[Crystal Growth & Design] Bottom-up Structural Design of Crystalline Drug-Excipient Composite Mi
We present a simple, bottom up method for the structural design of solid microparticles containing crystalline drug and excipient using microfluidic droplet-based processing. In a model system comprising 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (‘ROY’) as the drug and ethyl cellulose (‘EC’) as the excipient, we demonstrate a diversity of particle structures, with exquisite control over the structural outcome at the single-particle level. Within microfluidic droplets containing drug and excipient, tuning droplet composition and solvent removal rates allows us to controllably access structural diversity via an interplay of three physical processes (liquid-liquid phase separation, drug crystallization and polymer vitrification) occurring during solvent removal. Specifically, we demonstrate two levels of structural control – a coarse ‘macro’ particle structure and a finer ‘micro’ structure. Further, we elucidate the key mechanistic elements responsible for the observed structural diversity using a combination of systematic experiments, thermodynamic arguments based on a three-component phase diagram, and molecular simulations. We validate our method with two different excipient and drug combinations – ROY and poly(lactic-co-glycolic acid) (‘PLGA’), and EC and carbamazepine (‘CBZ’). Finally, we present preliminary investigations of in vitro drug release from two different types of CBZ-EC particles, highlighting how structural control allows the design of drug release profiles.
Eunice W.Q. Yeap, Denise Z. L. Ng, Prhashanna Ammu, Ambika Somasundar, Andrew J. Acevedo, Qisong Xu, Fatma Salahioglu, Marc V. Garland, and Saif A. Khan Cryst. Growth Des., Just Accepted Manuscript DOI: 10.1021/acs.cgd.6b01701 Publication Date (Web): April 21, 2017 Copyright © 2017 American Chemical Society