(175f) Overcoming the Challenges of Fluoro-Pharmaceutical Encapsulation Via Flash Nanoprecipitation through Solubility Parameter Matching

Nanoparticle-based drug delivery systems have shown great success in increasing bioavailability and reducing adverse effects of small molecule therapeutics. Flash Nanoprecipitation (FNP) is a well-established, scalable nanoparticle synthesis process used to encapsulate hydrophobic small molecule drugs into core-shell polymeric nanoparticles. Due to the unique properties of fluorine, which can improve absorption, distribution, metabolism and excretion of drugs, fluorinated active pharmaceutical ingredients (F-APIs) have been of increasing interest, reaching the popularity of biologics. However, due to the fluorous effect, highly electronegative fluoro- functional groups prevent anchoring of commonly used stabilizing polymers (PLA, PCL) onto the nanoparticle drug core formed during the precipitation process of FNP. Thus far, F-API’s have been challenging to encapsulate into nanoparticles via FNP.

Solution

Here, we present a strategy to overcome this challenge and successfully encapsulate a wide range of F-API’s into nanoparticles via FNP. We use a solubility parameter matching framework to guide our stabilizing polymer selection to enable the nanoparticle encapsulation of F-APIs via FNP. It is theorized that the highly electronegative fluorine groups cause an increase in dispersion forces. Additionally, while fluorine is not very polarizable on its own, it can induce changes in the electronic distribution of the overall molecule of interest and therefore the polar solubility parameter. Furthermore, fluorine is a poor hydrogen bond acceptor due to its high electronegativity, but it can act as a weak hydrogen bond donor. Introduction of fluorine atoms may disrupt or reduce the number of hydrogen bonding sites in a molecule and therefore affect the hydrogen bonding solubility parameter. Therefore, we hypothesized that the selection of core materials and fluorinated APIs with similar solubility parameters (dispersion, polarity, h-bonding) is crucial to stable encapsulation via FNP.

Methods

Hansen solubility parameters of core materials (e.g. polylactic acid, polystyrene, poly(4-chlorostyrene), polydimethylsiloxane, and polyvinyl caprolactam-polyvinyl acetate) and fluorinated APIs (e.g. aprepitant, GSK2193874, celecoxib, crizotinib, and riluzole) were calculated using Group Contributions Method and molecular modeling computational software. Core-shell nanoparticles were then formed via FNP, utilizing materials with matched and mismatched solubility parameters. Tetrahydrofuran was used as the solvent system and ultrapure water as the antisolvent. FNP was performed using a multi-inlet vortex mixer (MIVM). Particle size, polydispersity (PDI) and stability were characterized using dynamic light scattering (DLS), TEM and zeta potential. Drug loading, encapsulation efficiency (EE) and release kinetics were characterized via thermogravimetric analysis (TGA) and high performance liquid chromatography (HPLC).

Results and Implications

FNP encapsulation of fluorinated APIs with core materials of matching solubility showed both enhanced encapsulation efficiency and stability compared to traditional FNP strategies. While traditional PLA did not adequately encapsulate and stabilize the majority of the APIs, other stabilizing polymers showed significant improvements in formulation. For example, a substance P/neurokinin 1 receptor antagonist, known as Aprepitant (APT), showed instability during the particle synthesis process and dialysis when tested with PLA core material (Figure 1A). These particles (Table 1) had a size distribution of 80 nm, 0.15 PDI and extremely low encapsulation efficiency (0.1%). However, when tested with Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol), there was a clear improvement in encapsulation efficiency (81.0%) and stability throughout the purification and characterization (Figure 1B). This finding bridges the gap between scalable nanoscale drug delivery formulation systems and next-generation fluoro-pharmaceutical development. We provide a promising framework for formulating polymeric fluoro-pharmaceutical drug delivery systems which has remained a persistent obstacle for the FNP process. This further expands the types of APIs that can be encapsulated into nanoparticles via FNP.