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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.
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.
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.
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.
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.
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.
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.
Process monitoring of an intensified continuous production unit with compact NMR spectroscopy
(2016)
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.
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.
Online low-field NMR spectroscopy of an industrial lithiation reaction step for process control
(2016)
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.
Ugly spectra and lousy interfaces – challenges for compact NMR spectroscopy in process control
(2016)
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.
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.
Ugly Spectra and Lousy interfaces – Challenges for Compact NMR Spectroscopy in Process Control
(2016)
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.
Ugly Spectra and Lousy interfaces – Challenges for Compact NMR Spectroscopy in Process Control
(2016)
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.
Low field NMR spectroscopy for sustainable and flexible production of high quality chemical products
(2017)
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.
Process monitoring of an intensified continuous production unit with compact NMR spectroscopy
(2017)
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.
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.
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.
Validation report on NMR
(2017)
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).
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.