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Organisationseinheit der BAM
- 1.4 Prozessanalytik (20) (entfernen)
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.
The transition 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 comparison method”, independent of the matrix, it runs with very short set-up times in combination with “modular” spectral models. These are based on pure component NMR spectra without the need for tedious calibrations runs. We present approaches from statistical, (i.e., Partial Least Squares Regression) to physically motivated models (i.e., Indirect Hard Modelling).
Based on concentration measurements of reagents and products by the NMR analyser 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).
Improvement in deep process understanding is a mandatory prerequisite for the application of modern concepts like Industrial Internet of Things (IIoT) or “Industrie 4.0”. The direct hyphenation with online methods of process analytical technology (PAT) allows profound insights into the actual reactions within chemical and pharmaceutical production steps and provides necessary information for associated advanced control strategies.
While the industrial application of online Raman spectroscopy has already been successfully demonstrated, low-field NMR spectroscopy is not yet adequately developed as a robust online method for use in process industry. The high information content combined with the low calibration effort makes NMR spectroscopy a highly promising method for modern process automation with a high flexibility due to short set-up times and novel calibration concepts. This is a major advantage compared to other analytical methods, especially regarding multi-purpose plant strategies, as well as processes suffering from fluctuating quality of raw materials.
The work presented here focusses on the heterogeneous catalyzed hydrogenation of 2-butyne-1,4-diol, as a step of the synthesis of industrially important solvent tetrahydrofuran. This reaction is proceeding via an intermediate product and suffers from competitive reaction paths. In this application, online NMR and Raman spectroscopy were combined with data from classical process sensors, e.g., pressure, temperature, and flow transducers in a highly automated setup for the development of innovative control concepts.
Due to its advantages of being a direct comparison method, quantitative NMR spectroscopy (qNMR) becomes more and more popular in industry. While conventional high-field NMR systems are often associated with high investment and operational costs, the upcoming market of permanent-magnet based benchtop NMR systems show a considerable option for a lot of applications. The mobility of these systems allows to bring them more closely to the real production environment, e.g. for at-line quality control.
In this work we present an interlaboratory comparison study investigating the qNMR performance of state-of-the-art benchtop NMR spectrometers. Therefore, BAM prepared two samples of a mixture of NMR reference standards tetramethylbenzene (TMB) and tetrachloronitrobenzene (TCNB) at concentration levels of 200 mM and 10 mM. These “ready-to-use” samples were sent to participant laboratories, which performed analysis on their benchtop NMR equipment of different vendors and fields from 43 to 80 MHz. Raw data was reported back and further investigated by using different data analysis methods at BAM.
After this very first qNMR comparison study of benchtop NMR spectrometers show promising results, following studies are planned to cover more parts of the qNMR process, e.g. sample preparation and weighing, but also data analysis, as commonly done in similar studies for high-field NMR spectroscopy in industry and metrology.
Due to its advantages of being a direct comparison method, quantitative NMR spectroscopy (qNMR) becomes more and more popular in industry. While conventional high-field NMR systems are often associated with high investment and operational costs, the upcoming market of permanent-magnet based benchtop NMR systems show a considerable option for a lot of applications. The mobility of these systems allows to bring them more closely to the real production environment, e.g. for at-line quality control.
In this work we present an interlaboratory comparison study investigating the qNMR performance of state-of-the-art benchtop NMR spectrometers. Therefore, BAM prepared two samples of a mixture of NMR reference standards tetramethylbenzene (TMB) and tetrachloronitrobenzene (TCNB) at concentration levels of 200 mM and 10 mM. These “ready-to-use” samples were sent to participant laboratories, which performed analysis on their benchtop NMR equipment of different vendors and fields from 43 to 80 MHz. Raw data was reported back and further investigated by using different data analysis methods at BAM.
After this very first qNMR comparison study of benchtop NMR spectrometers show promising results, following studies are planned to cover more parts of the qNMR process, e.g. sample preparation and weighing, but also data analysis, as commonly done in similar studies for high-field NMR spectroscopy in industry and metrology.
Due to its advantages of being a direct comparison method, quantitative NMR spectroscopy (qNMR) becomes more and more popular in industry. While conventional high-field NMR systems are often associated with high investment and operational costs, the upcoming market of permanent-magnet based benchtop NMR systems show a considerable option for a lot of applications. The mobility of these systems allows to bring them more closely to the real production environment, e.g. for at-line quality control.
In this work we present an interlaboratory comparison study investigating the qNMR performance of state-of-the-art benchtop NMR spectrometers. Therefore, BAM prepared two samples of a mixture of NMR reference standards tetramethylbenzene (TMB) and tetrachloronitrobenzene (TCNB) at concentration levels of 200 mM and 10 mM. These “ready-to-use” samples were sent to participant laboratories, which performed analysis on their benchtop NMR equipment of different vendors and fields from 43 to 80 MHz. Raw data was reported back and further investigated by using different data analysis methods at BAM.
After this very first qNMR comparison study of benchtop NMR spectrometers show promising results, following studies are planned to cover more parts of the qNMR process, e.g. sample preparation and weighing, but also data analysis, as commonly done in similar studies for high-field NMR spectroscopy in industry and metrology.
Industrial applications of low-field NMR spectroscopy for process and quality control of silanes
(2020)
The combination of different silanes as starting materials and as a product of hydrolysis by several alcohols or water creates a range of hundreds of technical products for a wide range of applications. In recent years, functional trialkoxysilanes have proven to be multi-purpose organosilanes. Applications range from weather protection of buildings to additives for glass fiber industry, sealants, adhesives, coatings and paints to the modification of polymers.
Commercial benchtop NMR spectrometers have the potential to be used in silane chemistry as an online method for reaction monitoring and quality control. NMR nuclei of interest for silane products are 1H and 29Si. In a joint research cooperation between EVONIK and BAM, the applicability of low-field NMR spectroscopy for the chemical analysis of silanes was evaluated. It was shown how it can extend the application range where existing technologies like NIR, Raman, UV/VIS, etc. cannot be used quantitatively due to a lack of reference data.
In a first case study the process of hydrolysis and condensation was observed using online NMR analysis. For this purpose, the substituents of a trialkoxysilane are first hydrolyzed by adding water and corresponding silanols are formed, which can then bind to materials via SiOH functions and crosslink to form siloxane units. Another case study was dealing with the kinetics of the cleavage of a cyclic silane compound. Online NMR analysis was used both in the laboratory and in the manufacturing plant. For this purpose, a fully automated containment system was used, which enables the use of a commercial NMR spectrometer in ATEX-environments. In the third case study presented, quantitative 1H-NMR spectra were acquired on product mixtures of a trialkoxysilane and other components such as organic stabilizers, organotin compounds, an aromatic amine and organic peroxides. An automatic evaluation method based on Indirect Hard Modeling (IHM) was developed.
Chemische Prozesskontrolle für modulare Produktionskonzepte mit direkten analytischen Methoden
(2020)
Flexible Produktionskonzepte werden oft mit modularen, schnell rekonfigurierbaren Einheiten verbunden. Um die Vorteile dieser flexiblen Produktion tatsächlich nutzen zu können ist neben einer geeigneten Infrastruktur auch eine ebenso anpassungsfähige Qualitätskontrolle unverzichtbar. Analysengeräte und Sensoren werden heutzutage immer kompakter und kostengünstiger in ihrer Anschaffung. Dadurch wird es möglich eine große Anzahl von Messstellen innerhalb einer Anlage zu realisieren. Die erfassten Datenmengen erfordern zuverlässige und robuste Auswerteverfahren, die sich in das Gesamtkonzept der Automatisierung einer derart flexiblen Produktion nahtlos integrieren. Referenzdaten aus direkten Methoden wie der NMR-Spektroskopie können hier einen wertvollen Beitrag zur Generierung von Prozesswissen für die Entwicklung neuer Modelle für kostengünstigere Analysenverfahren leisten.
Aus der Kombination verschiedener Silane als Ausgangsstoffe und als Produkt der Hydrolyse durch eine Reihe von Alkoholen oder Wasser ergibt sich eine Palette von hunderten technischen Produkten für verschiedenste Anwendungen. Funktionelle Trialkoxysilane haben sich in den vergangenen Jahren als vielseitig einsetzbare Organosilane erwiesen. Die Einsatzgebiete erstrecken sich vom Witterungsschutz von Bauwerken über haftvermittelnde Eigenschaften in der Glasfaserindustrie, bei Dicht- und Klebstoffen, in Farben und Lacken bis hin zur Modifizierung von polymeren Werkstoffen.
Kommerzielle Benchtop-NMR-Spektrometer haben das Potential auch im Bereich der Silanchemie als Online-Methode zur Reaktionsüberwachung und für die Qualitätskontrolle eingesetzt zu werden. Interessante NMR-Kerne für die oben genanntem Produkte sind 1H und 29Si. In einer gemeinsamen Forschungs-kooperation zwischen EVONIK und BAM wurde anhand verschiedener Fallstudien die Anwendbarkeit der Niederfeld-NMR-Spektroskopie zur chemischen Analyse von Silanen evaluiert. Die Möglichkeiten der Konzentrationsbestimmung erweitern die Anwendungsgebiete, in denen bestehende Technologien wie z. B. NIR, Raman, UV/VIS, etc. mangels Referenzdaten nicht quantitativ eingesetzt werden können.
Eine Fallstudie setzte dazu an, den Hydrolyse- und Kondensationsverlauf mit geeigneter Online-NMR-Analytik zu beobachten, den Reaktionsfortschritt der Hydrolyse und Kondensation auf dieser Basis besser zu verstehen und zu optimieren. Zu diesem Zweck werden durch Zugabe von Wasser zunächst die Alkoxysubstituenten eines Trialkoxysilans hydrolysiert und entsprechende Silanole gebildet. Diese können dann über eine SiOH-Funktion an den zu modifizierenden Werkstoff anbinden und über weitere Silanolgruppen unter Ausbildung von Siloxaneinheiten vernetzen. In einer weiteren Fallstudie wurde die Kinetik der Aufspaltungen einer cyclischen Silanverbindung untersucht. Die Online-NMR-Analytik kam hierbei sowohl im Labor als auch in der industriellen Produktionsanlage zum Einsatz. Hierfür wurde eine automatisierte Einhausung verwendet, welche den Einsatz eines kommerziellen NMR-Spektrometers in explosionsgeschützten Bereichen ermöglicht.
Online-NMR- und -Raman-Spektroskopie – Kombination von PAT-Methoden für mehr Prozessverständnis
(2020)
Die Verbesserung des Prozessverständnisses ist eine notwendige Voraussetzung für die Anwendung von Konzepten wie „Industrial Internet of Things (IIoT)“ oder „Industrie 4.0“. Online-Methoden der Prozessanalytik (PAT) ermöglichen die direkte Verfolgung der ablaufenden Reaktionen innerhalb chemischer und pharmazeutischer Produktionsschritte und können somit einen wichtigen Beitrag für die Entwicklung von neuen, innovativen Prozessführungsstrategien liefern.
Während die Online-Raman-Spektroskopie bereits erfolgreich im industriellen Umfeld zum Einsatz kommt, ist der Entwicklungsstand für die Online-Niederfeld-NMR-Spektroskopie bislang noch nicht ausreichend für einen routinemäßigen Einsatz innerhalb industrieller Produktionsumgebungen. Der hohe Informationsgehalt der NMR-Daten in Verbindung mit einem geringen Kalibrieraufwand macht die Methode sehr interessant für moderne Konzepte flexibler Produktionsanlagen für die Herstellung vieler unterschiedlicher Produkte in wechselnden Kampagnen. Speziell in modularen Produktionskonzepten kann so die Rüstzeit der Prozessanalytik deutlich verkürzt werden.
Am Beispiel der heterogen katalysierten Hydrogenierung von 2-Butin-1,4-diol wird der Einsatz der Kombination von Online-NMR und -Raman-Spektroskopie demonstriert. Dieser Prozessschritt aus der industriellen Synthese des Lösungsmittels Tetrahydrofuran verläuft über ein Zwischenprodukt, welches konkurrierende Reaktionspfade aufweist. Die Kombination von Informationen aus der PAT, sowie von klassischen Prozessgrößen, wie Druck, Temperatur und Durchfluss in einem hoch automatisierten Aufbau erleichtert die Entwicklung und Erprobung von neuen Konzepten für die Prozessführung.