Physical stability of ethyl diatrizoate nanocrystalline suspension in steam sterilization.

PURPOSE: To study the effects of formulation variables on the physical stability of a submicron crystal (nanocrystal) suspension under steam sterilization conditions.
METHODS: Suspensions of ethyl diatrizoate nanocrystals were prepared by wet milling in the presence of the surfactant poloxamine 908. Particle size distribution and zeta potential were measured by photon correlation spectroscopy.
RESULTS: On heating, the mean particle size of the nanocrystal suspension remained essentially unchanged up to 110 degrees C, the cloud point of the stabilizing surfactant, but increased significantly above that temperature. The increase in particle size was a result of particle aggregation rather than crystal growth. Adding a cloud point booster to the suspension significantly minimized the particle aggregation at high temperatures. The purity of poloxamine 908 and the tonicity agent and buffer salt used also affected the heat stability of the suspension, the latter agents apparently through altering the surfactant cloud point.
CONCLUSIONS: The aggregation of the ethyl diatrizoate nanocrystalline suspension under steam sterilization conditions was a result of phase separation of the stabilizing surfactant at its cloud point. When formulated with a cloud point booster to prevent the phase-separation, the suspension maintained its physical stability under steam sterilization without any significant change in particle size distribution.