Continuous production of PVA-based hydrogel nanoparticles by membrane nanoprecipitation

The use of membranes as dispersing tools opens new development perspectives to the traditional nanoprecipitation technique by overcoming one of its major limitations, related to its exclusive use in batch processes and for small scale formulations. In this work the suitability of membrane nanoprecipitation for the formulation of uniform hydrogel nanoparticles (H-NPs) based on polyvinyl alcohol (PVA) in a continuous process has been demonstrated. This is a challenging formulation even for the traditional nanoprecipitation process, which has been well studied mainly for polymers of a hydrophobic nature. A systematic study of the phase composition and operating conditions of membrane nanoprecipitation allowed us to clarify the influence of the components involved in PVA nanoprecipitation promoted by non-solvent-induced phase separation and to identify the conditions to ensure the continuous production of uniform PVA hydrogel NPs. The size of PVA-H-NPs was tailored by tuning the solvent, non-solvent (dispersing medium), PVA concentration and volumetric ratio between solvent and non-solvent. The use of a porous membrane to assist nanoprecipitation in the batch allowed us to demonstrate that nanoprecipitation was not influenced by flux through the membrane or wall shear stress, but mainly by the solvent/non-solvent volumetric ratio. The obtained knowledge permitted to set up the membrane system for the continuous preparation of PVA-H-NPs, which was carried out in single-pass cross-flow mode. To the best of our knowledge, this is the first preparation of PVA-H-NPs in a continuous membrane nanoprecipitation process. Compared to batch nanoprecipitation, an order of magnitude higher mass productivity was achieved.