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 - TY - JOUR A1 - Bornemann-Pfeiffer, Martin A1 - Wolf, Jakob A1 - Meyer, Klas A1 - Kern, S. A1 - Angelone, D. A1 - Leonov, A. A1 - Cronin, L. A1 - Emmerling, Franziska T1 - Standardization and control of Grignard reactions in a universal chemical synthesis machine using online NMR T1 - Standardisierung und Kontrolle von Grignard-Reaktionen mittels Online-NMR in einer universellen chemischen Syntheseplattform N2 - A big problem with the chemistry literature is that it is not standardized with respect to precise operational parameters, and real time corrections are hard to make without expert knowledge. This lack of context means difficult reproducibility because many steps are ambiguous, and hence depend on tacit knowledge. Here we present the integration of online NMR into an automated chemical synthesis machine (CSM aka. “Chemputer” which is capable of small-molecule synthesis using a universal programming language) to allow automated analysis and adjustment of reactions on the fly. The system was validated and benchmarked by using Grignard reactions which were chosen due to their importance in synthesis. The system was monitored in real time using online-NMR, and spectra were measured continuously during the reactions. This shows that the synthesis being done in the Chemputer can be dynamically controlled in response to feedback optimizing the reaction conditions according to the user requirements. N2 - Ein Problem der chemischen Literatur ist die fehlende Standardisierung bezüglich genauer Bedingungen, auch Echtzeit-Korrekturen sind ohne Expertenwissen nur schwer möglich. Dieser Mangel an Details erschwert experimentelle Reproduzierbarkeit, da Schritte oft mehrdeutig sind und daher von implizitem Wissen abhängen. Hier präsentieren wir die Integration von Online-NMR Spektroskopie in eine automatisierte chemische Syntheseplattform (CSM aka. “Chemputer”, unter Verwendung einer universellen Programmiersprache zur Synthese kleiner Moleküle fähig), um eine automatisierte Analyse und Anpassung von Reaktionen im laufenden Betrieb zu ermöglichen. Das System wurde anhand von Grignard-Reaktionen, die aufgrund ihrer Bedeutung für die Synthese ausgewählt wurden, validiert und einem Härtetest unterzogen. Synthesen wurden in Echtzeit mit Online-NMR überwacht, und die Spektren wurden während der Reaktionen kontinuierlich aufgenommen und analysiert. Dies zeigt, dass der Chemputer dynamisch mittels einer Regelung kontrolliert werden kann, um die Reaktionsbedingungen entsprechend den Anforderungen des Benutzers zu optimieren. KW - Grignard reaction KW - NMR spectroscopy KW - Process analytical technology KW - Process control KW - Grignard-Reaktion KW - NMR-Spektroskopie KW - Prozessanalytik KW - Prozesskontrolle PY - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:b43-531260 SN - 1521-3773 SN - 1433-7851 N1 - Bibliografische Angaben für die deutsche Version: Angewandte Chemie 2021, Jg. 133, S. 1–7, ISSN 0044-8249, ISSN 1521-3757, https://doi.org/10.1002/ange.202106323 - Bibliographic information for the German version: Angewandte Chemie 2021, vol. 133, p. 1–7, ISSN 0044-8249, ISSN 1521-3757, https://doi.org/10.1002/ange.202106323 VL - 60 IS - 43 SP - 1 EP - 6 PB - Wiley-VCH CY - Weinheim AN - OPUS4-53126 LA - mul AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -