A continuously operated tubular crystallizer system with an inner diameter of 2.0 mm has been successfully operated. It allows the crystallization of active pharmaceutical ingredients (APIs) under controlled conditions. Acetylsalicylic acid (ASA) which was crystallized from ethanol (EtOH) was used as the model substance. An ethanolic suspension of ASA-seeds was fed into the tubular crystallizer system, where it was mixed with a slightly undersaturated ASA-EtOH solution that was kept at an elevated temperature in its storage vessel. Supersaturation was created via cooling and the seeds grew to form the product crystals. This work mainly focuses on the proof-of-concept and on the impact of the flow rates on the product crystals and the crystal size distribution (CSD). All other parameters including concentrations, temperatures, and loading of seeds were kept constant. Higher flow velocities generally resulted in reduced number and volume mean diameters, due to reduced tendency of agglomeration and decreased time for crystal growth due to shorter residence times of the suspension in the tube. Generally, all experiments unmistakably led to shifting of volume density distributions toward significantly larger values for product crystals in comparison to the seeds and were capable of yielding product masses in a g/min scale.

A continuous tubular crystallizer system with an inner diameter of 2.0 mm and an overall length of 27 m was used to generate acetylsalicylic acid seeds in situ from ethanolic solution via cooling and ultrasound irradiation and to grow the crystals in the tubing with a controlled temperature trajectory. In order to minimize the residence time distribution, air bubbles were introduced into the system to generate a segmented gas-slurry flow. The narrow residence time distribution and the tight temperature control in the small tubing due to the large surface to volume ratio resulted in relatively narrow crystal size distributions of the product. Generally, all experiments clearly demonstrated significant crystal growth for the product crystals in comparison to the seeds and yielded product masses on the g/min scale. Furthermore, it was demonstrated that the size of the product can be easily controlled via fines removal by dissolution due to rapid heating and varying the mass of seeds per mL of solution.

This study investigates the effects of seed loading on the mean crystal size of the model substance, acetylsalicylic acid, crystallized from ethanol in a continuously seeded tubular crystallizer. A hot, highly concentrated ethanolic acetylsalicylic acid solution was mixed with an acetylsalicylic acid-ethanol seed suspension. Subsequent cooling of the slurry in the tubing promoted supersaturation and hence crystal growth. The tubular shape of the 15 m-long crystallizer with an inner diameter of 2 mm enabled narrow residence time distributions of the crystals in the pipe and excellent temperature control in the radial direction and along the tubing. Crystals entering the crystallizer had both identical growth conditions in each section and about the same time for crystal growth. Narrow crystal size distributions were achieved with decreasing differences in the volume-mean-diameter sizes of the seed and product crystals as seed loadings increased. Decreasing the seed size had a similar effect as increasing the seed loading, since in that case the same amount of seed mass resulted in more individual seed particles. Altering the arrangement of the coiled crystallizer with respect to spatial directions (horizontal, vertical) did not lead to a significantly different outcome. All experiments produced considerably larger product crystals in comparison to the seeds despite relatively short crystallization times of less than 3 min. Moreover, product mass gains of a few hundred percent at a g/min-scale were achieved. Similarities in product crystal samples taken at different times at the outlet of the crystallizer showed that steady-state conditions were rapidly reached in the continuous flow crystallization device.

The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer system developed in our group overcomes obstacles like a slow response to changes in the outer parameters and inhomogeneous mixing. Therefore the applicable well mixed assumption facilitates detailed modeling of the crystallization process by means of population balance equations (PBE) coupled with mass and energy balances. Modeled results were validated by means of experiments. The amount of aggregation events during the crystallization could be quantified and it was proven that the growth of seeded crystals is almost exclusively responsible for solid mass uptake if the reactor is operated appropriately. The performed sensitivity analysis exposed which process settings should be maintained most accurately to avoid fluctuations in the product crystals' quality attributes and to limit undesired nucleation events.

The multibody dynamics and finite element simulation code has been developed since 1997. In the past years, more than 10 researchers have contributed to certain parts of HOTINT, such as solver, graphical user interface, element library, joint library, finite element functionality and port blocks. Currently, a script-language based version of HOTINT is freely available for download, intended for research, education and industrial applications. The main features of the current available version include objects like point mass, rigid bodies, complex point-based joints, classical mechanical joints, flexible (nonlinear) beams, port-blocks for mechatronics applications and many other features such as loads, sensors and graphical objects. HOTINT includes a 3D graphical visualization showing the results immediately during simulation, which helps to reduce modelling errors. In the present paper, we show the current state and the structure of the code. Examples should demonstrate the easiness of use of HOTINT.

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A versatile two-step method has been developed that allows linking of biomolecules covalently to hydrogen-terminated group-IV semiconductors by means of epoxy-alkenes. First, the terminal C==C double bond of the alkene forms a covalent bond with the silicon, germanium, or diamond surface by UV-mediated hydrosilylation. The terminal oxirane moiety then reacts with the biomolecule. As a model system, we investigated the attachment of an esterase B to a Si(111) surface by means of the linker molecule 1,2-epoxy-9-decene. Samples were characterized by X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. The immobilized enzyme retained its activity and exhibited good long-term stability.

Eine direkte Messung der Bewegung von Nanopartikeln bei den hohen Geschwindigkeiten ist meistens kaum realisierbar. Hier wurde die Gasströmung in einem einstufigen Niederdruckimpaktor mithilfe einer CFD-Modellierung simuliert. Auf der Basis des berechneten Strömungsverlaufs wurden die Bahnen monodisperser Partikeln, insbesondere die Trennkurven für verschiedene Partikelgrößen als Funktion des Impaktionsdruckes berechnet. Lage und Verlauf der berechneten und experimentell ermittelten Trennkurven wurden miteinander verglichen.Die gemessenen Trennkurven für kugelförmige versinterte Silber-Nanoparti-keln deuten darauf hin, dass die klassische Cunningham-Korrektur bei der Niederdruckimpaktion die Partikelbewegung nicht korrekt erfasst. Die Impaktionsgeschwindigkeiten liegen deutlich über den Vorhersagen klassischer Modelle zum Strömungswiderstand von Nanopartikeln bei hohen Knudsen-Zahlen. Die Erklärung für den reduzierten Strömungswiderstand könnte mit der Art der Reflektion der Gasmoleküle an der Partikeloberfläche zusammenhängen. Li und Wang erklärten einen solchen Effekt durch den Übergang von vorwiegend diffuser Reflektion der Gasmoleküle zu spiegelnder ("specular") Reflektion [1]. Allerdings fanden sie den Übergang für Partikeln von 2-3 nm. Die hier vorgestellten Messungen deuten aber darauf hin, dass eine Erniedrigung des Strömungswiderstands in gleicher Größenordnung wie der von Li und Wang gefundenen auch bei erheblich größeren Nanopartikeln auftreten kann. Die Quantifizierung dieses erniedrigten Strömungswiderstands ist unter anderem essenziell für die definierte Beschichtung von Oberflächen mit Nanopartikeln.[1] Z. Li, H. Wang, Phys. Rev. 2003, E 68.