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There have been an increasing number of publications on flow chemistry applications of compact NMR. Despite this, there is so far no comprehensive workflow for the technical design of flow cells. Here, we present an approach that is suitable for the design of an NMR flow cell with an integrated static mixing unit. This design moves the mixing of reactants to the active NMR detection region within the NMR instrument, presenting a feature that analyses chemical reactions faster (5–120 s region) than other common setups. During the design phase, the targeted mixing homogeneity of the components was evaluated for different types of mixing units based on CFD simulation. Subsequently, the flow cell was additively manufactured from ceramic material and metal tubing. Within the targeted working mass flow range, excellent mixing properties as well as narrow line widths were confirmed in validation experiments, comparable to common glass tubes.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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 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.
Mass Spectrometry (MS) and Nuclear Magnetic Resonance Spectroscopy (NMR) are valuable analytical and quality control methods for most industrial chemical processes as they provide information on the concentrations of individual compounds and by-products. These processes are traditionally carried out manually and by a specialist, which takes a substantial amount of time and prevents their utilization for real-time closed-loop process control. This paper presents recent advances from two projects that use Artificial Neural Networks (ANNs) to address the challenges of automation and performance-efficient realizations of MS and NMR. In the first part, a complete toolchain has been realized to develop simulated spectra and train ANNs to identify compounds in MS. In the second part, a limited number of experimental NMR spectra have been augmented by simulated spectra, to train an ANN with better prediction performance and speed than state-of-the-art analysis. These results suggest that, in the context of the digital transformation of the process industry, we are now on the threshold of a strongly simplified use of MS and MRS and the accompanying data evaluation by machine-supported procedures, and can utilize both methods much wider for reaction and process monitoring or quality control.
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.
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).
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.