STERILE FILTRATION OF NANOCRYSTAL(TM) DRUG FORMULATIONS

A NanoCrystal(TM) dispersion of the iodinated x-ray contrast agent iod ipamide was prepared by wet milling the drug substance in the presence of Pluronic(R) F127 stabilizer. The mean particle size of the formula tion was 98 nm and all drug particles in the formulation were smaller than 220 nm as determined by dynamic light scattering. Approximately I liter of dispersion was filtered through a sterile 0.2-mu m disposabl e capsule filter (Supor(R) 200 DCF(TM), 0.1 m(2) effective filtration area [EFA], Gelman Sciences) to condition the capsule. No drug concent ration or size distribution changes were detected after the filtration process. The microbiological validation tests were performed using Ps eudomonas diminuta organisms to challenge the capsule under simulated worst-case process conditions. The results showed that the Super 200 D CF was able to retain 100% Pseudomonas diminuta organisms (greater tha n or equal to 10(7) organisms per cm(2) of effective filtration area). Thus, this study demonstrated that terminal filtration is a feasible process to sterilize NanoCrystal(TM) drug dispersions that may be chem ically or physically unstable at elevated temperatures and thus not am enable to terminal heat sterilization.