Preparation of ibandronate trisodium

摘要

The trisodium salt of ibandronate of formula (I): A process of preparing said salt comprises:
a) mixing 3-(methylpentylamino)propionic acid hydrochloride, phosphorous acid (in a 2.5-3.5 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride), sunflower oil (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and phosphorus trichloride (in a 3-4 molar excess with respect to 3-(methylpentylamino)propionic acid hydrochloride);
b) adding water (in an amount of 6-9 volume parts for 1 weight part of 3-(methylpentylamino)propionic acid hydrochloride) and after separation of the phases;
c) adjusting pH of the water phase to pH 12.5;
d) adding a water-miscible co-solvent and cooling down to precipitate the product or evaporate to dryness. Another process for preparing the trisodium salt of ibandronate comprises admixing the monosodium salt of ibandronate or ibandronic acid or their solvates with water or a mixture water/sodium hydroxide and adjustment of pH to 12.5. Various crystalline, semicrystalline and amorphous forms of trisodium ibandronate are disclosed.