Parenteral formulation development for the positive inotropic agent RS-82856. Hydrolysis and oxidation kinetics, solubility and i.v. formulation considerations

Abstract

The degradation kinetics and solubility of N-cyclohexyl- N-methyl-4-(1,2,3,5-tetrahydroiniidazo[2,1-b]quinazolin-2-one-7-yloxy)butyramid (1, RS-82856) hydrogen sulfate in aqueous and organic solutions were investigated. It was found that 1 reached a ~ 50/50 equilibrium in water with its imidazole-ring opened product 2 (RS-31621), which then further degraded to give several secondary products. The rate constants for the acid catalyzed ( K H ), spontaneous or water-catalyzed ( k O ) and base-catalyzed ( k OH ) reactions for both the forward and reverse reactions were determined at 40°C, 60°C, and 80° C. The reacting species responsible for each reaction were proposed. Biphasic kinetics were also observed for the autoxidation of RS-82856 hydrogen sulfate in organic solvents; the 5-oxo analog (RS-82890) was the only product detected. The t 90s in propylene glycol, dimethylacetamide and dimethyl sulfoxide for the hydrogen sulfate salt at 25°C are less than 4 weeks. These stability results and various solubility data were combined to evaluate possible intravenous formulations for lexicological and clinical studies. It was concluded that all solution formulations (aqueous, aqueous-organic or organic) are unsuitable for RS-82856 hydrogen sulfate and alternatives should be sought.