Compositions of (z)-endoxifen and methods of enrichment thereof

A composition comprising a crystalline form of a compound of Formula (III):

• wherein the crystalline form of the compound of Formula (III) comprises:
• (a) Form IV as characterized by an x-ray powder diffraction pattern comprising major peaks at 4.7±0.3° 2θ, 23.3±0.3° 2θ, and 13.6±0.3° 2θ;
• (b) Form V as characterized by x-ray powder diffraction pattern comprising major peaks at 12.5±0.3° 2θ, 19.6±0.3° 2θ, and 8.9±0.3° 2θ;
• (c) Form VI as characterized by x-ray powder diffraction pattern comprising major peaks at 9.9±0.3° 2θ, 13.4±0.3° 2θ, and 13.7±0.3° 2θ;
• (d) Form VII as characterized by x-ray powder diffraction pattern comprising major peaks at 20.0±0.3° 2θ, 22.6±0.3° 2θ, and 10.6±0.3° 2θ;
• (e) Form VIII as characterized by x-ray powder diffraction pattern comprising major peaks at 4.8±0.3° 2θ, 18.9±0.3° 2θ, and 9.5±0.3° 2θ;
• (f) Form IX as characterized by x-ray powder diffraction pattern comprising major peaks at 19.0±0.3° 2θ, 12.9±0.3° 2θ, and 15.9±0.3° 2θ;
• (g) Form X as characterized by x-ray powder diffraction pattern comprising major peaks at 7.2±0.3° 2θ, 14.3±0.3° 2θ, 18.7±0.3° 2θ, 21.5±0.3° 2θ, and 22.7±0.3° 2θ;
• (h) Form XI as characterized by x-ray powder diffraction pattern comprising major peaks at 14.0±0.3° 2θ, 17.7±0.3° 2θ, 11.9±0.3° 2θ, 18.4±0.3° 2θ, 23.9±0.3° 2θ, 17.3±0.3° 2θ, 21.8±0.3° 2θ, 20.8±0.3° 2θ, and 23.0±0.3° 2θ;
• (i) Form XII as characterized by x-ray powder diffraction pattern comprising major peaks at 12.5±0.3° 2θ, 15.6±0.3° 2θ, and 19.0±0.3°2θ;
• (j) Form XIV as characterized by x-ray powder diffraction pattern comprising major peaks at 11.6±0.3° 2θ, 21.3±0.3° 2θ, and 19.3±0.3° 2θ;
• (k) Form XV as characterized by x-ray powder diffraction pattern comprising major peaks at 9.8±0.3° 2θ, 4.7±0.3° 2θ, and 14.0±0.3° 2θ;
• (l) Form XIX as characterized by x-ray powder diffraction pattern comprising major peaks at 4.7±0.3° 2θ, 23.6±0.3° 2θ, and 18.9±0.3° 2θ;
• or
• (m) a combination thereof.

A method of generating a crystalline form of a compound of Formula (III):

• the method comprising:
• incubating a solid form of the compound of Formula (III) in a solvent system in which at least a portion of the solid form of the compound of Formula (III) remains solid;
• converting the portion of the solid form of the compound of Formula (III) to the crystalline form;
• and
• collecting the crystalline form.

A method for producing a crystalline form of a compound of Formula (III), the method comprising:

• (a) dissolving the compound of Formula (III) in 2-propanol, and evaporating at least a portion of the 2-propanol;
• (b) dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran at a first temperature, and cooling the solvent system to a second temperature;
• (c) dissolving the compound of Formula (III) in a solvent system comprising heptane and 2-propanol at a first temperature, and cooling the solvent system to a second temperature;
• (d) dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and ethyl acetate at a first temperature, and cooling the solvent system to a second temperature;
• (e) dissolving the compound of Formula (III) in tetrahydrofuran, and combining the solvent system with water;
• (f) dissolving the compound of Formula (III) in a solvent system comprising 2-propanol and tetrahydrofuran, and evaporating at least a portion of the solvent system;
• (g) dissolving the compound of Formula (III) in acetone, and evaporating at least a portion of the acetone;
• (h) dissolving the compound of Formula (III) in a solvent system comprising acetone and tetrahydrofuran, and evaporating at least a portion of the solvent system;
• or
• (i) a combination thereof;
• thereby producing the crystalline form of the compound of Formula (III).

A method for producing a crystalline form of a compound of Formula (III), the method comprising:

• (a) dissolving the compound of Formula (III) in ethyl acetate, and adding the ethyl acetate to heptane;
• (b) dissolving the compound of Formula (III) in toluene, and evaporating at least a portion of the toluene;
• (c) dissolving the compound of Formula (III) in toluene, and adding the toluene to heptane;
• (d) dissolving the compound of Formula (III) in a solvent system comprising heptane and toluene, and heating the solvent system to between about 20° C. and about 50° C.;
• or
• (e) a combination thereof,
• thereby producing the crystalline form of the compound of Formula (III).

A method for producing a crystalline form of a compound of Formula (III), the method comprising:

• (a) dissolving the compound of Formula (III) in toluene at a first temperature, and cooling the solvent system to a second temperature;
• (b) dissolving the compound of Formula (III) in toluene, adding butyl methyl ether to the toluene to form a solvent system, and evaporating at least a portion of the solvent system;
• or
• (c) a combination thereof;
• thereby producing the crystalline form of the compound of Formula (III).

A method for producing a crystalline form of a compound of Formula (III), the method comprising:

• (a) dissolving the compound of Formula (III) in a solvent system comprising ethyl acetate, adding heptane to the solvent system, and incubating the solvent system at a temperature of between about 20° C. and about −20° C.;
• (b) dissolving the compound of Formula (III) in a solvent system comprising butyl acetate, adding heptane to the solvent system;
• (c) dissolving the compound of Formula (III) in ethyl acetate, adding the ethyl acetate to butyl methyl ether to form a solvent system, and evaporating at least a portion of the solvent system;
• (d) dissolving the compound of Formula (III) in ethyl acetate, adding butyl methyl ether to the ethyl acetate to form a solvent system, and evaporating at least a portion of the solvent system;
• (e) dissolving the compound of Formula (III) in acetone, combining the acetone with butyl methyl ether to form a solvent system, and evaporating at least a portion of the solvent system;
• or
• (f) a combination thereof;
• thereby producing the crystalline form of the compound of Formula (III).

A method for producing a crystalline form of a compound of Formula (III), the method comprising:

• (a) dissolving the compound of Formula (III) in acetone at a first temperature, combining the acetone with heptane to form a solvent system, and cooling the solvent system to a second temperature;
• (b) dissolving the compound of Formula (III) in tetrahydrofuran at a first temperature, combining the tetrahydrofuran with heptane to form a solvent system, and cooling the solvent system to a second temperature;
• or
• (c) a combination thereof;
• thereby producing the crystalline form of the compound of Formula (III).