Measuring nanoparticle size distributions (PSD), continuously and during production processes is still one of the most challenging tasks within modern particle engineeringand production environments. Here we show a fast and new method, Opto-Fluidic Force Induction (OF2i), which tackles the high requirements as an online working Process Analytical Technology (PAT) tool. In contrast to conventional Brownian motion or scattering-based technologies, OF2i uses a novel approach utilizing optical forces for (de)accelerating of simultaneously trapped particle ensembles in a micro fluidic flow cell [1]. The OF2i working principle uses optical gradient forces [2] to constrain and define the location of particle ensembles in a known and precisely defined optical field (Fig. 1). Additionally, they are continuously transported by a known and well-defined laminar flow field within a dead volume optimized OF2i flow cell. With appropriately chosen particle concentration, which is controlled via a subsequent continuous working sample preparation/dilution unit for various initial particle concentration ranges, (i) intensities from single particle light scattering, (ii) single particle trajectories and (iii) constrained particle number per transported volume is obtained over time via an ultramicroscopic setup for up to 4000 particles per minute. This information is used to continuously calculate particle size, number-based size distributions and particle concentration for multi disperse particle systems with sub minute system time resolution for process- and quality control [3]. We demonstrated OF2i in pilot case studies, reaching from industrial oil in water emulsion production, case studies within an EU project (NanoPAT: n°862583) to dynamic insights into nanoparticle formation processes in biophysical applications and other heterophase systems.

Supersaturation is the driving force in crystallization processes. It expresses how much more material is solved than thermodynamically stable. Closed-loop control of crystallization PAT processes, therefore, often aims to control supersaturation [1]. The goal is to drive a process towards thermodynamic equilibrium and low concentration at moderate supersaturation. High supersaturation may cause excessive nucleation and inclusion of impurities. Low supersaturation will lead to long process times. Supersaturation must be measured in-inline in order to apply supersaturation control. This is particularly hard to achieve in multi-component solutions where calibration of concentration measurements are hard and multiple components and/or multiple statevariables affect solubility. To overcome this hurdle we present direct growth rate control as an alternative PAT approach. We will present how the growth rate of a single crystal can be measured inline. A crystal is fixed in front of an in-line microscope’s lens. Image analysis based on Hough-transform is used to track the position of a single face of the fixed crystal. A Kalman-Filter estimates the current growth rate from these measurements. We used our new technique to measure the growth rate in a benchmark cooling crystallization process (Fig. 1) with predefined, linear temperature profile. This demonstrates that high growth rates were present in the beginning of the process and little growth occurred after half of the process time. In a second process with the same initial condition (Fig. 2), we used the measured growth rate as input for a PI-controller. It controlled the cooling power of the reactor and achieved a moderate growth rate throughout the process. (Graph)- Fig. 1 | Course of the growth rate in a benchmark process with predefined temperature profile. The process started at t=0min. Fig. 2 | Course of the process with controlled growth rate. The process started at t=0min with the same initial condition as the process shown in Fig. 1. TR: Reactor temperature TJ: Jacket temperature Gmeasured:Measured growth rate Gset: Command variable

Acoustic radiation forces are exerted on particles in suspension when exposed to ultrasound. This effect can be exploited to locally enhance their concentration in an ultrasonic standing wave - in other words an in-line sample of the solid can be generated directly inside the process. Particles in this context can be any structures that form an interface in the liquid, i.e. crystals, biological cells as well as oil droplets or gas bubbles. We from usePAT set out to apply this effect in an ultrasonic trap called soniccatch. The device can be used in different fields of application and industries ranging from pharmaceutical production to wastewater treatment. The talk will include examples of combining the soniccatch with vibrational spectroscopic methods as Raman spectroscopy or FTIR ATR absorption spectroscopy and are of high practical importance for in-line measuring solutions. The first lab experiment presented will describe how polymer particles can be caught directly in the focal point of a Raman probe, where they are readily available for determination [1,2]. Further examples will include measurements of cells suspensions, namely the physiological assessment of yeast cells with Raman spectroscopy in a classical bioprocess. The in-line acquired spectra of the yeast cells reveal the different chemical composition of the intracellular makeup during the fermentation. A more sophisticated approach was chosen when the selectivity of an FTIR ATR probe was tremendously improved by the application of soniccatch. Here, the combination of the two technologies was able to detect the product inside the cells and thus contribute to monitoring the fermentation process and identifying optimisation potentials of such advanced process control possibilities [3]. Finally in a close-to-production experiment the PHB content of Cyanobacteria could be directly measured inside a bioreactor, without interfering with the process [4].

Grinding processes for comminution or deagglomeration of solids are very important in the process industry. Products that have been ground are omnipresent in our everyday life. Grinding can be used to adjust the particle size distribution or the specific surface area of products in a very targeted manner and thus changing product properties.[1] For example, the rheological behaviour of pigment dispersions, but also their colour strength, transparency and gloss can be changed by grinding.[2] In order to produce particles in the small micrometre to nanometre range, which are prone to agglomeration, wet grinding processes are usually used.[1] The result of the grinding process, i.e., the particle size distribution is decisive for the product quality and is almost always analysed off-line or at best at-line. Laser diffraction (LD) and microscopy (optical OM and scanning electron microscopy SEM) are the main methods used. With all of those methods, some sample preparation is required prior to measurement (LD: dilution; OM: preparation on slides; SEM: drying, sputter coating with gold). The results are therefore only representative to a limited extent and are only available with a time delay. We will present Photon Density Wave (PDW) spectroscopy [3,4] as an on-line or in-line process analytical technology (PAT) [5] for monitoring wet milling processes in real time.