Pharmaceutical equivalence and bioequivalence between generic drug products and the reference listed drug (RLD) must be established for FDA approval. A slight alteration in manufacturing parameters of the propofol emulsion can cause differences in morphological properties, consequently causing contrasting pharmacokinetics and bioavailability between the generic and the RLD, even if they show qualitative/quantitative (Q1/Q2) sameness with other tests. Comparative characterization of physicochemical properties (Q3), such as morphological properties, will provide additional evidence of generic and RLD product sameness, which supports bioequivalence determination.<br/><br/>Propofol, a hydrophobic intravenous anesthesia drug substance, is formulated as an oil-in-water emulsion. Sufficient characterization of the morphological properties of propofol products are yet to be reported. Rapid plunge freezing and cryogenic transmission electron microscopy (cryo-TEM) techniques preserve the native structure of propofol products in a frozen hydrated state and provide nanometer resolution imaging of the emulsion and liposome particles, compared to traditional room temperature techniques.<br/><br/>Cryo-TEM imaging of the RLD and generic propofol products indicates the presence of colloidal mixtures of emulsions, liposomes and emulsion-liposome combined structures (Figure 1). Heterogeneous size distribution of oil globules and liposomes is revealed with the majority being in the range of 100-200 nm. Furthermore, small unilamellar vesicles (&lt; 100 nm) and large unilamellar vesicles (100-1,000 nm) are also observed in the propofol products. Overall, our findings outline a potential method for identifying individual components (e.g. nanoemulsion and liposomes) of complex formulations in their native states.

Characterization of coexistence of nanoemulsion droplets and liposomes in propofol drug products

254th National Meeting (2017)

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