Process for controlling crystal structure of 3-pyridyl-1-hydroxy-ethylidene-1,1-bisphosphonic acid salt (risedronate)

摘要

The present disclosure 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. Particularly disclosed is 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-l-hydroxy-ethylidene-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 Deg. C to about 60 Deg. 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 Deg. C to about 40 Deg. C to form a nucleating slurry of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sa (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; and (g) isolating 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid salt hemipentahydrate.