New unique PAT method and instrument for real-time inline size characterization of concentrated, flowing...

With the rise of nanotherapeutics -and nano based products in general-, there has been an increasing need for better understanding and control of nano-particle (NP) synthesis and formulation processes. Size characteristics are often primary, if not critical, quality attributes of nanodispersions. Process Analytical Technology (PAT) tools for inline size characterization during dispersion processing are therefore highly desired. Traditional methods for NP sizing -based on Dynamic Light Scattering (DLS) - are typically ill-suited for direct inline application: (i) typical dispersion turbidities in process conditions often exceed by far the application limits for DLS (ii) agitation/flow typical for process conditions is incompatible with standard DLS and (iii) direct and convenient inline application requires a non-invasive PAT tool giving measurements on process relevant time scales. In this article we describe a new non-invasive PAT instrument - the NanoFlowSizer (patent pending)- which provides continuous, real-time, inline size and PSD characterization of concentrated and/or flowing nanodispersions in process environments. The instrument employs Fourier Domain low coherence interferometry, yielding path length resolved dynamic light scattering data of nanodispersions. Particle size characteristics can be analyzed from these data while effects of flow and/or multiple scattering are simultaneously characterized and accounted for. As first application examples we describe (i) real-time monitoring of NP size characteristics by remote measurement of mono and bi-disperse suspensions at different turbidities in a stirred beaker (ii) real-time monitoring of NP size characteristics using an online sampling loop with a micro-flow cell and (iii) real-time inline monitoring of size characteristics of a pharmaceutical nanoemulsion during industrial pilot scale nano-emulsification and for a pharmaceutical NP suspension during circulation, at flowrates ranging up to ~l/min.