Paclitaxel solvates
AssigneeBristol-Myers Squibb Company
InventorsDaniel A. Benigni, Jack Z. Gougoutas, John D. DiMarco
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Abstract
Biologically active crystalline solvates of paclitaxel are precipitated using polar, aprotic, organic solvents. A pharmaceutical composition is also disclosed, as well as the preparation of the novel solvates and their uses as anti-tumor agents.
Claims39
A crystalline solvate comprising paclitaxel and an aqueous solvent selected from the group consisting of dimethylsulfoxide, N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone, and acetonitrile and combinations thereof.
A method for the preparation of crystalline paclitaxel solvates comprising:
- a) forming a mixture of:
- (i) a paclitaxel-containing material;
- and
- (ii) one or more organic solvents, each said solvent having solvent molecules compatible with solvent sites in the crystalline arrangement of the solvate;
- and
- b) removing solvent from the mixture to recover a solid, crystalline paclitaxel solvate having paclitaxel and solvent molecules within the crystal structure.
A crystalline solvate of paclitaxel comprising of about two molecules of paclitaxel, about 3 molecules of water, about 2 molecules of N-methyl-2-pyrrolidone and about one molecule of acetonitrile.
A crystalline solvate of paclitaxel comprising about two molecules of paclitaxel, about two molecules of water and about one molecule of N,N′-dimethylformamide.
A method for processing a paclitaxel-containing material to obtain paclitaxel comprising:
- a) forming a mixture of:
- (i) a paclitaxel-containing material, and
- (ii) an aqueous solution comprising one or more organic solvents;
- and
- b) removing solvent from the mixture to isolate a crystalline paclitaxel solvate;
- and
- c) desolvating the crystalline solid.
Form D paclitaxel solvate having a crystalline arrangement composed of:
- a) paclitaxel molecules;
- and
- b) solvent molecules located in solvent sites within the crystalline structure.
Form E paclitaxel solvate having a crystalline arrangement composed of:
- a) paclitaxel molecules;
- and
- b) solvent molecules located in solvent sites within the crystalline structure.
An orthorhombic paclitaxel solvate crystal containing a solvent, which is characterized by unit cell parameters a of about 9.54 Å, b of about 28.46 Å, and c of about 37.24 Å;
- and a space group symmetry p 21 21 21;
- the crystal consisting of eight paclitaxel molecules in an arrangement and conformations according to the fractional atomic coordinates expressed in Table 1;
- wherein the arrangement of the paclitaxel molecules forms solvent sites, the specific dimensions of said solvent sites varying according to the solvent contained therein.
An orthorhombic paclitaxel solvate crystal containing a solvent, which is characterized by unit cell parameters a of about 9.51 Å, b of about 27.79 Å, and c of about 34.79 Å;
- and a space group symmetry p 21 21 21;
- the crystal consisting of eight paclitaxel molecules in an arrangement and conformations according to the fractional atomic coordinates expressed in Table 1;
- wherein the arrangement of the paclitaxel molecules forms solvent sites, the specific dimensions of said solvent sites varying according to the solvent contained therein.
Dependencies are inferred from the claim text.