Effect of pH on the Stability of Intravenous Emulsions: Relevance of Zeta Potential and Particle Size Measurements
Using the Litesizer™ 500 in combination with the Dosing System, which automates pH changes directly in the measurement cuvette, is an effective method to investigate the stability of emulsions in response to pH. Here we have performed pH ramp-ups and ramp-downs on an oil-in-water emulsion destined for intravenous drug delivery. The emulsion’s stability was not affected by alkalinization up to the uppermost limit of our experiment (pH = 9.3), as evidenced by an unaltered particle size. In contrast, a sudden increase in particle size and a concomitant decrease in transmittance were observed when the solution was acidified to a pH below 3.5, suggesting that the emulsion started to degrade. The lowest point of the ramp-down (pH = 3.04) proved very close to the isoelectric point (ZP = - 2.7 mV), with a dramatic increase in particle size pointing out the emulsion’s impending breakdown.
Intravenous lipid emulsions are used for total parenteral nutrition and as carriers for lipophilic drugs. They are typically oil-in-water emulsions, consisting in lipid droplets dispersed in an aqueous phase with the help of an emulsifier.
For oil-in-water emulsions, a crucial stability factor is the electrostatic charge carried by the oil droplets. Particles that are highly positively or negatively charged will repel each other in solution and flocculation is less likely. The oil droplet surface charge is typically characterized by the emulsion’s zeta potential, a measure of the sign and magnitude of the surface charge which is defined by the electrophoretic mobility of the droplets. In a typical oil-in-water emulsion, the more negative the zeta potential is, the more stable the emulsion will be.
In the common case of particles which surface charge-determining ions are H+/OH−, the net surface charge of particles is in direct relation to the pH of the dispersant. As such, pH has an enormous influence on the stability of emulsions. However, intravenous lipid emulsions have additional constraints regarding their pH. The chemical stability of the individual components needs to be considered in order to preserve biological activity. Also, with regards to the administration route, the final pH value should be close to a physiological one (pH 7.4). Thus, investigating the influence of pH is an essential step of the manufacturing process for intravenous lipid emulsions.
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