A Simple and Noninvasive DOSY NMR Method for Droplet Size Measurement of Intact Oil-In-Water Emulsion Drug Products.

In a typical oil-in-water emulsion drug product, oil droplets with varied sizes are dispersed in a water phase and stabilized by surfactant molecules. The size and polydispersity of oil droplets are critical quality attributes of the emulsion drug product that can potentially affect drug bioavailability. More critically, to ensure accuracy in characterization of the finished drug product, analytical methods should introduce minimal physical perturbation (e.g., temperature variation or dilution) before the analysis. The classical methods of dynamic light scattering or electron microscopy can be used but they generally require sample dilution or harsh preparation conditions, respectively. By contrast, the size distribution of emulsion formulations can be assessed with a simple and noninvasive solution nuclear magnetic resonance method, namely, two-dimensional Diffusion Ordered SpectroscopY. The two-dimensional Diffusion Ordered SpectroscopY method probed signal decay of methyl resonances from oil and sorbate molecules and was applied to 3 types of U.S.-marketed emulsion drug products, that is, difluprednate, cyclosporine, and propofol, yielding measured droplet sizes of 40-280 nm in diameter. The high precision of ±6 nm of the new nuclear magnetic resonance method allows analytical differentiation of lot-to-lot and brand-to-brand droplet size differences in emulsion drug products, critical for drug-quality development, control, and surveillance.