Incompatibility of indometacin and benzalkonium in eye drops due to ion-pair formation

Eye drop formulations containing indometacin and benzalkonium salt often show an opalescence as a result of ion-pair formation. The insoluble ion pair was isolated and characterized by infrared and ultraviolet spectroscopy and thin layer chromatography. This ion pair is also responsible for the bad assay results of benzalkonium using the ion-pair extraction method with bromothymol blue as counterion. The distribution constant (KD = 1O4) of indometacin and the extraction constant (Kex = 3 X 1O4) of the ion pair indometacin-benzalkonium in a water-chloroform system at various pH values were determined. A discussion on the preservation of indometacin eye drop formulations with benzalkonium salt in view of this chemical incompatibility is presented.