| 摘要 |
Biphosphonates and especially disodium pamidronate are becoming more and more important for the therapy of a wide variety of diseases. Pure and stable disodium pamidronate is a prerequisite for the manufacture of the respective pharmaceutical formulations. In the literature, there is a controversy on the stability of the various hydrates of disodium 10 pamidronate. The present invention presents a facile, easy to scale-up method of producing disodium pamidronate pentahydrate of high purity and high stability, at yield >90 %. This method avoids any steps that may introduce impurities. It is based on the fact that pamidronic acid can be transferred into its diammonium salt at high concentration, at room temperature. This highly concentrated solution is converted into the disodium salt via ion-exchange, at conditions that maintain the high concentration. The ion-exchange step simultaneously eliminates any undesired divalent or trivalent cations. The disodium salt can be directly crystallized in the eluate of the ion-exchange column, without the need of further concentration and/or addition of any alcohol, by only lowering the temperature down to 5°C. |
