 52 to 88, wherein the second solid comprises a wt% of an impurity selected from an impurity having m / z of 300, an impurity’ having m / z of 330, an impurity having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 512, an impurity having m / z of 569, and any combinations thereof that is below detection limits as determined by HPLC.

90. The method of any one of claims 52 to 89, wherein the second solid comprises:less than or equal to 0.1 wt% of an impurity selected from an impurity having m / z of 716, an impurity having m / z of 512, and a combination thereof; andless than 0.03 wt% of an impurity selected an impurity having m / z of 300, an impurity having m / z of 330, an impurity’ having m / z of 402, an impurity having m / z of 416, an impurity having m / z of 511, an impurity having m / z of 569, an impurity having m / z of 716, and any combinations thereof.395KTS Docket No.: 116771-1539925-823WO191. The method of any one of claims 52 to 90, wherein the method further comprises suspending the compound of Formula (III) in an environmentally optimal amount of aqueous hydrochloric acid at a temperature from about 55°C to about 75°C prior to the first crystallization.

92. The method of any one of claims 52 to 91, wherein the method further comprises suspending the compound of Formula (III) in about 2 wt to about 3 wt of aqueous hydrochloric acid and about 9 wt to about 11 wt of ethyl acetate at a temperature from about 55°C to about 75°C for about 12 hours to about 15 hours prior to the first crystallization.

93. The method of claim 91 or claim 92, wherein the method further comprises suspending the compound of Formula (III) in an environmentally optimal amount of aqueous sodium hydroxide prior to the first crystallization.

94. The method of claim 91 or claim 92, wherein the method further comprises adding aqueous sodium hydroxide to the compound of Formula (III) and the aqueous hydrochloric acid to obtain a pH great than 12.

95. The method of any one of claims 52 to 90, wherein the method further comprises a preparative step comprising:(i) suspending the compound of Formula (III) in about 2 wt to about 3 wt of aqueous hydrochloric acid and about 9 wt to about 11 wt of ethyl acetate and heating to a temperature of about 65 °C to about 75 °C for about 12 hours to about 15 hours; (ii) cooling the compound of Formula (III) in the aqueous inorganic acid and ethyl acetate to a temperature of about 0°C to about 10°C;(iii) adding aqueous sodium hydroxide to the compound of Formula (III) to obtain a pH of greater than 12;(iv) adding about 4 wt of ethyl acetate to the compound of Formula (III);(v) adding aqueous sodium chloride to the compound of Formula (III) and extracting an organic layer comprising the compound of Formula (III);(vi) concentrating the organic layer to yield a concentrated organic layer; and(vii) adding about 9 wt of ethyl acetate to the concentrated organic layer,wherein steps (i) through (vii) are performed in an inert atmosphere prior to the first cry stalli zation.396KTS Docket No.: 116771-1539925-823WO196. The method of any one of claims 52 to 95, wherein the method further comprises slurrying the compound of Formula (IV) in an environmentally optimal amount of ethyl acetate to yield crystalline Form I of the compound of Formula (IV).

97. The method of any one of claims 52 to 96, wherein the method further comprises slurrying the compound of Formula (IV) in an about 3 wt of ethyl acetate to yield crystalline Form I of the compound of Formula (IV). 2.7 wt98. The method of any one of claims 52 to 97, wherein the method further comprises slurrying the compound of Formula (IV) in an about 3 wt of ethyl acetate to convert a mixture of crystalline Form I and cry stalline Form V of the compound of Formula (IV) to crystalline Form I of the compound of Formula (IV).

99. The method of any one of claims 52 to 98, wherein the compound of Formula (III) is prepared by subjecting a compound of Formula (II):Formula (II),and propiophenone to a McMurry reaction, thereby preparing the compound of Formula (III), wherein the method does not result in an exothermic event having an enthalpy of greater than 540 J / g as measured by differential scanning calorimetry.

100. The method of claim 99, wherein the McMurry reaction comprises contacting the compound of Formula (II) and the propiophenone with zinc and titanium (IV) chloride.

101. The method of claim 99 or claim 100, wherein the McMurry reaction comprises contacting the compound of Formula (II) and the propiophenone with about 0.8 equiv. to about 1 equiv. of zinc and about 1.2 equiv. to about 1.4 equiv. of titanium (IV) chloride.

102. The method of claim 100 or claim 101, wherein the zinc, the titanium (IV) chloride, or a combination thereof are dissolved or suspended in an environmentally optimal amount of tetrahydrofuran.397KTS Docket No.: 116771-1539925-823WO1103. The method of any one of claims 100 to 102, wherein the zinc, the titanium (IV) chloride, or a combination thereof is dissolved or suspended in about 8 wt to about 10 wt of tetrahydrofuran.

104. The method of any one of claims 100 to 103, wherein the zinc is dissolved or suspended in an environmentally optimal amount of tetrahydrofuran at a temperature of about -5°C to about 5°C.

105. The method of any one of claims 100 to 104, wherein the zinc is dissolved or suspended in about 8 wt to about 10 wt of tetrahydrofuran at a temperature of about -5°C to about 5°C.

106. The method of any one of claims 100 to 105, wherein the titanium (IV) chloride is added to the zinc dissolved or suspended the tetrahydrofuran.

107. The method of any one of claims 100 to 106, wherein the titanium (IV) chloride is added to the zinc dissolved or suspended in about 8 wt to about 10 wt of tetrahydrofuran.

108. The method of any one of claims 100 to 107, wherein the zinc and the titanium (IV) chloride are heated to a temperature of about 55°C to about 75°C.

109. The method of any one of claims 100 to 108, wherein the zinc and the titanium (IV) chloride are heated to a temperature of about 55°C to about 75°C for about 1 hours to about 3 hours.

110. The method of any one of claims 100 to 109, wherein the propiophenone is from about 0.7 equiv. to 1 equiv. of propiophenone.

111. The method of any one of claims 100 to 110, wherein the compound of Formula (II) is dissolved in about 5 wt to about 7 wt of tetrahydrofuran.

112. The method of any one of claims 100 to 111, wherein the McMurry reaction comprises heating a suspension comprising the compound of Formula (II), propiophenone, zinc, and titanium (IV) chloride to a temperature of not less than 60 °C.

113. The method of any one of claims 100 to 112, wherein the McMurry reaction comprises heating a suspension comprising the compound of Formula (II), the propiophenone, the zinc, and the titanium (IV) chloride to a temperature of not less than 60 °C for about 8 hours.398KTS Docket No.: 116771-1539925-823WO1114. The method of any one of claims 100 to 113, wherein the method further comprises performing one or more phase separations with an environmentally optimal amount of aqueous acid, aqueous base, or a combination thereof to form an organic layer.

115. The method of any one of claims 100 to 114, wherein the method further comprises performing one or more phase separations in an environmentally optimal amount of aqueous hydrochloric acid and one or more phase separations in an environmentally optimal amount of aqueous sodium hydroxide.

116. The method of any one of claims 100 to 115, wherein the method further comprises performing one or more phase separations with an environmentally optimal amount of aqueous acid, aqueous base, or a combination thereof to form an organic layer and washing the organic layer with an environmentally optimal amount of aqueous sodium hydroxide, aqueous sodium chloride, or a combination thereof.

117. The method of claim 99, wherein the McMurry reaction comprises:(a) dissolving or suspending about 0.8 equiv. to about 1 equiv. of zinc in about 8 wt to about 10 wt of tetrahydrofuran at a temperature from about -5 °C to about 5 °C; (b) adding about 1.3 equiv. to about 1.5 equiv. of titanium (IV) chloride to the zinc; (c) heating the zinc and titanium (IV) chloride to a temperature from about 55 °C to about 70 °C for about 2 hours;(d) adding the compound of Formula (II) and about 0.7 equiv. to about 0.9 equiv. of propiophenone to the zinc and titanium (IV) chloride to form a suspension; (e) heating the suspension to a temperature of not less than 60 °C for about 2 hours to about 10 hours;(f) distilling tetrahydrofuran from the suspension and adding 2-methyltetrahydrofuran to the suspension to reach 10 wt of total volume;(g) cooling the suspension to a temperature of about 5 °C to about 15 °C;(h) performing one or more phase separations with from about 3 wt to 4 wt of 35% aqueous hydrochloric acid, from about 2 wt to 3 wt of 16% aqueous sodium hydroxide, or a combination thereof to form an organic layer;(i) washing the organic layer with from about 2 wt to 3 wt of 16% aqueous sodium hy droxide, from about 3 to 5 wt 25% aqueous sodium chloride, or a combination thereof;399KTS Docket No.: 116771-1539925-823WO1(j ) concentrating the organic layer to form a concentrated organic layer;(k) adding from about 8 wt to about 16 wt of acetonitrile to the concentrated organic layer;and(l) removing the acetonitrile from the concentrated organic layer to yield a solid comprising the compound of Formula (III).

118. The method of any one of claims 99 to 117, wherein the compound of Formula (II) is prepared by subjecting a compound of Formula (I):OH jl J { zlO" X^ X< X / N XFormula (I),to a demethylation reaction, thereby producing the compound of Formula (II),wherein the demethylation reaction is performed inside a suitable reactor to normalize heat flow to a value of less than 15 W / kg.

119. The method of claim 118, wherein the demethylation reaction comprises suspending the compound of Formula (I) in an environmentally optimal amount of anhydrous tetrahydrofuran.

120. The method of claim 118 or claim 119, wherein the demethylation reaction comprises suspending the compound of Formula (I) in about 7 wt to about 9 wt of anhydrous tetrahydrofuran.

121. The method of any one of claims 118 to 120, wherein the demethylation reaction comprises contacting the compound of Formula (I) with diisopropylethylamine.

122. The method of any one of claims 118 to 121, wherein the demethylation reaction comprises contacting the compound of Formula (I) with about 0.8 equiv. to 1 equiv. of diisopropylethylamine.

123. The method of any one of claims 118 to 122, wherein the demethylation reaction comprises contacting the compound of Formula (I) with 1 -chloroethyl chloroformate.

124. The method of any one of claims 118 to 123, wherein the demethylation reaction comprises contacting the compound of Formula (I) with about 1 equiv. to 1.5 equiv. of 1 -chloroethyl chloroformate.400KTS Docket No.: 116771-1539925-823WO1125. The method of any one of claims 118 to 124, wherein the demethylation reaction comprises heating the compound of Formula (I) and the diisopropylethylamine to a temperature of about 60 °C to about 70 °C.

126. The method of any one of claims 118 to 125, wherein the demethylation reaction comprises heating the compound of Formula (I), the 1 -chloroethyl chloroformate, and the diisopropylethylamine to a temperature of about 60 °C to about 70 °C.

127. The method of any one of claims 118 to 126, wherein the demethylation reaction comprises heating the compound of Formula (I), the 1 -chloroethyl chloroformate, and the diisopropylethylamine to about 60 °C for about 8 hours to about 12 hours.

128. The method of claim 118, wherein the demethylation comprises:(a) suspending the compound of Formula (I) in about 8 wt of anhydrous tetrahydrofuran; (b) adding about 0.9 equiv. to 1 equiv. of diisopropylethylamine to the compound of Formula (I) and heating to about 60°C;(c) adding about 1 equiv. to about 1.5 equiv. of 1 -chloroethyl chloroformate dropwise to the compound of Formula (I) and the diisopropylethylamine over a period of time from about 120 minutes to about 180 minutes and heating at about 60°C for about 8 hours; (d) adding about 5 wt of methanol to the compound of Formula (I), the 1-chloroethyl chloroformate, and the diisopropylethylamine over a period time of not less than 3 hours at a temperature from about 60 °C to about 70 °C;(e) adding about 2 wt to about 3 wt of 35% aqueous hydrochloric acid over a period of time of not less than two hours, followed by adding an environmentally optimal amount of aqueous sodium hydroxide to achieve a pH from about 13 to about 13.5;(f) extracting the compound of Formula (II) with about 3 wt to 4 wt of ethyl acetate to form an organic layer and an aqueous layer, separating the organic layer from the aqueous layer, adding about 0.4 wt 35% aqueous hydrochloric acid to reach a pH from about 9 to about 9.5, separating the organic layer from the aqueous layer, and cooling the organic layer to a temperature from about -5°C to about 5°C to obtain a solid, collecting the solid, and washing the solid with about 3 wt of water:(g) slurrying the solid with about 3 wt water and about 0.8 wt of isopropanol and collecting the slurried solid;401KTS Docket No.: 116771-1539925-823WO1(h) washing the slurried solid with about 1 wt of water to obtain a washed solid and repeating step (g); and(i) drying the washed solid comprising the compound of Formula (II) at a temperature of not more than 60 °C.

129. A method of administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51.

130. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51 to the subject in need thereof, thereby treating the disease or disorder in the subject in need thereof.

131. A method of treating an ERα-mediated disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51 to the subject in need thereof, thereby treating the ERα-mediated disease or disorder in the subject in need thereof.

132. A method of inhibiting estrogen receptor alpha (ERa) in a subject in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51, thereby inhibiting estrogen receptor alpha (ERa) in the subject in need thereof.

133. A method of treating a PKCβ1-mediated disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51, thereby treating a PKCβ1-mediated disease or disorder in the subject in need thereof.

134. A method of inhibiting PKCβ1 in a subject in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 30 or the pharmaceutical composition of any one of claims 31 to 51, thereby inhibiting PKCβ1 in the subject in need thereof.402KTS Docket No.: 116771-1539925-823WO1135. The method of any one of claims 129, 132, or 134, wherein the subject in need thereof has a disease or disorder.

136. The method of any one of claims 129 to 135. wherein the subject in need thereof is characterized as having a tamoxifen-refractory' disease or disorder137. The method of any one of claims 129 to 136, wherein the subject in need thereof is characterized as having gynecomastia.

138. The method of any one of claims 129 to 137, wherein the subject in need thereof is characterized as being at risk of having gy necomastia.

139. The method of claim of 130 or claim 135, wherein the disease or disorder is selected from a cancer, a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, and any combinations thereof140. The method of any one of claims 131 or 136 to 138, wherein the ERα-mediated disease or disorder is selected from a cancer, a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, and any combinations thereof.

141. The method of any one of claims 133 or 136 to 138, wherein the PKCβ1-mediated disease or disorder is selected from a cancer, a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, and any combinations thereof.

142. The method of any one of claims 139 to 141, wherein the cancer is selected from breast cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, melanoma, colorectal cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, prostate cancer, cholangiocarcinoma, and any combinations thereof.

143. The method of claim 142. wherein the breast cancer is selected from triple negative breast cancer, ER+ breast cancer, ductal carcinoma in situ, lobular carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, and any combinations thereof.403KTS Docket No.: 116771-1539925-823WO1144. The method of any one of claims 139 to 141, wherein the hormone-dependent breast disorder is selected from benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, and any combinations thereof145. The method of any one of claims 139 to 141, wherein the hormone-dependent reproductive tract disorder is selected from is selected from precocious puberty, McCune-Albright Syndrome, and a combination thereof.

146. The method of any one of claims 129, 132, 134 or 136, wherein the subject in need thereof has a mental disorder, a mood disorder, or a combination thereof.

147. The method of claim 130, wherein the disease or disorder is selected from a mental disorder, a mood disorder, and any combinations thereof.

148. The method of claim 131 or claim 136, wherein the ERα-mediated disease or disorder is selected from a mental disorder and a mood disorder.

149. The method of claim 133 or claim 136, wherein the PKCβ1-mediated disease or disorder is selected from a mental disorder and a mood disorder.

150. The method of any one of claims 146 to 149, wherein the mood disorder is selected from depression, mania, hypomania, and a bipolar disorder.

151. The method of claim 150, wherein the depression is selected from major depressive disorder, dysthymia, and atypical depression.

152. The method of claim 150, wherein the bipolar disorder is selected from bipolar I disorder, bipolar II disorder, rapid cycling bipolar disorder, and any combinations thereof.

153. The method of claim 150 or claim 152, wherein the bipolar disorder comprises mania.

154. The method of claim 150 or claim 152, wherein the bipolar disorder comprises hypomania.

155. The method of any one of claims 146 to 149, the mental disorder is a psychotic disorder.404KTS Docket No.: 116771-1539925-823WO1156. The method of claim 155, the psychotic disorder is selected from a schizophrenic disorder, a schizoaffective disorder, a schizophreniform disorder, and any combinations thereof.

157. The method of any one of claims 146 to 156, wherein the subject in need thereof has depression.

158. The method of any one of claims 146 to 157, wherein the subject in need thereof has depressive episodes.

159. The method of any one of claims 146 to 156, wherein the subject in need thereof has a risk of depression.

160. The method of any one of claims 146 to 156 or 159, wherein the subject in need thereof has a risk of depressive episodes.

161. The method of any one of claims 146 to 160, wherein the subject in need thereof has manic episodes.

162. The method of any one of claims 129 to 161, wherein the administering is oral administering.

163. The method of any one of claims 129 to 162, wherein the therapeutically effective amount is administered once daily or twice daily.

164. The method of any one of claims 129 to 163, wherein the therapeutically effective amount is administered once daily.

165. The method of any one of claims 129 to 164. wherein the therapeutically effective amount is the amount of the composition or the pharmaceutical composition that comprises from about 10 mg to about 80 mg of (Z)-endoxifen.

166. The method of any one of claims 129 to 165. wherein the therapeutically effective amount is the amount of the composition or the pharmaceutical composition that comprises from about 10 mg to about 60 mg of (Z)-endoxifen.405KTS Docket No.: 116771-1539925-823WO1167. The method of any one of claims 129 to 166, wherein the therapeutically effective amount is the amount of the composition or the pharmaceutical composition that comprises about 10 mg, about 20 mg. about 40 mg. or about 60 mg of (Z)-endoxifen.406KTS Docket No.: 116771-1539925-823WO1

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