Preformulation and formulation of the anticancer drug, SarCNU

Abstract

SarCNU (NSC364432, 1-(2-chloroethyl)-3-sarcosinamide-1-nitrosourea), is a new antitumor agent of the nitrosourea family. Solubilization studies have shown that SarCNU is soluble in a variety of solvents including water. However, it is highly unstable in aqueous solutions with its t90 of 6 hrs in water. Therefore, the overall purpose of this project is to investigate the stabilization of this drug in various conditions. Two parental formulations are also proposed based on the result of stabilization study. The stability of SarCNU at different pH, temperature, and pharmaceutically acceptable solvents were investigated by HPLC. The influences of light, pH (2.0, 4.0, 6.0, and 8.5) at 0.01M and 0.1M phosphate buffer, antioxidants (ascorbic acid and sodium bisulfite), and a chelating agent (disodium EDTA) at pH 2.0 and pH 6.0 were studied at room temperature. The stability of the drug was also determined in water, pharmaceutically acceptable solvents, and in different combinations of these solvents at 4 different temperatures (25, 37, 50, and 60°C). The degradation of the drug, which was catalyzed not only by specific acid and base, but also by general acid and base, follows first order kinetics. Antioxidants, EDTA, and light have no effect on the degradation rate, suggesting oxidation is not the main degradation pathway. The t90 in pure cosolvent was twenty-five to fifty times higher than that in water or semi-aqueous vehicles. One major degradation product was confirmed by GC-MS and NMR. Two other possible degradation products were also suggested by GC-MS. The degradation products suggest that the degradation of SarCNU involves hydrolysis of its amide group. The stability profile suggests that we can increase the shelf life of the drug by the use of a pure cosolvent. This approach can be used to store drug so that it can be diluted with aqueous solvent prior to injection with the aid of a double syringe. A freeze-dried formulation is also studied. Neat tertiary butyl alcohol (TBA), a low toxicity, high vapor pressure and low melting solvent, was determined to be an excellent medium for SarCNU. Lyophilization of SarCNU from pure TBA produces a uniform cake composed of needle-shaped crystals. Thermal analysis and gas chromatography indicate that the cake contains less than 0.001% residual solvent. The SarCNU cake can be readily reconstituted with either water or an aqueous solution of 40% propylene glycol and 10% ethanol. These reconstituted solutions are stable for 4 and 13 hours, respectively.