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US RE39,251 E1Granted
Polymorphs of an epothilone analog
AssigneeBristol-Myers Squibb Company
InventorZhenrong Guo
Life of this patent
Estimating the term…
Abstract
There are provided in accordance with the present invention two crystalline polymorphs, designated Form A and Form B, respectively, as well as mixtures thereof, of an epothilone analog represented by the formula Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them and pharmaceutical dosage forms containing them.
Claims31
A crystalline polymorph of an epothilone analog represented by the formula
- comprising Form A characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 14.152(6) Å
- b = 30.72(2) Å
- c = 6.212(3) Å
- Volume = 2701(4) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.247
- Melting point
- 182-185° C. decomposition;
- and
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.):
- 5.69, 6.76, 8.38, 11.43, 12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03, 19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50, 26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08 and 31.52.
16 more elements
A crystalline polymorph of an epothilone analog represented by the formula
- comprising Form A characterized by powder x-ray diffraction substantially as shown in FIG. 1 and a Raman spectrum substantially as shown in FIG. 5.
A crystalline polymorph of an epothilone analog represented by the formula
- comprising Form A characterized by a solubility in water of 0.1254, a solubility in a 3% aqueous solution of polysorbate 80 of 0.2511, a melting point with decomposition between 182-185° C. and a heat of solution of 20.6 k/mol.
A crystalline material of an epothilone analog represented by formula I:
- comprising a mixture of Form A and Form B wherein Form A is characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 14.152(6) Å
- b = 30.72(2) Å
- c = 6.212(3) Å
- Volume = 2701(4) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.247
- Melting point
- 182-185° C. (decomposition);
- and
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.):
- 5.69, 6.76, 8.38, 11.43, 12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03, 19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50, 26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08 and 31.52;
- and Form B is characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 16.675(2) Å
- b = 28.083(4) Å
- c = 6.054(1) Å
- Volume = 2835(1) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.187
- Melting point
- 191-199° C. decomposition;
- and
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.):
- 6.17, 10.72, 12.33, 14.17, 14.93, 14.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.24, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55, 30.49 and 31.22.
35 more elements
A crystalline material of an epothilone analog represented by formula I;
- comprising a mixture of Form A and Form B wherein Form A is characterized by powder x-ray diffraction substantially as shown in FIG. 1 and a Raman spectrum substantially as shown in FIG. 5;
- and Form B is characterized by powder x-ray diffraction substantially as shown in FIG. 2 and a Raman spectrum substantially as shown in FIG. 6.
A crystalline material of an epothilone analog represented by formula I:
- comprising a mixture of Form A and Form B wherein Form A is characterized by a solubility in water of 0.1254, a solubility in a 3% aqueous solution of polysorbate 80 of 0.2511, a melting point with decomposition between 182-185° C. and a heat of solution of 20.6 kl/mol;
- and Form B is characterized by a solubility in water of 0.1907, a solubility in a 3% aqueous solution of polysorbate 80 to 0.5799, a melting point with decomposition between 191-199° C. and a heat of solution of 9.86 kl/mol.
A crystalline polymorph of an epothilone analog represented by the formula
- comprising Form B characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 16.675(2) Å
- b = 28.083(4) Å
- c = 6.054(1) Å
- Volume = 2835(1) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.187
- Melting point
- 191-199° C. decomposition and/or
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ1.5406 Å at 22° C.):
- 6.17, 10.72, 12.33, 14.17, 14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.34, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55, 30.49 and 31.22.
15 more elements
A pharmaceutical composition which comprises as an active ingredient an effective amount of a crystalline polymorph of an epothilone analog represented by formula I:
- and one or more pharmaceutically acceptable carriers, wherein said crystalline polymorph is a mixture of Form A and Form B, wherein Form A is characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 14.152(6) Å
- b = 30.72(2) Å
- c = 6.212(3) Å
- Volume = 2701(4) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.247
- Melting point
- 182-185° C. (decomposition);
- and
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.):
- 5.69, 6.76, 8.38, 11.43, 12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03, 19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50, 26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08, and 31.52;
- and Form B is characterized by:
- unit cell parameters approximately equal to the following:
- Cell dimensions
- a = 16.675(2) Å
- b = 28.083(4) Å
- c = 6.054(1) Å
- Volume = 2835(1) A3
- Space group
- P212121
- Orthorhombic
- Molecules/unit cell
- 4
- Density (calculated) (g/cm3)
- 1.187
- Melting point
- 191-199° C. decomposition;
- and
- characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.):
- 6.17, 10.72, 12.33, 14.17, 14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.24, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.65, 29.55, 30.49 and 31.22.
35 more elements
A crystalline polymorph of an epothilone analog represented by the formula
- comprising Form B characterized by powder x-ray diffraction substantially as shown in FIG. 2 and a Raman spectrum substantially as shown in FIG. 6.
A crystalline polymorph of an epothilone analog represented by the formula:
- comprising Form B characterized by a solubility in water of about 0.1907, a solubility in a 3% aqueous solution of polysorbate 80 of about 0.5799, a melting point with decomposition between about 191-199° C. and a heat of solution of about 9.86 kJ/mol.
Dependencies are inferred from the claim text.