Partition of antimicrobial additives in an intravenous emulsion and their effect on emulsion physical stability

A number of antimicrobial agents are potentially applicable to the preservation of small-volume parenteral emulsions. However, the physical stability of these emulsions is of paramount importance in ensuring their safety, and it is possible that antimicrobial additives could reduce the emulsion stability by a number of mechanisms. We have studied the effects of several antimicrobial agents on the physical stability of Diprivan®, an intravenous anaesthetic emulsion. A particular problem is that many antimicrobial additives require an acidic pH in order to be effective (e.g. sodium benzoate, sodium metabisulphite) and the emulsion surface potential is insufficient to stabilize the emulsion to coalescence under these conditions. In addition several antimicrobial agents (e.g. methyl paraben and benzoic acid) partition into the oil phase of the emulsion, requiring the use of increased concentrations to remain effective. We describe an assay technique to quantify the oil partition, liposomal partition, and droplet surface adsorption of the additives. This illustrates that significantly more additive is partitioned out of the water phase than might be predicted from simple oil/water partition experiments.