(15c) Very Large Scale Microfluidic Droplet Integration for Continuous Industrial Scale Manufacturing of Monodisperse Biodegradable Micro and Nanoparticles

Microfluidics has been used to enable precise control of multiphasic flows to generate micrometer- and nanometer-scale materials with control and uniformity not possible using conventional technique. These micro- and nano-engineered materials have generated particular enthusiasm in the pharmaceutical industry where they have created new opportunities to generate novel drug formulations that offer unprecedented spatial and temporal control of drug delivery within the body. In comparison to conventional particle formation techniques, such as spray drying or ball milling, microfluidic-generated formulations have demonstrated increased particle monodispersity, more uniform composition of drug within the particles, increased drug yield, longer lasting formulations that are still injectable, and reduced burst release of drug.

Despite these advances, the inherently low production rate of droplet microfluidic devices < 100 milligrams per hour remains a key challenge to successfully translate the many promising laboratory-scale results of microfluidics to commercial-scale manufacturing. One promising direction to scale-up production has been the development of architectures that make it possible to operate many microfluidic droplet generators in parallel. While great progress has been made in these approaches, current chips with parallelized devices are limited to production rates ϕmax ⪍ 1 L h^−1, have droplet homogeneities set by three-dimensional (3D) soft-lithography fabrication, are limited to low temperature and pressure operation, can only be used with the solvents compatible with the device’s polymer construction, or are unable to be adapted to produce higher-order emulsions and particles that require multi-step processing.

In this talk, we present a novel microfluidic design of architectures for an individual droplet maker as well as at the device level to incorporate > 10,000 droplet makers in a single 4-inch silicon wafer. The design principles to integrate 2 0 droplet makers are developed analogous to the metal layers that are used in integrated circuits to connect transistors. The design architecture is implemented completely in silicon and glass. The device is fabricated using conventional photolithography and deep reactive ion etch (DRIE). Due to its silicon and glass construction, it can operate at high pressures (P>1000 psi), high temperatures (T> 200 C), and is compatible with a broad range of organic solvents, and thus greatly expands the library of micro- and nano-materials that can be generated. Moreover, it is robust for stable, continuous operation for industrial-scale production of micro and nanoparticles. Similarly, to design an individual droplet maker, the physics of multiphase flows is considered such that the device can generate monodisperse emulsions at maximum flow rate with a small footprint.

The massively parallelized microfluidic chip is used to generate oil in water emulsions. Hexadecane droplets were generated with varying sizes ranging from 22 um to 40 um with a coefficient of variation of 3% and a production rate of 1 trillion droplets per hour (7 Liters per hour dispersed phase, 9.2 Liters per hour continuous phase). To test the generation of United States Food and Drug Administration (US FDA) approved biodegradable microparticles, polycaprolactone microparticles with sizes ranging from 8 um to 16 um with a CV < 5% and a production rate of 277 grams per hour were synthesized using this chip. In addition, we also show the industrial scale production of nanoparticles with precise control over their size and target density.

Acknowledgements:

National Science Foundation ((1554200), NIH (R01 EB022612) and Glaxo Smith Kline. D.L. acknowledge the support from NSF CBET 1604536.

References:

1. Silicon and Glass Very Larege Scale Microfluidic droplet integration for the terra scale generation of polymer microparticles, Sagar Yadavali, Heon Ho Jeong, Daeyeon Lee, David Issadore, Nature Communications, (2018) 9: 1222 (DOI: 10.1038/s41467-018-03515-2).
2. Sagar Yadavali, David Issadore &; Daeyeon Lee, “Large scale microdroplet generation apparatus and methods of manufacturing there of,” PCT/US2016/066501, filed on December 14 th , 2016; US62/268,205