Solubility behavior, phase transition, and structure-based nucleation inhibition of etanidazole in aqueous solutions.
OBJECTIVE
The solubility behavior, phase transition and inhibition of the nucleation process of etanidazole were characterized.


METHODS
Solubility measurements as a function of time permitted characterization of the solubility behavior and phase transition. The precipitate from saturated solutions was isolated and characterized by differential scanning 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 inhibitors.


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 excess of 150 mg/mL within one hour. Etanidazole solutions prepared at 150 mg/ mL contained crystals after rotating for 24 hours. The crystals were isolated and characterized as etanidazole monohydrate. the solubility of etanidazole monohydrate in water increased with time reaching an equilibrium solubility of 68 mg/mL after 24 hours. Therefore, the solubility studies were actually determining the solubility of the more stable monohydrate from of etanidazole. Etanidazole solutions at concentrations 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 transition in aqueous solutions to the more stable monohydrate when the solubility of the monohydrate is exceeded. The physical stability of etanidazole solutions at 4 degrees C is improved following autoclaving. The addition of structure-based nucleation inhibitors effectively stabilized the metastable systems.
Pharmacy R&D, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
M B
MB
Maurin
S M
SM
Rowe
K S
KS
Field
R C
RC
Swintosky
M A
MA
Hussain
D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D017341:Etanidazole / Q000737:chemistry*; D019856:Ethanolamine; D004983:Ethanolamines / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry; D008859:Microscopy, Polarization; D011838:Radiation-Sensitizing Agents / Q000737:chemistry*; D012995:Solubility; D014867:Water; D014961:X-Ray Diffraction
D004983:Ethanolamines; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; D014867:Water; D017341:Etanidazole; D019856:Ethanolamine; C029899:imidazole; C020283:diethanolamine