Dokument-ID Dokumenttyp Autoren/innen Persönliche Herausgeber/innen Haupttitel Abstract Auflage Verlagsort Verlag Herausgeber (Institution) Erscheinungsjahr Titel des übergeordneten Werkes Jahrgang/Band ISBN Veranstaltung Veranstaltungsort Beginndatum der Veranstaltung Enddatum der Veranstaltung Ausgabe/Heft Erste Seite Letzte Seite URN DOI Lizenz Datum der Freischaltung OPUS4-36333 Zeitschriftenartikel Zientek, Nicolai; Meyer, Klas; Kern, Simon; Maiwald, Michael Quantitative online NMR spectroscopy in a nutshell Online NMR spectroscopy is an excellent tool to study complex reacting multicomponent mixtures and gain process insight and understanding. For online studies under process conditions, flow NMR probes can be used in a wide range of temperature and pressure. This paper compiles the most important aspects towards quantitative process NMR spectroscopy in complex multicomponent mixtures and provides examples. After NMR spectroscopy is introduced as an online method and for technical samples without sample preparation in deuterated solvents, influences of the residence time distribution, pre-magnetization, and cell design are discussed. NMR acquisition and processing parameters as well as data preparation methods are presented and the most practical data analysis strategies are introduced. Weinheim, Germany Wiley-VCH Verlag GmbH & Co. KGaA 2016 Chemie Ingenieur Technik 88 6 698 709 10.1002/cite.201500120 2016-06-02 OPUS4-39323 Zeitschriftenartikel Michalik-Onichimowska, Aleksandra; Kern, Simon; Riedel, Jens; Panne, Ulrich; King, R.; Maiwald, Michael ''Click" analytics for ''click" chemistry - A simple method for calibration-free evaluation of online NMR spectra 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. Oxford Elsevier Inc. 2017 Journal of Magnetic Resonance 277 154 161 urn:nbn:de:kobv:b43-393232 10.1016/j.jmr.2017.02.018 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2017-03-13 OPUS4-37356 Zeitschriftenartikel Meyer, Klas; Kern, Simon; Zientek, Nicolai; Guthausen, G.; Maiwald, Michael Process control with compact NMR Compact nuclear magnetic resonance (NMR) instruments make NMR spectroscopy and relaxometry accessible in industrial and harsh environments for reaction and process control. An increasing number of applications are reported. To build an interdisciplinary bridge between "process control" and "compact NMR",we give a short overviewon current developments in the field of process Engineering such as modern process design, integrated processes, intensified processes along with requirements to process control, model based control, or soft sensing. Finally, robust field integration of NMR systems into processes environments, facing explosion protection or Integration into process control systems, are briefly discussed. Elsevier 2016 Trends in Analytical Chemistry 83 Part A / SI 39 52 urn:nbn:de:kobv:b43-373562 10.1016/j.trac.2016.03.016 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2016-09-15 OPUS4-41577 Beitrag zu einem Tagungsband Maiwald, Michael; Gräßer, Patrick; Wander, Lukas; Zientek, Nicolai; Guhl, Svetlana; Meyer, Klas; Kern, Simon Strangers in the Night—Smart Process Sensors in Our Current Automation Landscape The departure from the current automation landscape to next generation automation concepts for the process industry has already begun. Smart functions of sensors simplify their use and enable plug-and-play integration, even though they may appear to be more complex at first sight. Smart sensors enable concepts like self-diagnostics, self-calibration, and self-configuration/parameterization whenever our current automation landscape allows it. Here we summarize the currently discussed general requirements for process sensors 4.0 and introduce a smart online NMR sensor module as example, which was developed for an intensified industrial process funded by the EU's Horizon 2020 research and innovation programme (www.consens-spire.eu). Basel MDPI 2017 Proceedings 1 Eurosensors 2017 Conference Paris, France 03.09.2017 06.09.2017 628 631 urn:nbn:de:kobv:b43-415772 10.3390/proceedings1040628 http://creativecommons.org/licenses/by/3.0/de/deed.de 2017-08-24 OPUS4-43252 Beitrag zu einem Tagungsband Maiwald, Michael; Gräßer, Patrick; Wander, Lukas; Guhl, Svetlana; Meyer, Klas; Kern, Simon Innen hui und außen pfui - Smarte Prozess-Sensoren in der gegenwärtigen Automatisierungslandschaft der Prozessindustrie Der Wandel von der aktuellen Automation zum smarten Sensor ist im vollen Gange. Automatisierungstechnik, sowie die Informations- und Kommunikationstechnik (IKT) verschmelzen zunehmend. Eine Topologie für smarte Sensoren, die das Zusammenwirken mit daten- und modellbasierten Steuerungen bis hin zur Softsensorik beschreibt gibt es bis heute jedoch noch nicht. Um zu einer störungsfreien Kommunikation aller Komponenten auf Basis eines einheitlichen Protokolls zu kommen sollte die Prozessindustrie die Weichen für eine smarte und sichere Kommunikationsarchitektur stellen. Sie verwehrt stattdessen die Entwicklungen ihrer Zulieferer und wartet lieber ab. Der Beitrag greift die Anforderungen der Technologie-Roadmap „Prozess-Sensoren 4.0" auf und zeigt Möglichkeiten zu ihrer Realisierung am Beispiel eines Online-NMR-Analysators, der im Rahmen eines EU-Projekts entwickelt wurde. Berlin AMA Service GmbH AMA Verband für Sensorik und Messtechnik e.V. 2017 Tagungsband 13. Dresdner Sensor-Symposium 978-3-9816876-5-1 13. Dresdner Sensor Symposium Dresden, Germany 04.12.2017 06.12.2017 61 66 10.5162/13dss2017/2.1 2017-12-07 OPUS4-47715 Posterpräsentation Kern, Simon; Wander, Lukas; Meyer, Klas; Guhl, Svetlana; Gottu Mukkula, A. R.; Holtkamp, M.; Salge, M.; Fleischer, C.; Weber, N.; King, R.; Engell, S.; Paul, Andrea; Pereira Remelhe, M.; Maiwald, Michael Flexible Automation with compact NMR instruments 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. 2019 7th Annual PANIC Conference Hilton Head Island, South Carolina, USA 03.03.2019 07.03.2019 2019-04-03 OPUS4-48062 Zeitschriftenartikel Kern, Simon; Wander, Lukas; Meyer, Klas; Guhl, Svetlana; Gottu Mukkula, A. R.; Holtkamp, M.; Salge, M.; Fleischer, C.; Weber, N.; Engell, S.; Paul, Andrea; Pereira Remelhe, M.; Maiwald, Michael Flexible automation with compact NMR spectroscopy for continuous production of pharmaceuticals Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, 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 is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance. Heidelberg Springer Nature 2019 Analytical and Bioanalytical Chemistry 411 14 3037 3046 urn:nbn:de:kobv:b43-480623 10.1007/s00216-019-01752-y https://creativecommons.org/licenses/by/4.0/deed.de 2019-05-27 OPUS4-48063 Forschungsdatensatz Kern, Simon; Wander, Lukas; Meyer, Klas; Guhl, Svetlana; Gottu Mukkula, A. R.; Holtkamp, M.; Salge, M.; Fleischer, C.; Weber, N.; Engell, S.; Paul, Andrea; King, R.; Maiwald, Michael Raw data of pilot plant runs for CONSENS project (Case study 1) 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. Geneva Zenodo 2018 10.5281/zenodo.1438233 https://creativecommons.org/licenses/by/4.0/deed.de 2019-05-29 OPUS4-38385 Beitrag zu einem Tagungsband Kern, Simon; Michalik-Onichimowska, Aleksandra; Riedel, Jens; Panne, Ulrich; King, Rudibert; Maiwald, Michael Maiwald, Michael "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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 cam-paigns. 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 re-sulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via compara-bly 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 algo-rithm to interpret the ob-tained 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. 2016 Tagungsband – 12. Kolloquium Prozessanalytik, Berlin, 28.–30. November 2016 12. Kolloquium des Arbeitskreises Prozessanalytik Berlin, Germany 28.11.2016 30.11.2016 72 74 2016-11-22 OPUS4-40232 Beitrag zu einem Tagungsband Kern, Simon; Michalik-Onichimowska, Aleksandra; Riedel, Jens; Panne, Ulrich; King, R.; Maiwald, Michael "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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. Frankfurt a. M. DECHEMA e. V., Frankfurt 2017 Processdings of 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) Potsdam, Germany 10.05.2017 12.05.2017 156 157 2017-05-15 OPUS4-43553 Beitrag zu einem Tagungsband Kern, Simon; Michalik-Onichimowska, Aleksandra; Riedel, Jens; Panne, Ulrich; King, R.; Maiwald, Michael Herwig, Christoph "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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. Frankfurt a. M. Gesellschaft Deutscher Chemiker (GDCh) 2017 Tagungsband 11. Interdisziplinäres Doktorandenseminar 11. Interdisziplinäres Doktorandenseminar Berlin, Germany 12.03.2017 14.03.2017 33 35 urn:nbn:de:kobv:b43-435531 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2018-01-03 OPUS4-37317 Beitrag zu einem Tagungsband Kern, Simon; Meyer, Klas; Paul, Andrea; Maiwald, Michael Ugly Spectra and Lousy interfaces - Challenges for Compact NMR Spectroscopy in Process Control With the introduction of advanced process analytical technology, the closeness of key process variables to their limits can be directly controlled and the product can be classified or even released in real time. Compact NMR instruments can make NMR spectroscopy accessible in industrial and harsh environments for process control. Weinheim Wiley-VCH Verlag GmbH & Co. KGaA 2016 Chemie Ingenieur Technik 88 ProcessNet-Jahrestagung und 32. DECHEMA-Jahrestagung der Biotechnologen 2016 Aachen, Germany 12.09.2016 15.09.2016 1304 1317 10.1002/cite.201650243 2016-09-12 OPUS4-38675 Zeitschriftenartikel Kern, Simon; Meyer, Klas; Maiwald, Michael NMR-Spektroskopie im Feld - Eine neue Online-Methode für die Prozesskontrolle Flexible, modulare Produktionsanlagen auf der Basis von verfahrenstechnischen Teilmodulen stellen einen vielversprechenden Ansatz für die kontinuierliche Produktion von Fein- und Spezialchemikalien dar. Der Schwerpunkt des Horizont-2020-Projekts der Europäischen Kommission CONSENS (Integrated Control and Sensing) liegt in der Implementierung von innovativen Sensorkonzepten zur Prozessüberwachung und -regelung innerhalb von containerbasierten modularen Produktionsan lagen. In diesem Artikel wird die Feldintegration eines Online-NMR-Sensors als smartes Modul für die Prozesskontrolle beschrieben. Dieses Modul basiert auf einem kommerziell erhältlichen Niederfeld-NMRSpektrometer, das zurzeit für die Anwendung im Laborbereich erhältlich ist. Für die Feldintegration wurde ein ATEX-zertifiziertes, explosionsgeschütztes Gehäuse entwickelt sowie Automationsschemen für den unbeaufsichtigten Betrieb und für die spektrale Datenauswertung erstellt. Nachdem die Machbarkeit und Leistungsfähigkeit des Sensorkonzeptes in Laborexperimente an einer aromatischen Substitutionsreaktion bereits erfolgreich demonstriert wurde, ist die Inbetriebnahme des NMR-Sensormoduls in industrieller Umgebung für 2017 geplant. München DIV Deutscher Industrieverlag GmbH 2016 ATP-Edition (Automatisierungstechnische Praxis) 58 12 21 25 2016-12-14 OPUS4-44847 Zeitschriftenartikel Kern, Simon; Meyer, Klas; Guhl, Svetlana; Gräßer, Patrick; Paul, Andrea; King, R.; Maiwald, Michael Online low-field NMR spectroscopy for process control of an industrial lithiation reaction—automated data analysis 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. Berlin, Heidelberg Springer 2018 Analytical and Bioanalytical Chemistry 410 14 3349 3360 10.1007/s00216-018-1020-z 2018-05-07 OPUS4-40969 Vortrag Kern, Simon; Maiwald, Michael Low field NMR spectroscopy for process control - robust automated data preparation and analysis as prerequisites Berichtet wird über die automatisierte und spektral-modellgestützte Datenauswertung quantitativer Online-NMR-Spektren von technischen Systemen, die einen grundlegenden Beitrag zum Thematik Smart Sensors im Sinne kalibrierarmer bzw. kalibrierfreier Verfahren liefern. Die quantitative Online-NMR-Spektroskopie ist besonders reizvoll für diese Thematik: Sie kommt durch den direkten Nachweis der Kernspins ohne Kalibrierung aus und arbeitet auch in Konzentrationsrandbereichen äußerst linear. Als „absolute Vergleichsmethode" (direkte Proportionalität der Signale zu den Stoffmengen innerhalb eines Spektrums) ist die NMR-Spektroskopie für die durchgeführten Grundlagenuntersuchungen im Zusammenhang mit spektralen Modellen prädestiniert. 2017 Seminar des Institut für Mathematik, Universität Rostock Rostock, Germany 12.07.2017 12.07.2017 urn:nbn:de:kobv:b43-409694 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-07-13 OPUS4-50456 Forschungsdatensatz Kern, Simon; Liehr, Sascha; Wander, Lukas; Bornemann-Pfeiffer, Martin; Müller, S.; Maiwald, Michael; Kowarik, Stefan Training data of quantitative online NMR spectroscopy for artificial neural networks Data set of low-field NMR spectra of continuous synthesis of nitro-4'-methyldiphenylamine (MNDPA). 1H spectra (43 MHz) were recorded as single scans. Two different approaches for the generation of artificial neural networks training data for the prediction of reactant concentrations were used: (i) Training data based on combinations of measured pure component spectra and (ii) Training data based on a spectral model. Synthetic low-field NMR spectra First 4 columns in MAT-files represent component areas of each reactant within the synthetic mixture spectrum. Xi ("pure component spectra dataset") Xii ("spectral model dataset") Experimental low-field NMR spectra from MNDPA-Synthesis This data set represents low-field NMR-spectra recorded during continuous synthesis of nitro-4'-methyldiphenylamine (MNDPA). Reference values from high-field NMR results are included. Geneva Zenodo 2020 10.5281/zenodo.3677139 https://creativecommons.org/licenses/by/4.0/deed.de 2020-02-26 OPUS4-50750 Zeitschriftenartikel Kern, Simon; Liehr, Sascha; Wander, Lukas; Bornemann-Pfeiffer, Martin; Müller, S.; Maiwald, Michael; Kowarik, Stefan Artificial neural networks for quantitative online NMR spectroscopy Industry 4.0 is all about interconnectivity, sensor-enhanced process control, and data-driven systems. Process analytical technology (PAT) such as online nuclear magnetic resonance (NMR) spectroscopy is gaining in importance, as it increasingly contributes to automation and digitalization in production. In many cases up to now, however, a classical evaluation of process data and their transformation into knowledge is not possible or not economical due to the insufficiently large datasets available. When developing an automated method applicable in process control, sometimes only the basic data of a limited number of batch tests from typical product and process development campaigns are available. However, these datasets are not large enough for training machine-supported procedures. In this work, to overcome this limitation, a new procedure was developed, which allows physically motivated multiplication of the available reference data in order to obtain a sufficiently large dataset for training machine learning algorithms. The underlying example chemical synthesis was measured and analyzed with both application-relevant low-field NMR and high-field NMR spectroscopy as reference method. Artificial neural networks (ANNs) have the potential to infer valuable process information already from relatively limited input data. However, in order to predict the concentration at complex conditions (many reactants and wide concentration ranges), larger ANNs and, therefore, a larger Training dataset are required. We demonstrate that a moderately complex problem with four reactants can be addressed using ANNs in combination with the presented PAT method (low-field NMR) and with the proposed approach to generate meaningful training data. Berlin Springer 2020 Analytical and bioanalytical chemistry 412 18 4447 4459 urn:nbn:de:kobv:b43-507508 10.1007/s00216-020-02687-5 https://creativecommons.org/licenses/by/4.0/deed.de 2020-05-11 OPUS4-43254 Beitrag zu einem Tagungsband Kern, Simon; Guhl, Svetlana; Meyer, Klas; Wander, Lukas; Paul, Andrea; Maiwald, Michael Mathematical and statistical tools for online NMR spectroscopy in chemical processes Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied, which require excessive calibration effort. NMR spectroscopy has a high potential for direct loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and harsh environments for advanced process Monitoring and control, as demonstrated within the European Union's Horizon 2020 project CONSENS. We present a range of approaches for the automated spectra analysis moving from conventional multivariate statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modelling and Quantum Mechanical calculations). By using the benefits of traditional qNMR experiments data analysis models can meet the demands of the PAT community (Process Analytical Technology) regarding low calibration effort/calibration free methods, fast adaptions for new reactants or derivatives and robust automation schemes. Berlin AMA Service GmbH AMA Verband für Sensorik und Messtechnik e.V. 2017 Tagungsband 13. Dresdner Sensor-Symposium 978-3-9816876-5-1 13. Dresdner Sensor Symposium Dresden, Germany 04.12.2017 06.12.2017 P2, 209 212 10.5162/13dss2017/P2.07 2017-12-04 OPUS4-51391 Beitrag zu einem Tagungsband Kern, Simon; Guhl, Svetlana; Meyer, Klas; Wander, Lukas; Paul, Andrea; Bremser, Wolfram; Maiwald, Michael Mathematical and statistical tools for online NMR spectroscopy in chemical processes Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied, which require excessive calibration effort. NMR spectroscopy has a high potential for direct loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and harsh environ¬ments for advanced process monitoring and control, as demonstrated within the European Union's Horizon 2020 project CONSENS. We present a range of approaches for the automated spectra analysis moving from conventional multivariate statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modelling and Quantum Mechanical calculations). By using the benefits of traditional qNMR experiments data analysis models can meet the demands of the PAT community (Process Analytical Technology) regarding low calibration effort/calibration free methods, fast adaptions for new reactants or derivatives and robust automation schemes. New Jersey World Scientific 2018 Advanced Mathematical and Computational Tools in Metrology and Testing XI 89 978-9-813-27429-7 Advanced Mathematical and Computational Tools in Metrology and Testing conference Glasgow, United Kingdom 29.08.2017 31.08.2017 229 234 2020-10-06 OPUS4-40229 Beitrag zu einem Tagungsband Kern, Simon; Guhl, Svetlana; Meyer, Klas; Paul, Andrea; Wander, Lukas; Gräßer, Patrick; Maiwald, Michael Design and Validation of a Compact NMR Analyser Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and relatively inexpensive analysers, which feature advantages like low cost, low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, sufficient robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are currently not available off the rack. Intensified continuous processes are in focus of current research. Flexible (modular) chemical plants can produce different products using the same equipment with short down-times between campaigns and quick introduction of new products to the market. In continuous flow processes online sensor data and tight closed-loop control of the product quality are mandatory. If these are not available, there is a huge risk of producing large amounts of out-of-spec (OOS) products. This is addressed in the European Unionʼs Research Project CONSENS (Integrated Control and Sensing) by development and integration of smart sensor modules for process monitoring and control within such modular plant setups. The presented NMR module is provided in an explosion proof housing of 57 x 57 x 85 cm module size and involves a compact 43.5 MHz NMR spectrometer together with an acquisition unit and a programmable logic controller for automated data preparation (phasing, baseline correction) and evaluation. Indirect Hard Modeling (IHM) was selected for data analysis of the low-field NMR spectra. A set-up for monitoring continuous reactions in a thermostated 1/8" tubular reactor using automated syringe pumps was used to validate the IHM models by using high-field NMR spectroscopy as analytical reference method. Frankfurt a. M. DECHEMA e. V., Frankfurt 2017 Processdings of 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) Potsdam, Germany 10.05.2017 12.05.2017 72 73 2017-05-15 OPUS4-43552 Forschungsbericht Kern, Simon; Guhl, Svetlana; Meyer, Klas; Maiwald, Michael Maiwald, Michael Validation report on NMR The departure from the current automation landscape to next generation automation concepts for the process industry has already begun. Smart functions of sensors simplify their use and enable plug and play integration, even though they may appear to be more complex at first sight. Smart sensors enable concepts like self-diagnostics, self-calibration, and self-configuration/ parameterization whenever our current automation landscape allows it. Here we summarize the currently discussed general requirements for process sensors 4.0 and introduce a smart online NMR sensor module as example, which was developed for an intensified industrial process funded by the EU's Horizon 2020 research and innovation programme (www.consensspire.eu). 2017 1 31 urn:nbn:de:kobv:b43-435521 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2018-01-03 OPUS4-38841 Beitrag zu einem Tagungsband Kern, Simon; Gräßer, Patrick; Zientek, Nicolai; Maiwald, Michael First steps towards field integration of benchtop NMR spectroscopy for online monitoring and process control Online monitoring and process control requires fast and noninvasive analytical methods, which are able to monitor the concentration of reactants in multicomponent mixtures with parts-per-million resolution. Online NMR spectros-copy can meet these demands when flow probes are directly coupled to reactors, since this method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical com-parison method being independent on the matrix. Due to improved magnet design and field shimming strategies portable and robust instruments have been introduced to the market by several manufacturers during the last few years. First studies with this technology showed promising results to monitor chemical reaction in the laboratory. 2015 Tagungsband - 11. Kolloquium Arbeitskreis Prozessanalytik 11. Kolloquium Arbeitskreis Prozessanalytik Wien, Austria 30.11.2015 02.12.2015 43 44 urn:nbn:de:kobv:b43-388411 https://creativecommons.org/licenses/by-nc-sa/4.0/deed.de 2016-12-29 OPUS4-37389 Vortrag Kern, Simon Ugly Spectra and Lousy interfaces - Challenges for Compact NMR Spectroscopy in Process Control With the introduction of advanced process analytical technology, the closeness of key process variables to their limits can be directly controlled and the product can be classified or even released in real time. Compact NMR instruments can make NMR spectroscopy accessible in industrial and harsh environments for process control. 2016 ProcessNet-Jahrestagung und 32. DECHEMA-Jahrestagung der Biotechnologen 2016 Aachen, Germany 12.09.2016 15.09.2016 urn:nbn:de:kobv:b43-373895 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2016-09-19 OPUS4-38981 Vortrag Kern, Simon Online low-field NMR spectroscopy in modular plants for chemical production Die Online-Reaktionsverfolgung ist der Schlüssel zur chemischen Prozesskontrolle. Heute werden in diesem Bereich hauptsächlich Methoden der optischen Spektroskopie eingesetzt. Durch aktuelle Entwicklungen im Bereich kompakter Niederfeld-NMR-Spektrometer auf Basis von Permanentmagnetsystemen ist erstmals auch die Integration unmittelbar in einer industriellen Produktionsumgebung möglich. Diese Geräte sind robuste und relativ preiswerte Analysatoren, welche die Vorteile eines wartungsfreundlichen Betriebs ohne Notwendigkeit von kryogenen Flüssigkeiten, sowie eine einfache Handhabung vereinen. Aktuell auf dem Markt verfügbare Geräte sind jedoch ausschließlich auf den Einsatz im Laborbetrieb ausgerichtet. Für die Kopplung als Online-Methode im Prozesseinsatz ist die Entwicklung geeigneter Durchflusszellen notwendig. Diese ermöglichen idealerweise ein gutes Signal-Rausch-Verhältnis, eine ausreichende Robustheit und müssen die Anforderungen an die Integration in industrielle Anlagen erfüllen (z.B. Explosionsschutz, Temperierung). Intensivierte kontinuierliche Prozesse stehen im Fokus der aktuellen Forschung. Im Vergleich zu etablierten Batch-Verfahren besteht in modularen chemischen Anlagen die Möglichkeit durch kurze Umrüstzeiten zwischen Kampagnen effektiv auf die Marktentwicklung zu reagieren. Bei kontinuierlicher Prozessführung sind Online-Sensoren und eine zuverlässige und schnelle Regelung der Produktqualität essentiell. Andernfalls besteht ein großes Risiko, große Mengen nicht-spezifikationskonformer Produkte zu erhalten. Dies wird im Rahmen des Forschungsprojekts CONSENS (Integrated Control and Sensing) der Europäischen Union durch die Entwicklung und Integration intelligenter Sensormodule zur Prozessüberwachung und -steuerung in modularen Anlagenkonzepten thematisiert. Das vorgestellte NMR-Analysatormodul mit der Baugröße von 57 x 57 x 85 cm basiert auf einem kompakten 43,5-MHz-NMR-Spektrometer. Dieses ist zusammen mit einem Akquisitionsrechner und einer programmierbaren Steuerung für die automatisierte Daten-aufbereitung (Phasing, Baseline-Korrektur) und Auswertung in ein explosionsgeschütztes Gehäuse integriert. Für die automatisierte Datenanalyse kommt die Methode des Indirect Hard Modelings (IHM) zum Einsatz. Die entwickelten IHM-Modelle werden mittels Online-Hochfeld-NMR-Spektroskopie als Referenzverfahren in einem Versuchsaufbau zur Überwachung kontinuierlicher Reaktionen auf Basis eines mit Spritzenpumpen betriebenen 1/8" Rohrreaktors validiert. 2017 Praktische Probleme der Kernresonanzspektroskopie Erlangen, Germany 16.01.2017 17.01.2017 urn:nbn:de:kobv:b43-389819 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-01-23 OPUS4-39009 Posterpräsentation Kern, Simon Fitting of physically motivated spectral models - a simple calibration-free method for evaluation of online NMR spectra 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. 2017 Quantitative NMR Methods for Reaction and Process Monitoring (NMRPM) Kaiserslautern, Germany 19.01.2017 20.01.2017 2017-01-23 OPUS4-37405 Vortrag Kern, Simon Ugly spectra and lousy interfaces - challenges for compact NMR spectroscopy in process control With the introduction of advanced process analytical technology, the closeness of key process variables to their limits can be directly controlled and the product can be classified or even released in real time. Compact NMR instruments can make NMR spectroscopy accessible in industrial and harsh environments for process control. 2016 ProcessNet-Jahrestagung und 32. DECHEMA-Jahrestagung der Biotechnologen 2016 Aachen, Germany 12.09.2016 15.09.2016 2016-09-19 OPUS4-38585 Posterpräsentation Kern, Simon "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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 cam-paigns. 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 re-sulting simple one-pot reactions are so far only scarcely accompanied by an adequate optimization via compara-bly 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 algo-rithm to interpret the ob-tained 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. 2016 12. Kolloquium des Arbeitskreises Prozessanalytik Berlin, Germany 28.11.2016 30.11.2016 2016-12-06 OPUS4-44436 Posterpräsentation Kern, Simon Novel Flow Cell Designs for Process Monitoring with Compact NMR Spectroscopy Compact nuclear magnetic resonance (NMR) instruments make NMR spectroscopy and relaxometry accessible in industrial and harsh environments for reaction characterization and process control. Robust field integration of NMR systems have to face explosion protection or integration into process control systems with short set-up times. This paves the way for industrial automation in real process environments. The design of failsafe, temperature and pressure resistant flow through cells along with their NMR-specific requirements is an essential cornerstone to enter industrial production plants and fulfill explosion safety requirements. Additionally, if fast reactions are monitored, suitable mixing devices need to be placed in close vicinity to the measuring volume to mix the reactants properly. NMR-specific requirements aim at full quantitative pre-magnetization and acquisition with maximum sensitivity while reducing sample transfer times and dwell-times. All parameters are individually dependent on the applied NMR instrument. Luckily, an increasing number of applications are reported together with an increasing variety of commercial equipment. However, these contributions have to be reviewed thoroughly. The performance of sample flow cells commonly used in online analytics and especially for low-field NMR spectroscopy was experimentally and theoretically investigated by 1H-NMR experiments and numerical simulations. Especially, the applicability of 3D printed zirconium dioxide for innovative flow cell designs was of interest. Here, we demonstrate and discuss an automated test method to determine the critical parameters of flow through cells for quantitative online NMR spectroscopy. The setup is based on randomized setpoints of flow rates in order to reduce temperature related effects. Five flow cells and tubing were assessed and compared for high-field as well as low-field NMR spectrometers. 2018 Practical Applications of NMR in Industry Conference ​(PANIC) 2018 La Jolla, California, USA 04.03.2018 07.03.2018 urn:nbn:de:kobv:b43-444364 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2018-03-12 OPUS4-44680 Vortrag Kern, Simon Already Analyzing or Still Calibrating? - Demonstration of an online NMR analyzer in pilot scale The departure from the current automation landscape to next generation automation concepts for the process industry has already begun. Smart functions of sensors simplify their use and enable plug-and-play integration, even though they may appear to be more complex at first sight. Monitoring specific information (i.e., "chemical" such as physico-chemical properties, chemical reactions, etc.) is the key to "chemical" process control. Here we introduce our smart online NMR sensor module provided in an explosion proof housing as example. Due to NMR spectroscopy as an "absolute analytical comparison method", independent of the matrix, it runs with extremely short set-up times in combination with "modular" spectral models. Such models can simply be built upon pure component NMR spectra within a few hours (i.e., assignment of the NMR signals to the components) instead of tedious calibrations runs. We present a range of approaches for the automated spectra analysis moving from statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modelling and Quantum Mechanical calculations). Based on concentration measurements of reagents and products by the NMR analyzer a continuous production and direct loop process control were successfully realized for several validation runs in a modular industrial pilot plant and compared to conventional analytical methods (HPLC, near infrared spectroscopy). The NMR analyser was developed for an intensified industrial process funded by the EU's Horizon 2020 research and innovation programme ("Integrated CONtrol and SENsing", www.consens-spire.eu). 2018 analytica conference 2018 München, Germany 10.04.2018 13.04.2018 2018-04-12 OPUS4-35444 Vortrag Kern, Simon Online low-field NMR spectroscopy of an industrial lithiation reaction step for process control Online monitoring and process control requires fast and noninvasive analytical methods, which are able to monitor the concentration of reactants in multicomponent mixtures with parts-per-million resolution. Online NMR spectroscopy can meet these demands when flow probes are directly coupled to reactors, since this method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical comparison method being independent on the matrix. Due to improved magnet design and field shimming strategies portable and robust instruments have been introduced to the market by several manufacturers during the last few years. First studies with this technology showed promising results to monitor chemical reaction in the laboratory. Within the project CONSENS, the continuous production of high-value products in small production scale is advanced by introducing benchtop NMR spectroscopy. CONSENS is a research and innovation project on integrated control and sensing for sustainable operation of flexible intensified processes. This poster will present the first steps of the process integration of a benchtop NMR instrument for a lithiation process and outlines further fields of activity and potential challenges. Hereby, the following issues are going to be addressed: explosion-proof housing for the spectrometer, automation of signal processing (data pretreatment, evaluation and communication to the control system), flow cells and measuring conditions. Furthermore, first online spectra of the lithiation reaction in batch mode were acquired in lab scale. The reaction was performed in a 25 mL glass reactor with thermal jackets for temperature control of the reaction mixture. The Li-HMDS was dosed stepwise by using a glass syringe. First spectra in the proton and fluorine domain were recorded online using a flowrate of 3.5 mL min-1 and a simple 5 mm polytetrafluoroethylene tube (PTFE) as a flow cell. 2016 10. Interdisziplinaeres Doktorandenseminar Fachgruppe "Analytische Chemie" der GDCh Berlin, Germany 28.02.2016 urn:nbn:de:kobv:b43-354443 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2016-03-16 OPUS4-35108 Posterpräsentation Kern, Simon First steps towards field integration of benchtop NMR spectroscopy for online monitoring and process control Online monitoring and process control requires fast and noninvasive analytical methods, which are able to monitor the concentration of reactants in multicomponent mixtures with parts-per-million resolution. Online NMR spectroscopy can meet these demands when flow probes are directly coupled to reactors, since this method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical comparison method being independent on the matrix. Due to improved magnet design and field shimming strategies portable and robust instruments have been introduced to the market by several manufacturers during the last few years. First studies with this technology showed promising results to monitor chemical reaction in the laboratory. Within the project CONSENS, the continuous production of high-value products in small production scale is advanced by introducing MR-NMR spectroscopy. CONSENS is a research and innovation project on integrated control and sensing for sustainable operation of flexible intensified processes. This poster will present the first steps of the process integration of a benchtop NMR instrument for a lithiation process and outlines further fields of activity and potential challenges. Hereby, the following issues are going to be addressed: explosion-proof housing for the spectrometer, automation of signal processing (data pretreatment, evaluation and communication to the control system), flow cells and measuring conditions. Additionally, the first results of the lithiation reaction in lab scale regarding the pure components and reaction mixtures are going to be discussed. 2015 Small Molecule NMR Conference Small Molecule NMR Conference Baveno, Italy 17.09.2015 22.09.2015 urn:nbn:de:kobv:b43-351085 2016-02-20 OPUS4-35109 Posterpräsentation Kern, Simon First steps towards field integration of benchtop NMR spectroscopy for online monitoring and process control Online monitoring and process control requires fast and noninvasive analytical methods, which are able to monitor the concentration of reactants in multicomponent mixtures with parts-per-million resolution. Online NMR spectroscopy can meet these demands when flow probes are directly coupled to reactors, since this method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical comparison method being independent on the matrix. Due to improved magnet design and field shimming strategies portable and robust instruments have been introduced to the market by several manufacturers during the last few years. First studies with this technology showed promising results to monitor chemical reaction in the laboratory. Within the project CONSENS, the continuous production of high-value products in small production scale is advanced by introducing MR-NMR spectroscopy. CONSENS is a research and innovation project on integrated control and sensing for sustainable operation of flexible intensified processes. This poster will present the first steps of the process integration of a benchtop NMR instrument for a lithiation process and outlines further fields of activity and potential challenges. Hereby, the following issues are going to be addressed: explosion-proof housing for the spectrometer, automation of signal processing (data pretreatment, evaluation and communication to the control system), flow cells and measuring conditions. Additionally, the first results of the lithiation reaction in lab scale regarding the pure components and reaction mixtures are going to be discussed. 2015 Pro2NMR Autum School Pro2NMR Autum School Aachen, Germany 08.12.2015 08.12.2015 urn:nbn:de:kobv:b43-351097 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2016-02-20 OPUS4-35159 Posterpräsentation Kern, Simon First steps towards field integration of benchtop NMR spectroscopy for online monitoring and process control Online monitoring and process control requires fast and noninvasive analytical methods, which are able to monitor the concentration of reactants in multicomponent mixtures with parts-per-million resolution. Online NMR spectros-copy can meet these demands when flow probes are directly coupled to reactors, since this method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical com-parison method being independent on the matrix. Due to improved magnet design and field shimming strategies portable and robust instruments have been introduced to the market by several manufacturers during the last few years. First studies with this technology showed promising results to monitor chemical reaction in the laboratory. Wthin the project CONSENS (www.consens-spire.eu), the continuous production of high-value products in small production scale is advanced by introducing benchtop NMR spectroscopy. CONSENS is a research and innovation project on inte-grated control and sensing for sustainable operation of flexible intensified processes. This poster will present the first steps of the process integration of a benchtop NMR instrument for a lithiation process and outlines further fields of activity and potential challenges. Hereby, the following issues are going to be addressed: explosion-proof housing for the spectrometer, automation of signal processing (data pretreatment, evaluation and communication to the control system), flow cells and measuring conditions. Furthermore, first online spectra of the lithiation reaction in batch mode were acquired in lab scale. The reaction was performed in a 25 mL glass reactor with thermal jackets for temperature control of the reaction mixture. The Li-HMDS was dosed stepwise by using a glass syringe. First spectra in the proton and fluorine domain were recorded online using a flowrate of 3.5 mL min-1 and a simple 5 mm polytetrafluoroethylene tube (PTFE) as a flow cell. 2015 11. Kolloquium Prozessanalytik 11. Kolloquium Prozessanalytik Wien, Autria 30.11.2015 02.12.2015 urn:nbn:de:kobv:b43-351597 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2016-02-20 OPUS4-50196 Dissertation Kern, Simon Prozessüberwachung mittels Niederfeld-NMR-Spektroskopie als Online-Methode Die Geräteentwicklungen im Bereich der Niederfeld-NMR-Spektroskopie im vergangenen Jahrzehnt ermöglichen den Einsatz kompakter, portabler Magnete mit geringen Streufeldern in Laborumgebungen und industriellen Produktionsanlagen. Somit werden neue Möglichkeiten für hochauflösende NMR-Experimente zur Reaktionsüberwachung eröffnet. Im Rahmen des EU-Projekts CONSENS wurden die Möglichkeiten dieser Methode umfassend anhand einer technisch bedeutenden Reaktion (elektrophile aromatische Substitutionsreaktionen) evaluiert. Um die Flexibilität einer kontinuierlichen und modularen Pilotanlage durch Echtzeit- Qualitätskontrolle zu fördern, wurde ein vollständig automatisiertes Online- NMR-Modul entwickelt. Der Einsatz eines kommerziellen Niederfeld-NMR-Geräts im industriellen Umfeld wurde durch die entwickelten Lösungen der automatisierten Datenanlyse sowie durch ein zertifiziertes Sicherheitskonzept für den Betrieb in explosionsgefährdeten Zonen ermöglicht. Neben der Überwachung der Produktqualität wurden Online-NMR-Daten in einem neuen iterativen Optimierungsansatz zur Maximierung des Anlagenertrags eingesetzt und dienten als zuverlässige Referenz für die Kalibrierung eines Nahinfrarot-Spektrometers. Für die Entwicklung einer robusten Datenauswertung der NMR-Spektren, die dem Anspruch der Flexibilität bei Produktwechseln genügt, wurden zunächst Versuche im Labormaßstab durchgeführt, um eine Datenbasis zu schaffen. In diesen Versuchen wurden die aromatischen Amine Anilin, p-Toluidin und p-Fluoranilin mit o-Fluornitrobenzol gekoppelt. Durch Zugabe einer Organolithium-Verbindung (Li- HMDS) findet ein Protonenaustausch zwischen dem primären Amin und Li-HMDS statt. Dies führt zu einer hohen Reaktionsenthalpie und instabilen Aryllithium-Verbindungen. Die Reaktionen wurden hinsichtlich anfallender Zwischenprodukte mittels Hochfeld-NMR-Spektroskopie analysiert. Nachfolgend wurden die Reaktionen sowohl im Semi-Batch-Verfahren als auch im kontinuierlichen Laborbetrieb mit Online-Niederfeld-NMR-Spektroskopie und Online- Hochfeld-NMR-Spektroskopie untersucht. Da die gemessenen NMR-Spektren besonders im aromatischen Spektralbereich hohe Signalüberlappungen der Reaktanden aufweisen, wurden chemometrische Modelle entwickelt und anhand der Hochfeld-NMR-Methode validiert. Die verwendeten Durchflusszellen für die Niederfeld-NMR-Spektroskopie wurden hinsichtlich ihrer Anwendbarkeit für quantitative Messungen im kontinuierlichen Durchfluss untersucht. Es konnte gezeigt werden, dass Messungen mit einer additiv gefertigten Keramikdurchflusszelle prinzipiell möglich sind. Berlin Eigenverlag 2019 1 112 10.14279/depositonce-9404 10.14279/depositonce-9404 https://creativecommons.org/licenses/by/4.0/deed.de 2020-01-22 OPUS4-43099 Posterpräsentation Kern, Simon Simple calibration concept of an online NMR module demonstrated in a modularised production plant Monitoring specific information (such as physico-chemical properties, chemical re-actions, etc.) is the key to chemical process control. Within the CONSENS Project, the challenge to adapt a commercially available benchtop NMR spectrometer to the full requirements of an automated chemical production environment was tack-led. The developed online NMR module was provided in an explosion proof housing and involves a compact 43.5 MHz NMR spectrometer together with an acquisition unit, a programmable logic controller for automated triggering, flow con-trol, as well as data communication. First results of an aromatic coupling reaction in lab scale showed a general feasibil-ity according to the signal information in the acquired NMR spectra even though with a considerable overlap. Due to the comparatively low field strength of the NMR spectrometer multivariate methods had to be considered for the prediction of con-centration profiles based on spectral data. Typically, for industrial application of those methods, e.g. Partial Least Squares Regression (PLS-R) as well as Indirect Hard Modeling, large amount of calibration data is demanded, which must be ac-quired in time consuming lab-scale experiments and offline analytics. When it comes to changes in raw materials (e.g., varying functional groups, additional stabi-lizing agents) calibration experiments and data evaluation models are developed again. Here we present an approach of automated data analysis tools for low field NMR spectra with minimal calibration effort. The algorithms are based on Indirect Hard Modeling, whereby each component in each mixture spectra can be rep-resented by several flexible peak functions (pure component models). This means, that only pure component NMR spectra are needed to generate a first evaluation model. The flexibility of peak functions in the spectral model can be adjusted via constraints of peak parameters. The area of any pure component model can either be converted to concentrations based on a one-point calibration on raw material concentration or even neat solvent signals. In several cases it has been shown, the IHM works almost independently of the matrix of the real samples. Such a calibration can be repeated daily in the beginning of each process run with minimal time effort. Moreover, additional pure components can be added to the model or even substitut-ed while keeping the previously adjusted peak function constraints. The proposed method exhibited good agreement of resulting concentration data from low field NMR spectra, when compared to an online high field NMR spectrometer as refer-ence instrument. 2017 13. Kolloquium des Arbeitskreises Prozessanalytik der DECHEMA und der GDCh-Fachgruppe Analytische Chemie Esslingen, Germany 20.11.2017 22.11.2017 urn:nbn:de:kobv:b43-430999 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-11-24 OPUS4-43551 Vortrag Kern, Simon Process monitoring of intensified continuous production units with compact NMR spectroscopy Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and inexpensive analysers, which feature advantages like low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are currently not available off the rack. Intensified continuous processes are in focus of current research. Flexible (modular) chemical plants can produce different products using the same equipment with short down-times between campaigns and quick introduction of new products to the market. In continuous flow processes online sensor data and tight closed-loop control of the product quality are mandatory. Otherwise there is a huge risk of producing large amounts of out-of-spec (OOS) products. This is addressed in the European Union's Research Project CONSENS (www.consens-spire.eu) by development and integration of smart sensor modules for process monitoring and control within such modular plant setups. The presented NMR module is provided in an explosion proof housing with a module size of 57 x 57 x 85 cm and involves a compact 43.5 MHz NMR spectrometer together with an acquisition unit and a programmable logic controller for automated data preparation (phasing, baseline correction) and evaluation. Indirect Hard Modeling (IHM) was selected for data analysis of the low-field NMR spectra. A set-up for monitoring continuous reactions in a thermostated 1/8" tubular reactor using automated syringe pumps was used to validate the IHM models by using high-field NMR spectroscopy as analytical reference method. 2017 Seminar, Institute of Technical Biocatalysis, Hamburg University of Technology Hamburg, Germany 13.01.2017 13.01.2017 2018-01-02 OPUS4-43208 Posterpräsentation Kern, Simon Mathematical and statistical tools for online NMR spectroscopy in chemical processes Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied, which are calibration intensive. NMR spectroscopy has a high potential for direct loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and harsh environments for advanced process monitoring and control. Within the European Union's Research Project CONSENS (Integrated CONtrol and SENsing, www.consens-spire.eu) by development and integration of a smart NMR module for process monitoring was designed and delivers online spectra of various reactions. The presented NMR module is provided in an explosion proof housing of 57 x 57 x 85 cm module size and involves a compact spectrometer together with an acquisition unit and a programmable logic controller for automated data preparation (phasing, baseline correction), and evaluation. For reaction monitoring and process control using NMR instruments after acquisition of the FID the data needs to be corrected in real-time for common effects using fast interfaces and automated methods. When it comes to NMR data evaluation under industrial process conditions, the shape of signals can change drastically due to nonlinear effects. Additionally, the multiplet structure becomes more dominant because of the comparably low-field strengths which results in overlapping of multiple signals. However, the structural and quantitative information is still present but needs to be extracted by applying predictive models. We present a range of approaches for the automated spectra analysis moving from statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modelling and Quantum Mechanical calculations). By using the benefits of traditional qNMR experiments data analysis models can meet the demands of the PAT community (Process Analytical Technology) regarding low calibration effort/calibration free methods, fast adaptions for new reactants, or derivatives and robust automation schemes. 2017 13. Dresdner Sensor Symposium Dresden, Germany 04.12.2017 06.12.2017 urn:nbn:de:kobv:b43-432085 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-12-01 OPUS4-39233 Vortrag Kern, Simon Low field NMR spectroscopy for sustainable and flexible production of high quality chemical products The main development goal of process industries is to advance the continuous production of high-value products that meet high quality demands in flexible intensified continuous plants by introducing novel online sensing equipment and closed-loop control (CONSENS - integrated control and sensing- is funded from the European Union's Horizon 2020 research and innovation programme). Therefore, we present the field integration of a benchtop NMR instrument into a modular production environment, focussing on suitable equipment for operation in hazardous areas with risk of explosive atmospheres. We investigated a pharmaceutical reaction step in order to describe challenges for the experimental design, the evaluation of complex NMR spectra and demonstrate automated data analysis tools. 2017 5th Panic - Practical Applications of NMR in Industry Conferece Hilton Head Island, SC 29928, USA 20.02.2017 23.02.2017 urn:nbn:de:kobv:b43-392333 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-02-24 OPUS4-39397 Posterpräsentation Kern, Simon "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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 [1]. 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 algo-rithm 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. 2017 11. Doktorandenseminar 2017 des Arbeitskreis Prozessanalytik der GDCh und DECHEMA Berlin, Germany 12.03.2017 14.03.2017 2017-03-16 OPUS4-39399 Vortrag Kern, Simon Automated data preparation and spectral modeling For reaction monitoring and process control using NMR instruments, in particular, after acquisition of the FID the data needs to be corrected in real-time for common effects using fast interfaces and automated methods. Conventionally, sensors have to be calibrated in a first step to find a response curve between the sensor signal and physical or chemical properties of the sample. In a second step, a model of the response between these parameters (e.g., concentrations) and the targeted quality specifications is needed. Thanks to the direct proportionality of the molar concentrations and the NMR signal, it could directly be used in the near future to relate the process target quality specification to sensor data - also in combination with multiple other sensor or process information. 2017 qNMR Summit 2017 Berlin, Germany 16.03.2017 17.03.2017 urn:nbn:de:kobv:b43-393998 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-03-17 OPUS4-40282 Vortrag Kern, Simon Design and validation of a compact NMR analyser Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and relatively inexpensive analysers, which feature advantages like low cost, low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, sufficient robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are currently not available off the rack. Intensified continuous processes are in focus of current research. Flexible (modular) chemical plants can produce different products using the same equipment with short down-times between campaigns and quick introduction of new products to the market. In continuous flow processes online sensor data and tight closed-loop control of the product quality are mandatory. If these are not available, there is a huge risk of producing large amounts of out-of-spec (OOS) products. This is addressed in the European Union's Research Project CONSENS (Integrated Control and Sensing) by development and integration of smart sensor modules for process monitoring and control within such modular plant setups. The presented NMR module is provided in an explosion proof housing of 57 x 57 x 85 cm module size and involves a compact 43.5 MHz NMR spectrometer together with an acquisition unit and a programmable logic controller for automated data preparation (phasing, baseline correction) and evaluation. Indirect Hard Modeling (IHM) was selected for data analysis of the low-field NMR spectra. A set-up for monitoring continuous reactions in a thermostated 1/8" tubular reactor using automated syringe pumps was used to validate the IHM models by using high-field NMR spectroscopy as analytical reference method. 2017 EuroPACT 2017 Potsdam, Germany 10.05.2017 12.05.2017 urn:nbn:de:kobv:b43-402822 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-05-18 OPUS4-40283 Posterpräsentation Kern, Simon "Click" analytics for "click" chemistry - a simple method for calibration-free evaluation of online NMR spectra 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 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. 2017 EuroPACT 2017 Potsdam, Germany 10.05.2017 12.05.2017 2017-05-18 OPUS4-41949 Posterpräsentation Kern, Simon Reading between the lines - Automated data analysis for low field NMR spectra For reaction monitoring and process control using NMR instruments, in particular, after acquisition of the FID the data needs to be corrected in real-time for common effects using fast interfaces and automated methods. When it comes to NMR data evaluation under industrial process conditions, the shape of signals can change drastically due to nonlinear effects. Additionally, the multiplet structure becomes more dominant because of the comparably low-field strengths which results in overlapping of multiple signals. However, the structural and quantitative information is still present but needs to be extracted by applying predictive models. We present a range of approaches for the automated spectra analysis moving from statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modeling). By using the benefits of traditional qNMR experiments data analysis models can meet the demands of the PAT community (Process Analytical Technology) regarding low calibration effort/calibration free methods, fast adaptions for new reactants, or derivatives and robust automation schemes. 2017 Small Molecule NMR Conference (SMASH) Baveno, Italy 17.09.2017 20.09.2017 urn:nbn:de:kobv:b43-419498 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-09-18 OPUS4-46377 Vortrag Kern, Simon Advances of Model-Based Data Evaluation Concepts for Quantitative Online NMR Spectroscopy The departure from the current automation landscape to next generation automation concepts for the process industry has already begun. Smart functions of sensors simplify their use and enable plug-and-play integration, even though they may appear to be more complex at first sight. Monitoring specific information (i.e., "chemical" such as physico-chemical properties, chemical reactions, etc.) is the key to "chemical" process control. Here we introduce our smart online NMR sensor module used for process characterisation and optimisation. Due to NMR spectroscopy as an "absolute analytical comparison method", independent of the matrix, it runs with extremely short set-up times in combination with "modular" spectral models. Such models can simply be built upon pure component NMR spectra within a few hours (i.e., assignment of the NMR signals to the components) instead of tedious calibrations runs. We present a range of approaches for the automated spectra analysis moving from statistical approach, (i.e., Partial Least Squares Regression) to physically motivated spectral models (i.e., Indirect Hard Modelling and Quantum Mechanical calculations). Based on concentration measurements of reagents and products by online NMR spectroscopy a continuous production and direct loop process control were successfully realized for several validation runs in a modular industrial pilot plant and compared to conventional analytical methods (HPLC, near infrared spectroscopy). The NMR module was developed for an intensified industrial process funded by the EU's Horizon 2020 research and innovation programme ("Integrated CONtrol and SENsing", www.consens-spire.eu). 2018 SciX 2018 Atlanta, GA, USA 22.10.2018 26.10.2018 2018-10-29 OPUS4-38364 Beitrag zu einem Tagungsband Guhl, Svetlana; Meyer, Klas; Kern, Simon; Gräßer, Patrick; Maiwald, Michael Maiwald, Michael Process monitoring of an intensified continuous production unit with compact NMR spectroscopy Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and relatively inexpensive analyzers, which feature advantages like low cost, low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, sufficient robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are cur-rently not available off the rack. Recently, promising benchtop NMR instruments with acceptable performance came to market and process integrated sensors developed on basis of such laboratory instruments are on their way. 2016 Tagungsband – 12. Kolloquium Prozessanalytik 12. Kolloquium des Arbeitskreises Prozessanalytik Berlin, Germany 28.11.2016 30.11.2016 P17, 75 77 urn:nbn:de:kobv:b43-383646 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2016-11-21 OPUS4-39138 Posterpräsentation Guhl, Svetlana; Meyer, Klas; Kern, Simon Process monitoring of an intensified continuous production unit with compact NMR spectroscopy Monitoring chemical reactions is the key to chemical process control. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and inexpensive analysers, which feature advantages like low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are currently not available off the rack. Intensified continuous processes are in focus of current research. Flexible (modular) chemical plants can produce different products using the same equipment with short down-times between campaigns and quick introduction of new products to the market. In continuous flow processes online sensor data and tight closed-loop control of the product quality are mandatory. Otherwise there is a huge risk of producing large amounts of out-of-spec (OOS) products. This is addressed in the European Union's Research Project CONSENS by development and integration of smart sensor modules for process monitoring and control within such modular plant setups. The presented NMR module is provided in an explosion proof housing with a module size of 57 x 57 x 85 cm and involves a compact 43.5 MHz NMR spectrometer together with an acquisition unit and a programmable logic controller for automated data preparation (phasing, baseline correction) and evaluation. Indirect Hard Modeling (IHM) was selected for data analysis of the low-field NMR spectra. A set-up for monitoring continuous reactions in a thermostated 1/8" tubular reactor using automated syringe pumps was used to validate the IHM models by using high-field NMR spectroscopy as analytical reference method. 2017 Workshop for Process Industry - Tackling the Future of Plant Operation Frankfurt am Main, Germany 25.01.2017 25.01.2017 urn:nbn:de:kobv:b43-391386 http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.de 2017-02-10 OPUS4-45901 Beitrag zu einem Tagungsband Guhl, Svetlana; Kern, Simon; Meyer, Klas; Wander, Lukas; Bornemann-Pfeiffer, Martin; Maiwald, Michael Produzieren Sie schon oder kalibrieren Sie noch? - Online-NMR-Spektrometer als Smarte Feldgeräte Der Vortrag zeigt allgemeine Anforderungen an "smarte Feldgeräte" und deren Entwicklung in den vergangenen Jahren. Am Beispiel eines smarten Online-NMR-Sensors, der in einem EU-Projekt von der BAM entwickelt wurde, wird die Umsetzung der Anforderung aufgezeigt. Schließlich werden weitere Technologieanforderungen und Lösungsansätze vorgestellt. Weinheim Wiley-VCH Verlag GmbH & Co. KGaA DECHEMA, Gesellschaft für Chemische Technik und Biotechnologie e.V. 2018 Chemie Ingenieur Technik 90 ProcessNet-Jahrestagung und 33. DECHEMA-Jahrestagung der Biotechnologen Aachen, Germany 10.09.2018 13.09.2018 9 1236 1236 10.1002/cite.201855229 2018-09-12 OPUS4-40231 Beitrag zu einem Tagungsband Guhl, Svetlana; Kern, Simon; Meyer, Klas; Gräßer, Patrick; Wander, Lukas; Maiwald, Michael Online NMR Spectroscopy for Process Monitoring in Intensified Continuous Production Plants Process analytical techniques are extremely useful tools for chemical production and manufacture and are of particular interest to the pharmaceutical, food and (petro-) chemical industries. Today, mainly optical online methods are applied. NMR spectroscopy has a high potential for direct loop process control. Compact NMR instruments based on permanent magnets are robust and relatively inexpensive analysers, which feature advantages like low cost, low maintenance, ease of use, and cryogen-free operation. Instruments for online NMR measurements equipped with a flow-through cell, possessing a good signal-to-noise-ratio, sufficient robustness, and meeting the requirements for integration into industrial plants (i.e., explosion safety and fully automated data analysis) are currently not available off the rack. A major advantage of NMR spectroscopy is that the method features a high linearity between absolute signal area and sample concentration, which makes it an absolute analytical comparison method which is independent of the matrix. This is an important prerequisite for robust data evaluation strategies within a control concept and reduces the need for extensive maintenance of the evaluation model over the time of operation. Additionally, NMR spectroscopy provides orthogonal, but complimentary physical information to conventional, e.g., optical spectroscopy. It increases the accessible information for technical processes, where aromatic-toaliphatic conversions or isomerizations occur and conventional methods fail due to only minor changes in functional groups. As a technically relevant example, the catalytic hydrogenation of 2-butyne-1,4-diol and further pharmaceutical reactions were studied using an online NMR sensor based on a commercially available low-field NMR spectrometer within the framework of the EU project CONSENS (Integrated Control and Sensing). Frankfurt a. M. DECHEMA e. V., Frankfurt 2017 Processdings of 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) 4th European Conference on Process Analytics and Control Technology (EuroPACT 2017) Potsdam, Germany 10.05.2017 12.05.2017 103 103 2017-05-15 OPUS4-52453 Zeitschriftenartikel Gottu Mukkula, A. R.; Kern, Simon; Salge, M.; Holtkamp, M.; Guhl, Svetlana; Fleischer, C.; Meyer, Klas; Remelhe, M.; Maiwald, Michael; Engell, S. An Application of Modifier Adaptation with Quadratic Approximation on a Pilot Scale Plant in Industrial Environment The goal of this work is to identify the optimal operating input for a lithiation reaction that is performed in a highly innovative pilot scale continuous flow chemical plant in an industrial environment, taking into account the process and safety constraints. The main challenge is to identify the optimum operation in the absence of information about the reaction mechanism and the reaction kinetics. We employ an iterative real-time optimization scheme called modifier adaptation with quadratic approximation (MAWQA) to identify the plant optimum in the presence of plant-model mismatch and measurement noise. A novel NMR PAT-sensor is used to measure the concentration of the reactants and of the product at the reactor outlet. The experiment results demonstrate the capabilities of the iterative optimization using the MAWQA algorithm in driving a complex real plant to an economically optimal operating point in the presence of plant-model mismatch and of process and measurement uncertainties. Amsterdam Elsevier 2020 IFAC-PapersOnLine 53 2 11773 11779 urn:nbn:de:kobv:b43-524531 10.1016/j.ifacol.2020.12.685 https://creativecommons.org/licenses/by-nc-nd/4.0/deed.de 2021-04-19 OPUS4-45902 Beitrag zu einem Tagungsband Gottu Mukkula, A. R.; Engell, S.; Kern, Simon; Guhl, Svetlana; Meyer, Klas; Maiwald, Michael PAT-basierte iterative Optimierung der Fahrweise eines kontinuierlichen organischen Syntheseprozesses Im Zuge der Digitalisierung der Prozessindustrie werden zunehmend modellbasiere Echtzeitoptimierungsverfahren eingesetzt, sog. „Advanced Process Control". Mithilfe der sogenannten Modifier-Adaptation ist eine iterative Betriebspunktoptimierung auch mit ungenauen Modellen möglich, sofern zuverlässige Prozessdaten zur Verfügung stehen. Am Beispiel eines smarten Online-NMR-Sensors, der in einem EU-Projekt von der BAM entwickelt wurde, konnte das Konzept in einer modularen Produktionsanlage zur Herstellung eines pharmazeutischen Wirkstoffs erfolgreich getestet werden. Weinheim Wiley-VCH Verlag GmbH & Co. KGaA DECHEMA, Gesellschaft für Chemische Technik und Biotechnologie e.V. 2018 Chemie Ingenieur Technik 90 ProcessNet-Jahrestagung und 33. DECHEMA-Jahrestagung der Biotechnologen Aachen, Germany 10.09.2018 13.09.2018 1237 1237 10.1002/cite.201855233 2018-09-12