Formation and anion-exchange of crystalline echinocandin ammonium salts
AssigneeEli Lilly and Company
InventorsBrian Weston Dalder, Michael Anthony Dotlich, Neil John Kallman, Samuel Dean Larsen, Sharon Van Den Berghe Snorek, Jeffrey Thomas Vicenzi
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Abstract
A method is described for forming a crystalline Echinocandin nucleus salt from its mixed broth and/or partially purified process streams by the steps of nano-filtration to form a concentrate, addition of an aldehyde derivatizing agent which interacts with an aldehyde impurity, addition of an acid/metal salt to form a solubilized echinocandin nucleus salt having the desired anion, and subsequent cooling of the mixture to crystallize the salt.
Claims11
A method for forming a crystalline echinocandin nucleus salt from its mixed broth or partially purified process streams comprising in the following order the steps of:
- providing a solution comprising an echinocandin nucleus or amorphous salt thereof, an aldehyde impurity and a solvent;
- concentrating said solution by means of a nanofiltration process to form a concentrate;
- adding a derivatizing agent which selectively interacts with said aldehyde impurity;
- adjusting the pH of said concentrate to less than 4.0;
- adding an acid or metal salt;
- and
- cooling said concentrate.
A crystalline hydrochloride salt of echinocandin B nucleus prepared by the steps of
- providing a solution comprising echinocandin B nucleus or amorphous salt thereof, an aldehyde impurity and a solvent;
- concentrating said solution by means of a nanofiltration process to form a concentrate;
- adding sodium bisulfite;
- adjusting the pH of said concentrate to less than 4.0;
- adding a chloride metal salt;
- and
- cooling said concentrate.
A crystalline salt form of echinocandin B nucleus represented by the formula
- CP—NH3+A−, (CP—NH3+)2A−2, or (CP—NH3+M+)A−2
- wherein CP—NH3+ is represented by the structure
- 5
- A− is chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, hydrogen oxalate, hydrogen tartrate, benzoate, methanesulfonate, or p-toluenesulfonate;
- M+ is ammonium, lithium, sodium, potassium or tetraalkylammonium,
- A−2 is sulfate, oxalate, hydrogen phosphate, tartrate or fumarate;
- and
- pharmaceutically acceptable solvates or hydrates thereof.
A crystalline inner-salt form of an echinocandin nucleus represented by the formula
- (CP—NH3+A−)(M+A−) or ((CP—NH3+)2A−2)(M+2A−2)
- wherein CP—NH3+ is represented by the structure
- 6
- A− is chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, hydrogen oxalate, hydrogen tartrate, benzoate, methanesulfonate, or p-toluenesulfonate;
- M+ is ammonium, lithium, sodium, potassium or tetraalkylammonium;
- A−2 is sulfate, oxalate, hydrogen phosphate, tartrate or fumarate;
- M+2 is calcium or magnesium;
- and
- pharmaceutically acceptable solvates or hydrates thereof.
Dependencies are inferred from the claim text.