Development of a Parenteral Formulation of an Investigational Anticancer Drug, 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone

Abstract

ABSTRACTThe objective of this study was to develop an injectable formulation of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) suitable for intravenous infusion. The solubility of 3-AP in different solvents and pH conditions was determined. The developed formulation underwent stability assessment and compatibility testing with large volume parenteral (LVP) solutions. The aqueous solubility of 3-AP was found to be 0.1 mg/ml and could only be increased marginally by altering the pH or adding surfactants. To achieve the desired concentration (>4 mg/ml), 3-AP was formulated at 5–10 mg/ml in a nonaqueous system consisting of 70% polyethylene glycol 300 and 30% ethanol. However, 3-AP readily precipitated from this formulation when diluted with LVP solutions. Dilution-induced drug precipitation was eliminated by acidifying the solution with citric acid. Ascorbic acid, 0.1%, was found to minimize oxidative degradation of 3-AP. Accelerated stability data indicated that the formulation is compatible with the packaging components and is chemically stable at 2–8°C, and retained >90% of 3-AP at 40°C for 3 months. Simulated infusion studies showed that the citric acid formulation was compatible with LVP solutions. However, because of the potential of extraction of plasticizers from polyvinyl chloride (PVC) plastic containers, it is recommended that the formulation be diluted in glass containers prior to administration.