Physicochemical Stability of Pharmaceutical Phosphate Buffer Solutions II. Complexation Behavior of Al(III) with Additives in Phosphate Buffer Solutions

Abstract

To find conditions to prevent precipitation in parenteral phosphate buffer solutions, the complexation behavior of Al (III), the principal metal found in the precipitate, was studied, in the presence of the usual pharmaceutical additives, on the basis of precipitation-prevention factor, R^Al (a molar ratio of complexed Al (III) to additive at a complete dissolution point of Al (III)). Among the additives studied, citric acid and condensed phosphates more strongly complexed Al (III) in a certain pH range than ethylenediaminetetraacetic acid. In view of the gel filtration result and information from the literature, this was assumed to be due to the formation of a polymeric aluminum complex. For example, an average composition of Al ³²(OH)⁸⁴(H ²O)²⁸(citrate)¹⁴ (molecular weight = ca. 6000). Other carboxylic acids such as glycolic acid, diglycolic acid, lactic acid, malic acid, malonic acid, and oxalic acid complexed Al (III) favorably in acidic solutions, and amino acids, salicylic acid, iminodiacetic acid, and gluconic acid in alkaline solutions. From the result that the additives, in general, complexed Al (III) more strongly at pH values close to their pKa values, it was concluded that pH of the solutions should be selected carefully for physicochemical ly stable parenteral formulations.