A Design of Experiment Study of Nanoprecipitation and Nano Spray Drying as Processes to Prepare PLGA Nano- and Microparticles with Defined Sizes and Size Distributions.

PURPOSE: Aim of this study was to explore the potential of a design of experiments approach to nanoprecipitation (NPR) and nano spray drying (NSD) as processes for preparing poly (lactic-co-glycolic acid, PLGA) nano- and microparticles. In particular, we determined the feasible size range, critical factors influencing particle size, size distribution or yield, and the robustness towards variations of the batch size. METHODS: A fractional factorial design for response surface was applied to study the influence on continuous, categorical and discrete factors. RESULTS: NPR yielded nanoparticles (150-200 nm) with narrow size distribution (PDI < 0.15). Polymer concentration was the main factor in this process, which was found to be very robust to varying the batch size (0.625-50.0 ml). In contrast, NSD yielded microparticles (2-163 µm). The latter process appeared, however, to be influenced by various factors and, therefore, more difficult to control and less robust towards varying the batch size (5-40 ml). By a factorial design approach to NPR, we succeeded to derive an equation, which allowed the prediction of several optimal formulations with defined particle sizes and distributions. CONCLUSION: DOE can help to understand innovative manufacturing processes for nano- and microparticulate drug delivery systems, as well as to optimize these processes regarding particle size, size distribution and yield. Such understanding of these processes is instrumental for their subsequent scale up and quality control as needed for preclinical and clinical test batches.

Preparation and characterization of highly stable lipid nanoparticles with amorphous core of tuneable viscosity.

Lipid nanoparticles (LNP) have been designed based on low cost and human-use approved excipients, and manufactured by an easy, robust, and up-scalable process. Fluid colloidal dispersions or gel viscous formulations of highly stable nanoparticles (more than 12 month stability is achieved for some formulations) can be obtained. Their physicochemical properties are studied by Dynamic Light Scattering, Differential Scanning Calorimetry, and NMR. The results picture nanoparticles with a non-crystalline core, which viscosity can be finely tuned by the lipid composition and the temperature. A design of experiments has been used to investigate the limits of the system colloidal stability. The impact of core and surfactant weight fractions have been explored both experimentally and using the design of experiments. The versatility of this physicochemical system could open the way to a wide range of future pharmaceutical applications.

The development of high quality seals for silicon patch-clamp chips.

Planar patch-clamp is a two-dimensional variation of traditional patch-clamp. By contrast to classical glass micropipette, the seal quality of silicon patch-clamp chips (i.e. seal resistance and seal success rate) have remained poor due to the planar geometry and the nature of the substrate and thus partially obliterate the advantages related to planar patch-clamp. The characterization of physical parameters involved in seal formation is thus of major interest. In this paper, we demonstrate that the physical characterization of surfaces by a set of techniques (Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), X-ray Photoelectron Spectroscopy (XPS), surface energy (polar and dispersive contributions), drop angles, impedance spectroscopy, combined with a statistical design of experiments (DOE)) allowed us discriminating chips that provide relevant performances for planar patch-clamp analysis. Analyses of seal quality demonstrate that dispersive interactions and micropore size are the most crucial physical parameters of chip surfaces, by contrast to surface roughness and dielectric membrane thickness. This multi-scale study combined with electrophysiological validation of chips on a diverse set of cell-types expressing various ion channels (IRK1, hERG and hNa(v)1.5 channels) unveiled a suitable patch-clamp chip candidate. This original approach may inspire novel strategies for selecting appropriate surface parameters dedicated to biochips.