J. Roy et al., Diclofenac sodium injection sterilized by autoclave and the occurrence of cyclic reaction producing a small amount of impurity, J PHARM SCI, 90(5), 2001, pp. 541-544
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-2-one, which is also an int
ermediate from which diclofenac sodium is generally synthesized. It is only
the condition of the autoclave method (i.e., 123 +/- 2 degreesC) that enfo
rces the intramolecular cyclic reaction of diclofenac sodium forming the in
dolinone derivative and sodium hydroxide. The formation of this impurity ha
s been found to depend on the initial pH of the formulation. The reaction f
ollows 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 reactio
n. 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 th
us preferable to use an alternative sterilization method; that is, an asept
ic filtration method in which the formation of this impurity can be avoided
. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J P
harm Sci 90:541-544, 2001.