Physicochemical Stability of Pharmaceutical Phosphate Buffer Solutions III. Gel Filtration Chromatography of Al(III) Complex Formed in Phosphate Buffer Solutions

Abstract

The effects of various factors on the gel filtration patterns of Al (III) complex with citric acid in phosphate buffer solutions were studied. In the range of pH 5 to pH 7, a mixed complex with low and high molecular weights was formed. At pH4 and pH8 only the complex with low molecular weight was formed. In view of the formation of a mixed complex, even in the Al (III)-pyrophosphate system and the low-molecular complex alone in Al(III)-EDTA, Ca (II)-EDTA and Ca(II)-citric acid systems, strong complexation of Al (III) with citric acid or pyrophosphate was related to the formation of a polymeric complex with high molecular weight. By means of the Al recovery test in the low-molecular and high-molecular complex fractions in phosphate buffer solutions containing citric acid, it was found that the low-molecular complex formed at pH 4 or pH 8 became unstable on aging, while the low-molecular complex in a mixed complex formed near pH 6 was significantly stable, possibly owing to an equilibrium between the low-molecular and high-molecular complex fractions and stabilization effect of the former complex by the latter complex. This result was confirmed to be associated with the physicochemical stability of the phosphate buffer solutions. In addition, the determination results of Al (III), citric acid and Na in each complex fraction suggested that the low-molecular complex may be soluble by dissociation of citric acid in the complex and the high-molecular complex by hydration of the complex. Consequently effective prevention effect against precipitation in parenteral phosphate buffer solutions was considered to be obtained at pH values close to the pKa values of complexing agents.