Interactions between polysorbate and antimicrobial preservatives in aqueous parenteral products

Biological drugs intended for multidose use normally contain both preservatives and non-ionic surfactants. However, most common preservatives and surfactants in parenteral formulations are considered to be physically incompatible with each other. In this study, the phase separation of polysorbate 20 and polysorbate 80 in the presence of phenolic preservatives is systematically mapped. The observed precipitation is found to be the result of a dramatic surfactant cloud point depression caused by the preservative. A limited study was also performed for poloxamer 188 and dodecylmaltoside. This verified that also poloxamer clouds in the presence of phenol. The concentration where poloxamers induce clouding of phenol is higher than for polysorbates. No clouding was observed for dodecylmaltoside. The effect of other common excipients on polysorbate cloud point depression was also investigated, and it was demonstrated that the presence of sugar, salt, and buffer further increases the surfactant-preservative incompatibility area caused by clouding. Nonetheless, for all studied preservatives (phenol, metacresol, and benzyl alcohol) there is a region where it is possible to formulate stable, non-clouding solutions at relevant preservative concentrations.