Diclofenac Sodium Injection Sterilized by Autoclave and the Occurrence of Cyclic Reaction Producing a Small Amount of Impurity

Abstract

A known impurity is formed in the production of a parenteral dosage form of diclofenac sodium if terminally sterilized by autoclave. This impurity has been detected as 1‐(2,6‐diclorophenyl) indolin‐2qone, which is also an intermediate from which diclofenac sodium is generally synthesized. It is only the condition of the autoclave method (i.e., 123 ± 2°C) that enforces the intramolecular cyclic reaction of diclofenac sodium forming the indolinone derivative and sodium hydroxide. The formation of this impurity has been found to depend on the initial pH of the formulation. The reaction follows first‐order kinetics, and the energy of activation is 5.34 kcal/mol. The other excipients in the formulation do not have a role in this reaction. The concentration of the impurity in the resultant product in the ampule goes beyond the limit of the raw materials in the pharmacopoeias. It is thus preferable to use an alternative sterilization method; that is, an aseptic filtration method in which the formation of this impurity can be avoided. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:541–544, 2001