Galenic Stability of Propofol Emulsions After Expiry: Assessment After 3 Years

Propofol (2,6-diisopropylphenol) is a potent intravenous hypnotic widely used for the induction and maintenance of general anesthesia and sedation in various medical settings. Despite its widespread use, propofol emulsions, formulated as oil-in-water (O/W) due to its low solubility in water, pose formulation-related challenges. Emulsion stability is critical to prevent phase separation and droplet aggregation, which can lead to embolisms. This study builds upon a previous investigation assessing the stability of propofol emulsions up to six months post-expiration, extending the evaluation to three years after expiry by examining visual appearance, pH, droplet diameter, sterility and zeta potential.

Fifteen ampoules of Propofol (Propofol Fresenius, 10 mg/ml) from the same batch, expired for three years, were used. Stability measurements included visual observation, pH, droplet diameter, polydispersity index, sterility, and zeta potential. The study was conducted under ICH Q1A storage conditions (30°C ± 2°C). Samples were prepared and analyzed using a Zeta nanosizer v6.12 (Malvern Instrument) for droplet size and zeta potential, and an Eutech pH meter 510 for pH measurements. Sterility testing, performed according to USP <71> guidelines, while statistical analyses using Jamovi software (version 2.6.2). Results were compared to the previous study conducted six months after expiration to identify trends in galenic stability. Results: No phase separation or visible particles were observed in any of the six tubes during visual examination. The mean droplet diameter ranged from 94.42 nm to 106.37 nm, significantly lower than the 109.52–125.15 nm reported in the six-month post-expiration study, reflecting enhanced galenic stability over time. The polydispersity index ranged from 0.14 to 0.16, also lower compared to the previous study, indicating improved droplet uniformity. The pH measured between 6.85 and 7.07, and the zeta potential ranged from -42.7 mV to 68.9 mV, with trends consistent with the earlier findings. All samples maintained unimodal droplet size distribution, aligning with USP guidelines for injectable lipid emulsions. Additionally, sterility testing confirmed the absence of microbial contamination in all samples, further supporting their safety and stability over time.

The propofol emulsion demonstrated galenic stability up to three years post-expiration, showing consistent improvements in droplet diameter and uniformity compared to the six-month study. These results suggest the potential for post-expiry use of propofol emulsions in emergency situations, particularly during shortages. Further comprehensive stability studies, including bacterial endotoxin detection, and an assay of the active substance to detect any potential degradation are recommended to ensure the safety and efficacy of post-expiry use.