Solid-State Phase Transition Mechanism and Physical–Chemical Study of the Crystal Forms of Monosodium Alendronate: Trihydrate versus Anhydrate

Abstract

Alendronic acid is one of the most effective diphosphonate compounds used for clinical treatment of bone disorders. It is administered orally as its monosodium salt, for which hydrate and anhydrous crystal forms are known. The monosodium alendronate trihydrate form (NaH4A·3H2O) is incorporated into medicines as the Active Pharmaceutical Ingredient (API). The NaH4A·3H2O form can be dehydrated at temperatures above 115 °C, resulting in the anhydrous form (NaH4A). Although the crystal structures of both forms have already been reported, an investigation of the reversible dehydration/hydration solid-phase transition is presented here for the first time. A solid-state mechanism for the phase transition, which involves the reversible dehydration–hydration of the NaH4A·3H2O and NaH4A forms, is also proposed. A systematic study comparing the equilibrium solubility and discriminatory intrinsic dissolution of the NaH4A·3H2O and NaH4A forms is included. To achieve this goal, an alternative method of quantifying alen...