Journal
CRYSTAL GROWTH & DESIGN
Volume 17, Issue 6, Pages 3030-3039Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.cgd.6b01701
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Funding
- GSK-EDB fund for Sustainable Manufacturing in Singapore
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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 dissipative particle dynamics simulations. We validate our method with two different excipient and drug combinations-ROY and poly(lactic-co-glycolic acid), and EC and carbamazepine (CBZ). Finally, we present preliniinary 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.
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