(432g) Microfluidic Studies of the Production of Polymer Microparticles By Solvent Extraction from Polymer Solution Droplets

Solvent extraction is a popular method to prepare polymer microparticles for drug delivery. In this process, a polymer is dissolved in an organic solvent or oil, and the solution is emulsified into an aqueous bulk phase, chosen such that it is partially miscible with the solvent in the drop phase. The idea is to selectively dissolve the solvent in the aqueous(bulk) phase, thereby increasing the polymer concentration in the drop phase. When sufficient solvent has been extracted from the polymer solution, the residue is typically the polymer in a glassy state with very low solvent concentration, which is dried to produce a polymer microparticle.

Several bench-scale studies have examined the solvent extraction method of preparing polymer microparticles^1-5. An important conclusion from these studies is that the extraction rate of the solvent depends on several parameters such as, solvent concentration in the aqueous phase, solvent type and solubility, dispersed to continuous phase volume ratio, polymer composition and concentration, etc. More importantly, the extraction rate directly impacts the morphology and the porosity of the microparticle, by affecting the polymer concentration distribution during the solvent extraction process, and also, by creating water droplet inclusions within the polymer solution drop. However, to establish these connections, many of these works only measured the averaged residual solvent content in the particles and did not determine the dynamic process by which the residual content was reached. It is highly desirable to understand the dynamics of emulsification, extraction, and solidification at the level of a single drop, and their relationships with the resulting microparticle morphology⁶. In our work here, we will discuss our experimental observations on the nature of the solvent extraction dynamics for drops under sheared conditions.

Droplet-based microfluidics is a popular platform for generating monodisperse drops for a variety of purposes. While there are several investigations in the literature touting the capability of this platform to produce monodisperse polymer particles, researchers have only recently recognized the capability of this platform to implement a careful and systematic investigation of the details of emulsification, solvent extraction and microparticle formation under shear. The contribution of our lab to the microfluidic literature is the microfluidic extensional flow device (MEFD)^7,8, which is a diagnostic platform for emulsion-related studies. Our experiments, conducted in an MEFD, have enabled us to create a hydrodynamic trap in a diamond shaped channel, where we can trap Hele-Shaw drops and observe their dissolution process under shear for an extended period of time.

In this project, we have focused on the combination of the polymer poly(lactic-co-glycolic acid) or PLGA, the solvent ethyl acetate (EtOAc), and the compatibilizing surfactant polyvinyl alcohol (PVA) in water as the aqueous phase. PVA is a commonly used stabilizer and tablet coating material in the pharmaceutical industry and PLGA is a polymer, used commonly for targeted drug delivery device production and controlled release treatments. In the talk, we will discuss the dynamics of the EtOAc extraction process from a PLGA drop under shear, and elucidate the effects of extensional rate, EtOAc concentration in the bulk aqueous phase, the initial drop size, and the polymer concentration in the drop on the extraction rate and the resulting polymer particle morphology.

References

1. Jeyanthi, R., Thanoo, B., Metha, R. & DeLuca, P. Effect of solvent removal technique on the matrix characteristics of polylactide/glycolide microspheres for peptide delivery. Journal of Controlled Release 38, 235–244 (1996).

2. Sah, H. Microencapsulation techniques using ethyl acetate as a dispersed solvent: effects of its extraction rate on the characteristics of PLGA microspheres. Journal of Controlled Release 47, 233–245 (1997).

3. Bahl, Y. & Sah, H. Dynamic changes in size distribution of emulsion droplets during ethyl acetate-based microencapsulation process. AAPS PharmSciTech 1, 41–49 (2000).

4. Soppimath, K. & Aminabhavi, T. Ethyl acetate as a dispersing solvent in the production of poly (DL-lactide-co-glycolide) microspheres: effect of process parameters and polymer type. Journal of microencapsulation 19, 281–292 (2002).

5. Godbee, J., Scott, E., Pattamunuch, P., Chen, S. & Mathiowitz, E. Role of solvent/non-solvent ratio on microsphere formation using the solvent removal method. Journal of microencapsulation 21, 151–160 (2004).

6. Kinoshita, K., Parra, E., Hussein, A., Utoft, A., Walke, P., De Bruijn, R. & Needham,D. From single microparticles to microfluidic emulsification: fundamental properties (solubility, density, phase separation) from micropipette manipulation of solvent, drug and polymer microspheres. Processes 4, 49 (2016).

7. Motagamwala, A. H. A Microfluidic, Extensional Flow Device for Manipulating Soft Particles. M.A.Sc. Thesis, University of Toronto (2013).

8. Goel, S., Joshi, N., Uddin, M. S., Ng, S., Acosta, E. & Ramachandran, A. Interfacial tension of the water-diluted bitumen interface at high bitumen concentrations measured using a microfluidic technique. Langmuir 35, 15710–15722 (2019).