Oral Dosage Development of a Human Rhinovirus and Non-Polio Enterovirus Inhibitor

Abstract

WIN 63843, a Picornavirus replication inhibitor, is physically and chemically stable in the solid state, to light, elevated temperature, and humidity. This 3-ary15-trifluoromethyl disubstituted 1,2,4-oxadiazole compound has very low water solubility but is highly soluble in ethanol and in safflower seed and corn oils. Solubility in the vegetable oils is doubled by the synergistic effect of ethanol at the 16% alcohol concentration. Vegetuble oil solutions of WIN 63843 are thermally stable but react slowly in the presence of light resulting in an amidoxime compound (WIN 65489) formed by opening of the 1,2,4-oxadiazole ring. This reaction does not occur in oil solutions containing small concentrations of ethanol. Of biophannaceutical interest, the addition of ethanol or PEG-400 solutions of WIN 63843 to human gastric fluid resulted in oily droplet formation whereas crystals form upon addition of these solutions to water. Also, the compound is greater than 8,000 times more soluble in human gastric fluid.