Process for controlling crystal structure of risedronate
AssigneeThe Procter & Gamble Company
InventorJane Ellen Godlewski
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Abstract
The present invention relates to a process for controlling the crystal form of 3-pyridyl-1-hydroxy-ethylidene-1,1-bisphosphonic acid salt (Risedronate). The process employs a pH adjustment step to induce the proper hydrate form and thereby avoiding inadvertent nucleation of undesired hydrate forms.
Claims27
A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
- a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphonic acid and an inorganic base in sufficient amount to provide a pH of 6, to form a solution;
- b) heating the solution from about 50° C. to about 60° C. to form a heated solution;
- c) filtering said heated solution to form a filtered solution;
- d) adjusting the pH of said filtered solution with an inorganic acid to a pH range of from 4.7 to 5 while maintaining the temperature at the level oblained in step (b) to form a neutralized solution;
- e) cooling the neutralized solution to a temperature of about 20° C. to about 40° C. to form a nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt;
- f) adding to said slurry isopropyl alcohol and sufficient inorganic acid to provide a pH of from 4.7 to 5.2 to form a ripened slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form;
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- g) isolating 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate.
A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
- a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and an inorganic base in sufficient amount to provide a pH of 6, to form a solution;
- b) heating the solution from about 50° C. to about 60° C. to form a heated solution;
- c) filtering said heated solution to form a filtered solution;
- d) adjusting the pH of said filtered solution with an inorganic acid to a pH range of from 4.7 to 5 while maintaining the temperature at the level obtained in step (b) to form a neutralized solution;
- e) cooling the neutralized solution to a temperature of about 20° C. to about 40° C. to form a nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt;
- and
- f) isolating 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate.
A process for preparing 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form, said process comprising the steps of:
- a) dissolving in an admixture of isopropyl alcohol and water, 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid arid NaOH in sufficient amount to provide a pH of 6, to form a solution;
- b) heating the solution to 55° C. to form a heated solution;
- c) filtering said heated solution to form a filtered solution, while maintaining a temperature of 55° C.;
- d) adjusting the pH of said filtered solution with HCl to a pH range of from 4.7 to 5, while maintaining a temperature of 55° C., to form a neutralized solution;
- e) cooling the neutralized solution to 25° C. to form nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt;
- and
- f) adding to said slurry isopropyl alcohol and sufficient HCl to provide a pH of from 4.7 to 5.2 to form a ripened slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt in the hemipentahydrate crystal form.
Dependencies are inferred from the claim text.