Real time size measurements of turbid, flowing lipid nanoparticle suspensions

C. Schuurmans, M. Hermes, R. Arribas Bueno, A. Gerich, R. Besseling

Keywords: continuous manufacturing/nanoparticles/


The development, production and quality control of therapeutics involve complex processes with many critical parameters to monitor. One essential monitoring parameter for nanoparticle based therapeutics is the hydrodynamic diameter of the therapeutic vector (typical size range: ~10-300 nm). Until recently, methods to monitor particle size during processes were not available, with most sizing analysis being performed through analysis of samples taken during the process or on the end product. Often these samples have to be processed for measurement, potentially altering the therapeutic’s observed particle size. These additional steps can result in impractical and/or incorrect measurements. Here, we introduce the NanoFlowSizer, an in-line measuring device that can determine the hydrodynamic size of nanoparticulate suspensions whilst in flow. The NanoFlowSizer is based on Spatially Resolved Dynamic Light Scattering (SR-DLS), a technique that combines low coherence interferometry with traditional dynamic light scattering. Through the use of SR-DLS, it becomes possible to simultaneously resolve both the diffusion speed and position of nanoparticles in suspension, allowing for sizing measurements to be done in flow. Additionally, SR-DLS confers the ability to differentiate between multiple and single scattered light, making particle size determination in highly turbid formulations possible. The ability to non-invasively measure particle size of nanotherapeutics in flow allows for a myriad of options and opportunities in the analysis and control of therapeutical manufacturing processes. Specifically the application of the Nanoflowsizer in in situ process control measurements of lipid-based nanoparticles will be shown.