(626a) Liposome Processing Using a Turbulent Jet in Co-Flow: Experiments and Multi-Scale Models

Mukherjee, R., UConn
Costa, A., UConn
Gupta, A., UConn
Yenduri, G., UConn
Xu, X., Office of Testing and Research, U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Chaudhuri, B., University of Connecticut
Burgess, D., UConn

Continuous processing administers considerable advantages over batch manufacturing to improve scalability, automated control and incorporation of process analytical technology. Liposomes are complex dosage forms with multiple FDA approved drug products presently available. Conventional methods to form liposomes do not provide for precise control of the particle size and particle size distribution both of which can directly impact encapsulation efficiency, cellular uptake and biodistribution. The continuous manufacturing platform provides precise control over liposome formation including monitoring of particle size and size distribution. The present study focuses on coaxial turbulent jet flow design to control liposome properties and quantify them as a function of the flow conditions (velocity, temperature, Reynold’s number). Computational Fluid Dynamics (CFD) is further performed to verify the dynamics of the environment at site of liposome formation. Molecular Dynamics (MD) simulation are being further performed to analyze the lipid-lipid interactions and lipid-salt interactions at the liposomal formation site.


Liposomes were formed using an ethanol injection method with a custom-built continuous processing system that is controlled using a program developed using National Instruments LabVIEW. Briefly, the continuous processing system consists of multiple tanks that contain lipid dissolved in ethanol and another set of tanks for the aqueous components (e.g.DI water or buffer salts). At-line particle size measurements were performed with a Malvern Zetasizer Nano using a flow-through cell. Particle size measurements were measured off-line and compared with the at-line measurements. Fluid flow profiles (i.e. Flow Velocity ratio (FVR) vs Reynolds number (Re) were related to the liposomal size distribution (i.e.Z-Average particle size and PDI). CFD geometry similar to the continuous liposome manufacturing unit was developed using ANSYS 19.0. Species Transport Equations were implemented to predict the fluidic microenvironment at the site of liposome formation and was validated with experimental data by image analysis and fluid flow dimensions (FVR and Re) of the co-axial jet formed from ethanol water mixture.


The continuous processing system at UConn can form monodispersed liposomes. Process parameters can be controlled to regulate the velocity, density, and viscosity at the co-axial jet. The liposome mean particle size can also be controlled and has dependence on the Reynolds number of the mixed fluid. The CFD studies have successfully be used to predict the experimental flow properties observed at the co-axial jet. Based on the FVR and Re, the model provides insight on the alteration of the micro-environment at the liposome formation site. In addition, MD modeling can be used to understand the differences in liposome formation based on factors such as type of lipid and aqueous phase additives.


The liposome size and PDI can be systematically controlled using a co-axial turbulent jet in co-flow. The non-linear increment of the ethanol-water mixture viscosity at the site of liposome formation (predicted from the CFD studies), plays a significant role to alter the fluid properties and can be directly related to the liposome dimensions and distribution. MD simulations are being performed to predict the mechanism of liposome formation due to variability of fluid flow properties and physical properties of the formulation.


This work was supported by the FDA (1U01FD005773-01).


This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.