Andreas Eitzlmayr

Mechanistic modeling of modular co-rotating twin-screw extruders

In this study, we present a one-dimensional (1D) model of the metering zone of a modular, co-rotating twin-screw extruder for pharmaceutical hot melt extrusion (HME). The model accounts for filling ratio, pressure, melt temperature in screw channels and gaps, driving power, torque and the residence time distribution (RTD). It requires two empirical parameters for each screw element to be determined experimentally or numerically using computational fluid dynamics (CFD). The required Nusselt correlation for the heat transfer to the barrel was determined from experimental data. We present results for a fluid with a constant viscosity in comparison to literature data obtained from CFD simulations. Moreover, we show how to incorporate the rheology of a typical, non-Newtonian polymer melt, and present results in comparison to measurements. For both cases, we achieved excellent agreement. Furthermore, we present results for the RTD, based on experimental data from the literature, and found good agreement with simulations, in which the entire HME process was approximated with the metering model, assuming a constant viscosity for the polymer melt.

In‐Vitro Permeability of Neutral Polystyrene Particles via Buccal Mucosa

Drugs can be absorbed well in the oral cavity, which eliminates problems related to intestinal and hepatic first-pass metabolism. Although it is well-established that nanoparticles are small enough to penetrate/permeate epithelial barriers, there is no clear understanding of how they interact with the buccal mucosa. This work provides useful information regarding particle properties with regard to mucosal uptake and can be used for the rational design of nanocarriers. In the buccal mucosa, the uptake of neutral polystyrene nanoparticles (PP) is size-dependent. Compared to 25 and 50 nm particles, 200 nm PP particles penetrate into deeper regions of the mucosa. This is attributed to the structure of the buccal mucosa, i.e., mucus layer and microplicae. The particles permeate the mucus layer and deposit in ridge-like folds of superficial buccal cells. Thus, the effects of thermodynamic driving forces and/or interparticle electrostatic repulsion are enhanced and cellular uptake might be reduced for smaller particle sizes.

Nano-extrusion: a promising tool for continuous manufacturing of solid nano-formulations.

Since more than 40% of todays drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween(®) 80 as a stabilizer. The matrix material (Soluplus(®)) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano-extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano-extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance.

Modeling and simulation of polyacrylic acid/protamine nanoparticle precipitation

In this study a model for the prediction of polyacrylic acid/protamine nanoparticle precipitation was developed, which constitutes the first numerical approach for modeling the precipitation of organic nanoparticles. Due to the complexity of the process, a spatial resolution (i.e., a simulation via computational fluid dynamics) was not the target. For the description of the precipitation process, population balance equations, accounting for nucleation, growth and aggregation were used and coupled with the engulfment model for mixing. Furthermore, experiments have been carried out by turbulent mixing of precursors in a vortex mixer. Measurements of the resulting particle size distributions and of the final concentrations in the liquid were performed. Finally, by selecting unknown parameters, it was possible to achieve a good agreement of experimental and numerical results. It was found that the formation of the electrostatic surface charge, caused by a layer of protamine on the particle surface, cannot be described instantaneously. Small deviations in the final liquid concentrations and particle size distributions are probably caused by the significant simplifications introduced by the engulfment model and by the description of the solid/liquid equilibrium. However, the presented model may serve as a basis for further development, i.e., by replacing the engulfment model by more sophisticated approaches, e.g., via computational fluid dynamics.

Thinking continuously: a microreactor for the production and scale-up of biodegradable, self-assembled nanoparticles

Scale-up of nanoparticle batch productions continues to be a major challenge in the pharmaceutical nanotechnology. Continuously operating microreactors have great potential to circumvent the scale-up difficulties. In this work a passive microreactor was used for the first time for the electrostatic self-assembly of biodegradable, mucoadhesive thiomer–protamine nanoparticles for drug delivery. The influence of three different parameters (the overall flow rate, the educt mass ratio and the molecular weight of the thiomer) on the particle characteristics was tested for the microreactor production and compared to the results of a successful 1 ml-batch reaction. As the flow rate increased (2, 5, 9, 16 ml min−1), the particle sizes and the polydispersity indexes decreased. In addition, the protamine : 5 kDa thiomer binding ratio and hence the zeta potential, as a measure of the suspensions stability, increased to >+40 mV due to better mixing during the microreactor production at a flow rate of 16 ml min−1. Producing nanoparticles from different mass ratios of 5 kDa thiomer : protamine (1 : 1, 1 : 3, 1 : 5) in the microreactor at this flow rate resulted in smaller particles with more distinct zeta potentials than those prepared by the 1 ml-batch reaction. Using a higher molecular weight thiomer (30 kDa) for the microreactor production at a flow rate of 16 ml min−1 led to slightly increased mean particle sizes (125.0 nm) compared to those produced by the 1 ml-batch reaction (102.9 nm). However, there was still a decrease in the width of the particle size distributions. In addition to the experimental work, a numerical model based on the population balance equation was developed. The results presented in this paper are in agreement with the experimental findings, especially with regard to the trends of decreased particle size and polydispersity with the increasing flow rate. The model results confirm that mixing effects to a great extent determine the particle size distribution of the resulting nanoparticles and show that spatial inhomogeneity of the mixing process must be taken into account. The unprecedented use of a passive microreactor for the production of biodegradable thiomer–protamine nanoparticles by electrostatic self-assembly was a success. Due to the reactors continuous way of operation, not only were the scale-up problems of batch reactions overcome, but particle characteristics were also improved because of a better mixing effect.