TY - CONF A1 - Kern, Simon A1 - Wander, Lukas A1 - Meyer, Klas A1 - Guhl, Svetlana A1 - Gottu Mukkula, A. R. A1 - Holtkamp, M. A1 - Salge, M. A1 - Fleischer, C. A1 - Weber, N. A1 - King, R. A1 - Engell, S. A1 - Paul, Andrea A1 - Pereira Remelhe, M. A1 - Maiwald, Michael T1 - Flexible Automation with compact NMR instruments N2 - Modular plants using intensified continuous processes represent an appealing concept to produce pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes, and it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and includes a compact Nuclear Magnetic Resonance (NMR) spectrometer for online quality monitoring as well as a new model-based control approach. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including ro-bust evaluation of sensor data. Here, we present alternatives for the quantitative determination of the analytes using modular, physically motivated models. These models can be adapted to new substances solely by the use of their corresponding pure component spectra, which can either be derived from experimental spectra as well as from quantum mechanical models or NMR predictors. Modular means that spec-tral models can simply be exchanged together with alternate reagents and products. Beyond that, we comprehensively calibrated an NIR spectrometer based on online NMR process data for the first time within an industrial plant. The integrated solution was developed for a metal organic reac-tion running on a commercial-scale modular pilot plant and it was tested under industrial conditions. T2 - 7th Annual PANIC Conference CY - Hilton Head Island, South Carolina, USA DA - 03.03.2019 KW - Online NMR Spectroscopy PY - 2019 AN - OPUS4-47715 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - GEN A1 - Kern, Simon A1 - Wander, Lukas A1 - Meyer, Klas A1 - Guhl, Svetlana A1 - Gottu Mukkula, A. R. A1 - Holtkamp, M. A1 - Salge, M. A1 - Fleischer, C. A1 - Weber, N. A1 - Engell, S. A1 - Paul, Andrea A1 - King, R. A1 - Maiwald, Michael T1 - Raw data of pilot plant runs for CONSENS project (Case study 1) N2 - In case study one of the CONSENS project, two aromatic substances were coupled by a lithiation reaction, which is a prominent example in pharmaceutical industry. The two aromatic reactants (Aniline and o-FNB) were mixed with Lithium-base (LiHMDS) in a continuous modular plant to produce the desired product (Li-NDPA) and a salt (LiF). The salt precipitates which leads to the formation of particles. The feed streams were subject to variation to drive the plant to its optimum. The uploaded data comprises the results from four days during continuous plant operation time. Each day is denoted from day 1-4 and represents the dates 2017-09-26, 2017-09-28, 2017-10-10, 2017-10-17. In the following the contents of the files are explained. KW - Process Analytical Technology KW - Multivariate Data Analysis KW - Nuclear Magnetic Resonance KW - Near Infrared Spectroscopy KW - Continuous Manufacturing KW - CONSENS PY - 2018 U6 - https://doi.org/10.5281/zenodo.1438233 PB - Zenodo CY - Geneva AN - OPUS4-48063 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Michalik-Onichimowska, Aleksandra A1 - Kern, Simon A1 - Riedel, Jens A1 - Panne, Ulrich A1 - King, R. A1 - Maiwald, Michael T1 - ‘‘Click” analytics for ‘‘click” chemistry – A simple method for calibration–free evaluation of online NMR spectra N2 - Driven mostly by the search for chemical syntheses under biocompatible conditions, so called "click" chemistry rapidly became a growing field of research. The resulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via comparably straightforward and robust analysis techniques possessing short set-up times. Here, we report on a fast and reliable calibration-free online NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement of 1H spectra with a time interval of 20 s per spectrum, and a robust, fully automated algorithm to interpret the obtained data. As a proof-of-concept, the thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was conducted in a variety of non-deuterated solvents while its time-resolved behaviour was characterized with step tracer experiments. Overlapping signals in online spectra during thiol-ene coupling could be deconvoluted with a spectral model using indirect hard modeling and were subsequently converted to either molar ratios (using a calibrationfree approach) or absolute concentrations (using 1-point calibration). For various solvents the kinetic constant k for pseudo-first order reaction was estimated to be 3.9 h-1 at 25 °C. The obtained results were compared with direct integration of non-overlapping signals and showed good agreement with the implemented mass balance. KW - Online NMR Spectroscopy KW - Reaction Monitoring KW - Automated Data Evaluation KW - Thiol-ene click chemistry KW - Click Chemistry KW - Process Analytical Technology PY - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-393232 UR - http://www.sciencedirect.com/science/article/pii/S1090780717300575 VL - 277 SP - 154 EP - 161 PB - Elsevier Inc. CY - Oxford AN - OPUS4-39323 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Krämer, D. A1 - Violet, N. A1 - Paul, Andrea A1 - Maiwald, Michael A1 - King, R. T1 - Robustification of partial least squares predictions based on near infrared spectroscopy trough nonlinear state estimation N2 - The Cultivation of “Saccharomyces cerevisiae” for enzyme production was monitored using Near-infrared spectroscopy. An inline NIR optrode was therefore immersed in a 15 L vessel. The calibration was done using a Partial Least Squares (PLS) model with reference measurements of glucose, ammonium, phosphate, ethanol, and optical density. A nonlinear biological process model based on an extended Kalman Filter (EKF) was used to describe the fermentation behavior. It was found that EKF corrects inaccurate PLS predictions. T2 - 11. Kolloquium Arbeitskreis Prozessanalytik CY - Wien, Austria DA - 30.11.2015 KW - PLS-R KW - Near infrared spectroscopy KW - Prozess-Spektroskopie KW - Process analytical technology KW - Fermentation PY - 2015 SP - 77 EP - 77 PB - Bundesanstalt für Materialforschung und -prüfung (BAM) CY - Berlin AN - OPUS4-38844 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Kern, Simon A1 - Michalik-Onichimowska, Aleksandra A1 - Riedel, Jens A1 - Panne, Ulrich A1 - King, R. A1 - Maiwald, Michael ED - Herwig, Christoph T1 - “Click” analytics for “click” chemistry – a simple method for calibration-free evaluation of online NMR spectra N2 - Currently, research in chemical manufacturing moves towards flexible plug-and-play approaches focusing on modular plants, capable of producing small scales on-demand with short down-times between individual campaigns. This approach allows for efficient use of hardware, a faster optimization of the process conditions, and thus, an accelerated introduction of new products to the market. Driven mostly by the search for chemical syntheses under biocompatible conditions, so-called “click” chemistry rapidly became a growing field of research. The resulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via comparably straightforward and robust analysis techniques. Here we report on a fast and reliable calibration-free online high field NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement with a time interval of 20 s per spectrum, and a robust, automated algorithm to interpret the obtained data. All spectra were acquired using a 500 MHz NMR spectrometer (Varian) with a dual band flow probe having a 1/16-inch polymer tubing working as a flow cell. Single scan 1H NMR spectra were recorded with an acquisition time of 5 s, relaxation delay of 15 s. As a proof-of-concept, the thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was conducted in non-deuterated solvents while its time-resolved behaviour was characterised with step tracer experiments. Through the application of spectral modeling the signal area for each reactant can be deconvoluted in the online spectra and thus converted to the respective concentrations or molar ratios. The signals which were suitable for direct integration were used herein for comparison purposes of both methods. T2 - 11. Interdisziplinäres Doktorandenseminar CY - Berlin, Germany DA - 12.03.2017 KW - Process Monitoring KW - Online NMR Spectroscopy KW - Indirect Hard Modeling KW - Process Control KW - Process Analytical Technology KW - CONSENS KW - Click Chemistry PY - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-435531 SP - 33 EP - 35 PB - Gesellschaft Deutscher Chemiker (GDCh) CY - Frankfurt a. M. AN - OPUS4-43553 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Kern, Simon A1 - Michalik-Onichimowska, Aleksandra A1 - Riedel, Jens A1 - Panne, Ulrich A1 - King, R. A1 - Maiwald, Michael T1 - “Click” analytics for “click” chemistry – a simple method for calibration-free evaluation of online NMR spectra N2 - Currently research in chemical manufacturing moves towards flexible plug-and-play approaches focusing on modular plants, capable of producing small scales ondemand with short down-times between individual campaigns. This approach allows for efficient use of hardware, a faster optimization of the process conditions, and thus, an accelerated introduction of new products to the market. Driven mostly by the search for chemical syntheses under biocompatible conditions, so-called “click” chemistry rapidly became a growing field of research. The resulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via comparably straightforward and robust analysis techniques. Here we report on a fast and reliable calibration-free online high field NMR monitoring approach for technical mixtures. It combines a versatile fluidic system, continuous-flow measurement with a time interval of 20 s per spectrum, and a robust, automated algorithm to interpret the obtained data. All spectra were acquired using a 500 MHz NMR spectrometer (Varian) with a dual band flow probe having a 1/16 inch polymer tubing working as a flow cell. Single scan 1H spectra were recorded with an acquisition time of 5 s, relaxation delay of 15 s. As a proof-of-concept, the thiol-ene coupling between N-boc cysteine methyl ester and allyl alcohol was conducted in non-deuterated solvents while its time-resolved behaviour was characterised with step tracer experiments Through the application of spectral modeling the signal area for each reactant can be deconvoluted in the online spectra and thus converted to the respective concentrations or molar ratios. The signals which were suitable for direct integration were used herein for comparison purposes of both methods. T2 - 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) CY - Potsdam, Germany DA - 10.05.2017 KW - Online NMR Spectroscopy KW - Process Analytical Technology KW - Click Chemistry KW - Reaction Monitoring KW - Process control KW - Indirect Hard Modeling KW - Spectral Modeling PY - 2017 SP - 156 EP - 157 CY - Frankfurt a. M. AN - OPUS4-40232 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Kern, Simon A1 - Meyer, Klas A1 - Guhl, Svetlana A1 - Gräßer, Patrick A1 - Paul, Andrea A1 - King, R. A1 - Maiwald, Michael T1 - Online low-field NMR spectroscopy for process control of an industrial lithiation reaction—automated data analysis N2 - Monitoring specific chemical properties is the key to chemical process control. Today, mainly optical online methods are applied, which require time- and cost-intensive calibration effort. NMR spectroscopy, with its advantage being a direct comparison method without need for calibration, has a high potential for closed-loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and rough environments for process monitoring and advanced process control strategies. We present a fully automated data analysis approach which is completely based on physically motivated spectral models as first principles information (Indirect Hard Modelling – IHM) and applied it to a given pharmaceutical lithiation reaction in the framework of the European Union’s Horizon 2020 project CONSENS. Online low-field NMR (LF NMR) data was analysed by IHM with low calibration effort, compared to a multivariate PLS-R (Partial Least Squares Regression) approach, and both validated using online high-field NMR (HF NMR) spectroscopy. KW - Online NMR spectroscopy KW - Process analytical technology KW - Partial Least Squares Regression KW - Indirect Hard Modeling KW - Benchtop NMR Spectroscopy KW - Smart Sensors KW - CONSENS PY - 2018 UR - https://link.springer.com/article/10.1007/s00216-018-1020-z U6 - https://doi.org/10.1007/s00216-018-1020-z SN - 1618-2642 SN - 1618-2650 VL - 410 IS - 14 SP - 3349 EP - 3360 PB - Springer CY - Berlin, Heidelberg AN - OPUS4-44847 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -