SOLUBILITY BEHAVIOR, PHASE-TRANSITION, AND STRUCTURE-BASED NUCLEATIONINHIBITION OF ETANIDAZOLE IN AQUEOUS-SOLUTIONS

Purpose, The solubility behavior, phase transition and inhibition of t he nucleation process of etanidazole were characterized. Methods. Solu bility measurements as a function of time permitted characterization o f the solubility behavior and phase transition. The precipitate from s aturated solutions was isolated and characterized by differential scan ning calorimetry polarized light microscopy, x-ray powder diffraction and coulometric analysis. The physical stability of metastable systems was examined in the presence of various structure-based nucleation in hibitors. Results, Etanidazole is soluble in water with an equilibrium solubility of 68.1 mg/mL, pH 6.5 with changes in pH having virtually no effect on the solubility. Etanidazole reaches concentrations in exc ess of 150 mg/mL within one hour. Etanidazole solutions prepared at 15 0 mg/mL contained crystals after rotating for 24 hours. The crystals w ere isolated and characterized as etanidazole monohydrate. The solubil ity of etanidazole monohydrate in water increased with time reaching a n equilibrium solubility of 68 mg/mL after 24 hours. Therefore, the so lubility studies were actually determining the solubility of the more stable monohydrate form of etanidazole. Etanidazole solutions at conce ntrations of 50, 100 and 150 mg/mL were stabilized to varying degrees with structure-based nucleation inhibitors (imidazole, ethanolamine or diethanolamine). Conclusions, Anhydrous etanidazole undergoes a trans ition in aqueous solutions to the more stable monohydrate when the sol ubility of the monohydrate is exceeded. The physical stability of etan idazole solutions at 4 degrees C is improved following autoclaving. Th e addition of structure-based nucleation inhibitors effectively stabil ized the metastable systems.