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

Abstract

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-tobrand droplet size differences in emulsion drug products, critical for drug-quality development, control, and surveillance.

Multiphase Drug Distribution and Exchange in Oil-in-Water Nanoemulsion Revealed by High-Resolution 19F qNMR

“…All data acquisition and processing including the use of a 4 mm NMR tube followed the previously published DOSY method which was verified using various o/w emulsion DPs. 3 The cryo-TEM imaging was performed using a JEOL JEM 1400 transmission electron microscope/scanning transmission electron microscope equipped with a Leica EM GP TEM grid plunge freezer and a Gatan 914 cryogenic transfer holder. Briefly, an aliquot of 5 μL of each sample was first transferred via a micropipette to glow-discharged (EMS 150T S flow discharger) QUANTIFOIL copper grids with holey carbon films (R 2/1, 200 mesh) and mounted in a grid plunge freezer (Leica EM GP) at 25 °C and 90% humidity.…”

“…2,6,11 In a previous study, a similar NE size distribution was measured using diffusion-ordered NMR spectroscopy (DOSY-NMR). 3 In certain cases, when the o/s ratio was optimized, the coexistence of the NE and ME in the emulsion could be identified. 17…”

Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects

“…This modification did not alter the granulometric profile that stayed narrow with PDI below 0.2 or the system’s stability. Finally, compared to commonly commercialized intravenous drug-loaded NEs such as Propofol, exhibiting mean diameters between 250 and 280 nm, the slight increase of the hydrodynamic diameter did not alter the capacity of the system to be intravenously administered ( Patil et al, 2019 ).…”

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

“…The peaks were readily assignable with the help of chemical shift databases [ 29 , 30 ] or 2D 1 H- 13 C spectra. The excipient polysorbate 80 (PS80) had a more complicated spectrum, with major peaks at 3.7, 2.3, 2.0, 1.6, 1.3 and 0.9 ppm [ 31 ]. Importantly, all excipient peaks should be excluded when protein HOS comparison is performed.…”