Production of hyaluronic acid (HA) nanoparticles by a continuous process inside microchannels: Effects of non-solvents, organic phase flow rate, and HA concentration

Abstract

Nanostructured materials have drawn increased interest due to their potential applications in various scientific and technological areas. Additionally, interest in natural polymers has grown because of their biodegradability and non-toxicity. Although hyaluronic acid (HA) is an attractive natural polymer capable of hydration and interaction with cells of the immunological system, there have been few studies on the preparation of HA nanoparticles. Nanoparticles have generally been prepared through emulsification or nanoprecipitation in discontinuous processes. In this work, we describe an innovative process for production of HA nanoparticles by nanoprecipitation at the interface of organic solvent/water phases, flowing in laminar flow inside microchannels. The results showed that the production of nanosized HA nanoparticles crosslinked with adipic dihydrazide and chloride carbodiimide was feasible in a cross junction microchannel. This continuous process provided better controlled conditions, which led to more homogeneously sized nanoparticles than the conventional discontinuous processes. The influence of the organic solvent (HA non-solvent), its flow rate, and the HA concentration were studied. The produced nanoparticles presented sizes ranging from 140 to 460 nm, depending on operational conditions, low polydispersity, and negative zeta potential irrespective of the experimental conditions. The smallest particles were obtained with ethanol, due to its higher affinity for water, at the lower HA concentrations or with the higher flow rates of the organic phase.