Processes for preparation of crystalline mycophenolate sodium
OwnerSandor Molnar, Csaba Szabo +4inventors
InventorsSandor Molnar, Csaba Szabo, Tivadar Tamas, Janos Hajko, Adrienne Kovacsne-Mezei, Judith Aronhime
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Abstract
Provided are crystalline mycophenolate sodium forms and processes for their preparation.
Claims38
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of mycophenolic acid in a C1-C4 alcohol;
- (b) combining a base and a source of sodium with the solution to obtain a reaction mixture;
- (c) crystallizing the crystalline form the mixture;
- and
- (d) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of mycophenolic acid in a C3-C8 ester;
- (b) combining a base and a source of sodium with the solution to precipitate the crystalline form;
- (c) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in 1-butanol;
- (b) crystallizing the crystalline form from the solution;
- and
- (c) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of mycophenolic acid in a C3-C8 ketone;
- (b) combining a base and a source of sodium with the solution to precipitate the crystalline form;
- and
- (c) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in ethanol;
- (b) crystallizing the crystalline form from the solution;
- (c) recovering the crystalline form;
- and
- (d) drying the recovered crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in ethyl lactate;
- (b) combining acetone with the solution to precipitate the crystalline form;
- and
- (c) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in dimethylformide;
- (b) combining 2-propanol with the solution to precipitate the crystalline form;
- (c) recovering the crystalline form;
- and
- (d) drying the recovered crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in methanol;
- (b) combining an antisolvent with the solution to precipitate the crystalline form;
- (c) recovering the crystalline form;
- and
- (d) drying the recovered crystalline form,
- wherein the antisolvent is selected from the group consisting of C3 to C8 ketone, ester and mixtures thereof.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of sodium mycophenolate in methanol;
- (b) combining the solution with an antisolvent to precipitate the crystalline form;
- and
- (c) recovering the crystalline form,
- wherein the antisolvent is selected from the group consisting of C3 to C8 ketone, C3 to C8 ester, C2 to C8 ether, C2 to C4 alcohol, nitromethane, tetrahydrofuran and mixtures thereof.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of:
- (a) preparing a solution of mycophenolic acid in a mixture of dichloromethane and methanol;
- and
- (b) combining a base and a source of sodium with the solution to precipitate the crystalline form;
- and
- (c) recovering the crystalline form.
A process for preparing anhydrous crystalline mycophenolate sodium (Form M2) characterized by a powder XRD pattern with peaks at 5.3, 8.0, 9.8, 10.7, and 21.9±0.2 degrees 2-theta comprising the steps of heating a solid mixture of a crystalline mycophenolate sodium (Form M1) characterized by a powder XRD pattern with peaks at 4.7, 6.6, 11.2 and 15.6±0.2 degrees 2-theta and a crystalline mycophenolate sodium (Form M3) characterized by at least one of a powder XRD pattern with peaks at 6.0, 9.3, 15.5, and 18.4±0.2 degrees 2-theta.
Dependencies are inferred from the claim text.