One class of complex drug products is emulsion formulations, which are composed of oil droplets dispersed in a continuous water phase. 5 These quality attributes can affect drug bioavailability, efficacy, safety, immunogenicity, and PK/PD properties, and present challenges for drug manufacturers and regulatory agencies to define robust and sensitive methods for measuring these critical quality attributes. Complex drug products can have molecular, compositional, or drug distribution heterogeneity, pertaining to differences in higher order structure, particle size distribution (PSD), 1, 2 chemical composition, 3, 4 or multiphase dosage forms.
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The high precision of ☖ 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.Īdvances in pharmaceutical sciences and manufacturing methods have given rise to an increase in the development and approval of complex drug products. 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. 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 classical methods of dynamic light scattering or electron microscopy can be used but they generally require sample dilution or harsh preparation conditions, respectively. 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 size and polydispersity of oil droplets are critical quality attributes of the emulsion drug product that can potentially affect drug bioavailability.
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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.