title: Core-Shell Composite Hydrogels for Controlled Nanocrystal Formation and Release of Hydrophobic Active Pharmaceutical Ingredients.
abstract: Although roughly 40% of pharmaceuticals being developed are poorly water soluble, this class of drugs lacks a formulation strategy capable of producing high loads, fast dissolution kinetics, and low energy input. In this work, a novel bottom-up approach is developed for producing and formulating nanocrystals of poorly water-soluble active pharmaceutical ingredients (APIs) using core-shell composite hydrogel beads. Organic phase nanoemulsion droplets stabilized by polyvinyl alcohol (PVA) and containing a model hydrophobic API (fenofibrate) are embedded in the alginate hydrogel matrix and subsequently act as crystallization reactors. Controlled evaporation of this composite material produces core-shell structured alginate-PVA hydrogels with drug nanocrystals (500-650 nm) embedded within the core. Adjustable loading of API nanocrystals up to 83% by weight is achieved with dissolution (of 80% of the drug) occurring in as little as 30 min. A quantitative model is also developed and experimentally validated that the drug release patterns of the fenofibrate nanocrystals can be modulated by controlling the thickness of the PVA shell and drug loading. Thus, these composite materials offer a "designer" drug delivery system. Overall, our approach enables a novel means of simultaneous controlled crystallization and formulation of hydrophobic drugs that circumvents energy intensive top-down processes in traditional manufacturing.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Abu Zayed Md
authors.initials: AZ
authors.lastname: Badruddoza
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Godfrin
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Allan S
authors.initials: AS
authors.lastname: Myerson
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Bernhardt L
authors.initials: BL
authors.lastname: Trout
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Doyle
mesh_terms: D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D011345:Fenofibrate / Q000737:chemistry / Q000493:pharmacokinetics; D020100:Hydrogels / Q000737:chemistry / Q000493:pharmacokinetics; D053758:Nanoparticles / Q000737:chemistry*; D011142:Polyvinyl Alcohol / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D011142:Polyvinyl Alcohol; D011345:Fenofibrate
keywords: confinement; core-shell hydrogels; crystallization; formulation; nanocrystals