Biocompatible Alginate Microgel Particles as Heteronucleants and Encapsulating Vehicles for Hydrophilic and Hydrophobic Drugs

Biocompatible materials that can control crystallization while carrying large amounts of active pharmaceutical ingredients (APIs) with diverse chemical properties are in demand in industrial practice. In this study, we investigate the utility of biocompatible alginate (ALG) hydrogels as a rational material for crystallizing and encapsulating model APIs that present drastically different solubilities in water. Acetaminophen (ACM) and fenofibrate (FEN) are utilized as the model hydrophilic and hydrophobic moieties, respectively. ALG hydrogels with different ALG concentrations (hence different mesh sizes) are utilized as heteronucleants to control the nucleation kinetics of ACM from solution. ALG hydrogels with smaller mesh sizes showed faster nucleation kinetics. We hypothesize that this behavior is due to the interplay between the polymer–solute interactions and the mesh-induced confinement effects. The loading of ACM into hydrogels by equilibrium partitioning is quantified and found to be inversely proportional to ALG concentration. For hydrophobic model APIs, loading via equilibrium partitioning is inefficient; hence, we suggest emulsion-laden hydrogels where emulsion droplets are encapsulated inside the hydrogel matrix. The incorporation of emulsion droplets inside hydrogels enables the high loading of the hydrophobic API leveraging the high solubility of the hydrophobic API in the dispersed emulsion droplets. By carefully choosing the emulsification method and the dispersed phase, we demonstrate significant loading (up to ∼80% w/w) and crystallization of the stable form of FEN. Our results provide new insights for designing biocompatible nucleation-active materials capable of carrying industrially significant amounts of water-soluble and insoluble APIs in the crystalline form.Novartis-MIT Center for Continuous Manufacturin