Imaging, Predicting, and Controlling Reversible Flocculation of Nanocarriers for Advanced Processing

Abstract

Flash NanoPrecipitation (FNP) is a nanocarrier formulation technique that has been used to enhance the oral bioavailability of poorly water-soluble drugs. FNP is a continuous process that can be easily scaled up and implemented in large-scale nanocarrier manufacturing.1–4 However, the drying process of nanocarriers that results in stable, easily transportable dry powder is time-consuming and energetically intensive for large volumes of dilute nanocarriers, which hinders the translation of FNP to large-scale manufacturing when the desired final product is a dry powder.2–4 Thus, acid-based flocculation was previously investigated as a potential method for concentrating the nanocarriers prior to spray drying.4 The method was shown to successfully flocculate the nanocarriers in a reversible manner, so this thesis examined ways to optimize the concentration step to further improve processing at scale.4 In large-scale processing, we anticipate the flocculated nanocarrier suspension will need to be managed using pumps/stirrers and other equipment that applies mechanical shear on the flocculates. This thesis therefore also examined the effect of shear on nanocarrier flocs to determine whether or not shear leads to floc breakup, hindering settling time and filtration. This thesis investigated the effects of process conditions on the flocculation time and resulting floc fractal dimension. Nanocarriers were formulated using the FNP. A small amount of 1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine perchlorate (DiI) dye was included in the nanocarriers’ core to allow for confocal imaging together with polystyrene (PS), and hydroxypropyl methylcellulose acetate succinate 126 (HPMCAS- 126) was used as a stabilizer. Nanocarriers were then flocculated under various process conditions and imaged using confocal microscopy to capture the flocculation dynamics and the resulting floc fractal dimension. Nanocarriers were also sheared using a rheometer at different shear rates and dwell times. Samples were let to settle while being continuously photographed to examine the effects of shear stress on nanocarrier settling time. Confocal images were analyzed using custom Mathematica scripts to measure the nanocarrier settling dynamics in different process conditions and calculate the fractal dimension of the resulting flocs. These results can be used in the future to inform the optimization of the nanocarrier concentration step. We also find that applying shear stress to flocculated nanocarrier suspension does not break up the flocs. Instead, shear stress application compresses the flocs and slightly enhances nanocarrier settling, implying that pumping operations to manipulate flocculated nanocarrier suspensions are feasible at scale.