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

Abstract

An oil-in-water (o/w) nanoemulsion (NE), composed of oil globules, stabilized by a surfactant, and dispersed in an aqueous phase, is increasingly developed in complex drug formulation. Kinetically stable NEs are used to formulate hydrophobic drugs and typically provide higher dosage strengths and better content uniformity. However, little is known accurately about drug distribution in its multiphase solution, especially for the possible drug presence in the surfactant (s) phase, the interface layer between the dispersed oil (o) and the continuous water (w) phases. Here, high-resolution 19 F quantitative NMR spectroscopy was applied directly and noninvasively on an o/w NE drug product containing difluprednate (DFPN). The wellresolved 19 F peaks of DFPN depended on the shielding molecules in each phase, which revealed mass-balanced DFPN distribution in multiple phases of (w), (s), and (o) of NE globules at a quantity of 1.8 ± 0.1, 35 ± 2, and 59 ± 3% per labeled content, respectively. Furthermore, the dilution-dependent 19 F peak line broadening and shift suggested a millisecond dynamic exchange between the NE and the less-noticed smaller but thermodynamically stable microemulsion (ME) globules in NE solution. The high-resolution NMR result revealed that the drug availability could be quickly achieved using an o/w NE formulation because of the drug multiphase distribution and the ME-assisted fast drug exchange among globules.

Fast Dynamics of Difluprednate in Micelles or Swollen-Micelles Revealed by 19F Nuclear Magnetic Resonance Spin Relaxation Rates

“…The chemical shift of F28 was sensitive to its environment of PS-80 surfactant or castor oil and experienced a 0.1 ppm change when DFPN was exchanged from s-micelle to the surfactant layer of the larger nanoglobule due to globule collision. 2 The chemical exchange of F28 in the s-micelle sample was observed before in oil-in-water emulsion 2 and confirmed in the current CPMG dispersion test (Figure S1).…”

“…The calculated R 2 rates of F28 in s-micelle differed by −39% from R exp of 600 MHz, more than the −16% of R exp of 400 MHz (Table ), due to the chemical exchange contribution ( R ex ) in s-micelle (dashed lines in Figure B). The chemical shift of F28 was sensitive to its environment of PS-80 surfactant or castor oil and experienced a 0.1 ppm change when DFPN was exchanged from s-micelle to the surfactant layer of the larger nanoglobule due to globule collision . The chemical exchange of F28 in the s-micelle sample was observed before in oil-in-water emulsion and confirmed in the current CPMG dispersion test (Figure S1).…”

“…Amphiphilic surfactant molecules assemble into nanometer (nm) sized micelle globules, which are dispersed in an aqueous solution. Micelles can be utilized to encapsulate hydrophobic drug molecules. − Additionally, oil can be incorporated into a micelle structure to enhance drug solubility, forming swollen micelles (s-micelles) or microemulsion (ME) globules (Figure A). , Viscosities of both surfactant and oil are 2 orders of magnitude higher than that of water; however, little is known about the dynamics of drug molecules in the viscous hydrophobic phase inside micelles. Knowledge of rotational motion is critical to explain NMR peak line shape and assess the applicability and accuracy of quantitative NMR (qNMR).…”

“…The DFPN peaks in the micelle were sharp. The DFPN peaks in s-micelles had more line-broadening and shifted to a higher field due to more shielding from oil molecules . The R 1 and R 2 relaxation rates were measured using inversion recovery (Figure A) and Carr–Purcell–Meiboom–Gill (CPMG) (Figure B) pulse sequences, respectively, at 600 and 400 MHz field strength (Figure C–F, Table ).…”

“…Molecular dynamics simulation may shed light on predictions of small molecular rotational diffusion including slip-boundary motion, but not necessarily using the no-slip boundary SED equation . Practically, the fast nanosecond dynamics of small molecules in viscous media suggests that quantitative NMR (qNMR) could be universally applicable in complex soft-core solutions or drug formulations, advancing our knowledge in quantifying molecular distribution and interactions in complex drug formulations …”