Polymeric Drug Nanocarrier Production by Nanoprecipitation-Solvent Neutralization: A Chemically Driven Route to Rapid Solvent Removal

Abstract

We report a bottom-up strategy, termed nanoprecipitation-solvent neutralization, for the preparation of drug-loaded polymeric nanospheres and nanocapsules for pharmaceutical applications. The method is compatible with hydrolysis-sensitive drug molecules and accommodates pharmaceutically approved polymers and excipients that are water-insoluble across the entire pH range. In this approach, an organic phase containing polymer and, when appropriate, additional hydrophobic components dissolved in glacial acetic acid is combined with an aqueous phase containing a stabilizer, inducing nanoparticle nucleation and growth via the Ouzo effect. Glacial acetic acid serves both as the nanoprecipitation solvent and as a chemically removable species that can be converted into a water-soluble salt through a simple acid–base reaction. Following particle formation, solvent neutralization substantially reduces solvent-removal times relative to conventional evaporation-based nanoprecipitation without the need for specialized equipment. No significant degradation of polymers-drugs, or stabilizers was observed by GPC and HPLC analyses despite the presence of hydrolysis-sensitive bonds. The use of a weak base following the transient acidic step was fundamental for maintaining formulation stability by generating a buffering system in the near-neutral pH range. Mechanistic insights obtained using an environment-sensitive photophysical probe revealed a transition in the medium polarity and pH consistent with efficient solvent-to-salt conversion following nanoparticle formation. The method was effective across systems containing hydrophobic components and enabled the preparation of nanoparticles stabilized with nonionic, anionic, or cationic surfactants, allowing modulation of surface charge. The resulting nanoparticles exhibited diameters ranging from 146 to 272 nm and spherical morphology with smooth surfaces, as confirmed by TEM. The salt formed during solvent neutralization could be readily removed without affecting nanoparticle properties. Overall, this approach establishes a chemically driven route to nanoprecipitation in which solvent removal is not governed by mass transport, providing a simple and versatile platform for the production of polymeric nanoparticles for pharmaceutical applications.