Preparation method of azithromycin hydrates
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsJudith Aronhime, Claude Singer, Michael Pesachovich
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Abstract
This invention relates to a method for preparing azithromycin dihydrate from crude azithromycin by the gradual crystallization of azithromycin from acetone by the addition of a minimal amount of water to effect crystal formation is disclosed. This invention also relates to a method of making azithromycin from desmethyl-azithromycin by dissolving desmethyl-azithromycin in acetone, adding activated carbon, adding formaldehyde, adding formic acid; refluxing the desmethyl-azithromycin acetone solution, adding sodium hydroxide to induce precipitation of azithromycin, and isolating azithromycin.
Claims37
A method of making azithromycin from desmethyl-azithromycin comprising the steps of:
- (a) dissolving desmethyl-azithromycin in acetone;
- (b) refluxing the desmethyl-azithromycin acetone solution;
- (c) adding formaldehyde;
- (d) adding formic acid;
- (e) adding activated carbon;
- (f) adding sodium hydroxide to induce precipitation of azithromycin;
- and isolating azithromycin.
A process for making azithromycin dihydrate comprising:
- dissolving azithromycin in acetone;
- adding a first portion of water to the acetone to form a mixture;
- maintaining the mixture, with optional mixing, until definite crystals of azithromycin dihydrate are observed;
- and
- adding a second portion of water to the mixture.
A process for making azithromycin dihydrate comprising:
- dissolving azithromycin in acetone;
- adding a first portion of water to the acetone over at least 2 hours to form a mixture;
- and
- adding a second portion of water to the mixture.
An azithromycin dihydrate composition having less than about 0.1% isomers of azithromycin.
A formulation comprising azithromycin dihydrate having less than about 0.1% isomers of azithromycin.
A process for making azithromycin from desmethyl-azithromycin comprising:
- admixing desmethyl-azithromycin, acetone, formaldehyde and formic acid to form a first mixture in which the desmethyl-azithromycin is dissolved;
- heating the first mixture;
- adding water to the first mixture to form a second mixture;
- and
- recovering the azithromycin.
A process for making azithromycin from desmethyl-azithromycin comprising:
- admixing desmethyl-azithromycin, acetone, formaldehyde and formic acid to form a first mixture in which the desmethyl-azithromycin is dissolved;
- refluxing the first mixture;
- cooling the first mixture to less than about 40° C.;
- adding water to the first mixture to form a second mixture;
- removing the acetone from the second mixture;
- adjusting the pH of the second mixture sufficiently to precipitate azithromycin;
- and
- recovering the azithromycin.
A process for making azithromycin monohydrate comprising:
- dissolving azithromycin in acetone;
- adding a first portion of water to form a first mixture;
- maintaining the first mixture at about 40° C.;
- adding a second portion of water, thereby initiating precipitation of azithromycin monohydrate;
- adding a third portion of water;
- and optionally cooling the second mixture.
A process for making azithromycin dihydrate comprising:
- dissolving azithromycin in acetone;
- adding a first portion of water to the acetone over at least 2 hours to form a mixture;
- maintaining the mixture, with optional mixing, for about 4 hours;
- and
- adding a second portion of water to the mixture at a rate of up to 0.2 volumes of water per volume of acetone per hour,
- wherein the temperature is maintained at a temperature ranging from about 20° C. to about 25° C., and
- wherein the ratio of the volume of the acetone to the total volume of water, after the step of adding the second portion of water, ranges from about 0.5 to 1.5.
Dependencies are inferred from the claim text.