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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.
The talk introduces a smart online NMR sensor module provided in an explosion proof housing as example. This sensor was developed for an intensified industrial process (pharmaceutical lithiation reaction step) funded by the EU’s Horizon 2020 research and innovation programme (www.consens-spire.eu). 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.
The talk also generally covers current aspects of high-field and low-field online NMR spectroscopy for reaction monitoring and process control.
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.
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.
Chemical companies must find new paths to successfully survive in a changing environment. The potential of digital technologies belongs to these. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds.
Therefore, fully automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. The advances of a fully automated NMR sensor were exploited, using a given pharmaceutical lithiation reaction as an example process within a modular pilot plant. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as, e.g., explosion safety, field communication, and robust evaluation of sensor data. It was thereof used for direct loop advanced process control and real-time optimization of the process. NMR appeared as preeminent online analytical tool and allowed using a modular data analysis tool, which even served as reliable reference method for further PAT applications. In future, such fully integrated and intelligently interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
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.
Chemical companies must find new paths to successfully survive in a changing environment. The potential of digital technologies belongs to these. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds.
Therefore, fully automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. The advances of a fully automated NMR sensor were exploited, using a given pharmaceutical lithiation reaction as an example process within a modular pilot plant. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as, e.g., explosion safety, field communication, and robust evaluation of sensor data. It was thereof used for direct loop advanced process control and real-time optimization of the process. NMR appeared as preeminent online analytical tool and allowed using a modular data analysis tool, which even served as reliable reference method for further PAT applications. In future, such fully integrated and intelligently interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
Chemical companies must find new paths to stay productive in a rapidly changing environment. One of these is the potential of digital technologies. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market. Process safety is improved due to smaller amounts processed and the abilities of efficient heat-transfer allow for otherwise difficult-to-produce compounds.
To exploit these advantages, a fully automated process control along with real-time quality control is mandatory and should be based on “chemical” information. The advances of a fully automated NMR analyzer were demonstrated, using a given pharmaceutical reaction step operated within a modular pilot plant. A commercially available benchtop NMR spectrometer was integrated to the requirements of an automated chemical production environment such as explosion safety, field communication, and robust data evaluation. Obtained results were used for direct loop advanced process control and real-time optimization of the process.
NMR spectroscopy appeared as excellent online analytical tool and allowed a modular data analysis approach, which even served as reliable reference method for further PAT applications. Using the available datasets, a second data analysis approach based on artificial neural networks (ANN) was evaluated.Therefore, amount of data was augmented to be sufficient for training. The results show comparable performance, while improving the calculation time tremendously. In future, such fully integrated and interconnecting “smart” systems and processes can increase the efficiency of the production of specialty chemicals and pharmaceuticals.
Compact NMR Spectroscopy in the field: A Versatile Tool for Automated Continuous- Flow Production
(2021)
Chemical companies must find new paths to successfully survive in a changing environment. The potential of digital technologies belongs to these. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds.
Therefore, fully automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as, e.g., explosion safety, field communication, and robust evaluation of sensor data. It was thereof used for direct loop advanced process control and real-time optimization of the process. Field studies in modular and conventional production plant setups show promising results gaining process knowledge for further optimization. NMR appeared as preeminent online analytical method and allow using a modular data analysis tool, which even served as reliable reference method for further PAT applications (e.g. NIR spectroscopy). In the future, such fully integrated and intelligently interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
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.
Compact NMR Spectroscopy in the field: A Versatile PAT Tool for Production of Specialty Chemicals
(2022)
Companies of chemical industry find themselves more often in a rapidly changing environment, e.g., due to variability of raw material quality or energy costs and efficiency. Process optimization and new process concepts become more and more important. For example, flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds like exothermic reactions with high heat dissipation.
Therefore, fully automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as explosion safety, field communication, and robust evaluation of sensor data. Field studies in modular and conventional production plant setups show promising results gaining process knowledge for further optimization. NMR appeared as preeminent online analytical method and allow using a modular data analysis approach, which can even serve as reliable reference method for further calibration-dependent PAT applications (e.g., NIR spectroscopy). Based on experiences from these field studies an improved analyzer enclosure setup was developed and built, including the option of a secondary method besides NMR spectroscopy. Integrated control systems allow for a flexible implementation based on the available automation infrastructure at the chemical plant or pilot plant setup. In the future, fully integrated and intelligently interconnecting “smart” PAT systems and processes have the potential speed up the setup of production equipment for chemicals and pharmaceuticals and therefore help to reduce the time-to-market.
Compact NMR Spectroscopy in the field: A Versatile PAT Tool for Production of Specialty Chemicals
(2022)
Chemical companies must find new paths to successfully survive in a changing environment, especially by utilizing the potential of digital technologies. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products.
Therefore, fully automated process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of chemical production environment such as explosion safety, field communication, and robust evaluation of sensor data. It was used for direct loop advanced process control and real-time optimization of the process. Field studies in modular and conventional production plants show promising results gaining process knowledge. NMR appeared as preeminent online analytical method and allow using a modular data analysis tool, which even served as reliable reference method for further PAT applications (e.g. NIR spectroscopy). In the future, fully integrated and interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
Compact NMR Spectroscopy in the field: A Versatile PAT Tool for Production of Specialty Chemicals
(2022)
Chemical companies must find new paths to successfully survive in a changing environment, especially by utilizing the potential of digital technologies. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products.
Therefore, fully automated process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of chemical production environment such as explosion safety, field communication, and robust evaluation of sensor data. It was used for direct loop advanced process control and real-time optimization of the process. Field studies in modular and conventional production plants show promising results gaining process knowledge. NMR appeared as preeminent online analytical method and allow using a modular data analysis tool, which even served as reliable reference method for further PAT applications (e.g. NIR spectroscopy). In the future, fully integrated and interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
Compact NMR Spectroscopy in the field: A Versatile Tool for Automated Continuous-Flow Production
(2022)
Chemical companies must find new paths to successfully survive in a changing environment. The potential of digital technologies belongs to these. Flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds.
Therefore, fully automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as, e.g., explosion safety, field communication, and robust evaluation of sensor data. It was thereof used for direct loop advanced process control and real-time optimization of the process. Field studies in modular and conventional production plant setups show promising results gaining process knowledge for further optimization. NMR appeared as preeminent online analytical method and allow using a modular data analysis tool, which even served as reliable reference method for further PAT applications (e.g. NIR spectroscopy). In the future, such fully integrated and intelligently interconnecting “smart” systems and processes can speed up the high-quality production of specialty chemicals and pharmaceuticals.
The use of benchtop-NMR instruments is constantly increasing during the recent years. Advantages of being affordable, portable and easy-to-operate without the need for trained staff make them especially interesting for industrial applications in quality control. However, applications of NMR spectroscopy as an online PAT tool are still very rare but offer a huge potential for process optimization and control. A key task to exploit this potential is hardware field integration of the lab-instruments in a rough environment of a chemical plant. Additionally, developments in automation and data evaluation are mandatory to ensure a robust unattended operation with low maintenance requirements. Here, we show an approach of a fully automated analyzer enclosure considering explosion safety, field communication, as well as environmental conditions in the field.
Temperature sensitivity is still a limitation of benchtop-NMR instruments in flow applications. Recent developments of manufacturers allow for limited operation at static temperature levels, however, a dynamic system for continuous operation is still not available. Using a prototype system offering a larger bore, active temperature shielding studies with thermostated air were performed evaluating the performance.
Automated data evaluation of NMR spectra using a modular indirect hard modeling (IHM) approach showed good results and flexibility. A second data analysis approach based on artificial neural networks (ANN) was evaluated.Therefore, amount of data was augmented to be sufficient for training. The results show comparable performance, while improving the calculation time tremendously, offering new ways to simultaneously evaluating large numbers of different models.
The application of compact NMR instruments to hot flowing samples or exothermically reacting mixtures is limited by the temperature sensitivity of permanent magnets. Typically, such temperature effects directly influence the achievable magnetic field homogeneity and hence measurement quality. The internal-temperature control loop of the magnet and instruments is not designed for such temperature compensation. Passive insulation is restricted by the small dimensions within the magnet borehole.
Here, we present a design approach for active heat shielding with the aim of variable temperature control of NMR samples for benchtop NMR instruments using a compressed airstream which is variable in flow and temperature. Based on the system identification and surface temperature measurements through thermography, a model predictive control was set up to minimise any disturbance effect on the permanent magnet from the probe or sample temperature.
This methodology will facilitate the application of variable-temperature shielding and, therefore, extend the application of compact NMR instruments to flowing sample temperatures that differ from the magnet temperature.
Compact NMR Spectroscopy in the field: A Versatile PAT Tool for Production of Specialty Chemicals
(2023)
Companies of chemical industry find themselves more often in a rapidly changing environment, e.g., due to variability of raw material quality or energy costs and efficiency. Process optimization and new process concepts become more and more important. For example, flexible and modular chemical plants can produce various high-quality products using multi-purpose equipment with short downtimes between campaigns and reduce time to market for new products. Intensified continuous production plants allow for difficult to produce compounds like exothermic reactions with high heat dissipation.
Highly automated “chemical” process control along with real-time quality control are prerequisites to such concepts and thus should be based on “chemical” information. A commercially available benchtop NMR spectrometer was integrated to the full requirements of an automated chemical production environment such as explosion safety, field communication, and robust evaluation of sensor data. Field studies in modular and conventional production plant setups show promising results gaining process knowledge for further optimization. NMR appeared as preeminent online analytical method and allow using a modular data analysis approach, which can even serve as reliable reference method for further calibration-dependent PAT applications (e.g., NIR or Raman spectroscopy).
Based on experiences from earlier field studies an improved NMR analyzer enclosure setup was developed and built, including the option of a secondary method (e.g., optical spectroscopy). Integrated control systems allow for a flexible implementation based on the available automation infrastructure at the chemical plant or pilot plant setup. In the future, fully integrated and intelligently interconnecting “smart” PAT systems and processes have the potential speed up the setup of production equipment for chemicals and pharmaceuticals and therefore help to reduce the time-to-market.
Global demand for pigments is expected to increase to around 13.4 million tons per year by 2030, representing approximately $22 billion – 5% of which will be azo pigments as the main organic pigments. Azo pigments, i.e., especially the azo bridge required for them, are almost exclusively produced in technology by the so-called azo coupling reaction in large-scale approaches on the scale of 50–100 cubic meters. Among other things, one of the reasons why large-scale production itself is still essentially discontinuous is the lack of analytical methods for a continuous azo pigment synthesis.
In an azo coupling process, an aromatic amine is diazotized to form the diazonium compound (diazo compound), which then reacts with a coupling component, i.e., "couples". A slight excess of the coupler is desired for the end of the reaction, which stoichiometrically consumes the remaining (harmful) diazo compound, i.e., below 500 ppm. This is carried out with a manual spotting reaction of a fast-binding coupler.
To carry out continuous azo coupling, care must be taken to ensure that the actual coupling reaction proceeds as rapidly as possible, i.e., preferentially, compared with possible side reactions. Reliable measuring methods are thus a decisive criterion for the useful performance of a continuous azo pigment synthesis. An analytical online procedure is difficult due to several limitations at once: solid dispersions extremely limit the range of reproducible analytical procedures. In addition, the appearance of a signal (e.g., excess of a starting material) in the ppm range must be reliably detected against the matrix background.
The back-titration method and benchtop NMR spectroscopy were used to overcome these problems. We present a feasibility study for a suitable process analysis with benchtop NMR spectroscopy on disperse systems for equimolar dosing of the "diazotization" or "coupling" sub-step in azo coupling, which was carried out in cooperation with a chemical company. This could replace tedious manual spotting
The application of compact NMR instruments to continuously flowing samples at higher temperatures or exothermically reacting mixtures is limited by the temperature sensitivity of permanent magnets. Typically, such temperature effects directly influence the achievable magnetic field homogeneity and hence measurement quality. The internal-temperature control loop of the magnet and instruments is typically not designed for compensation of such effects. Passive insulation is restricted by the small dimensions within the magnet borehole.
Here, we present a design approach for active heat shielding with the aim of variable temperature control of NMR samples for benchtop NMR instruments using a compressed airstream which is variable in flow and temperature. Based on the system identification and surface temperature measurements using an optical thermo-graphy setup, a model predictive control was set up to minimize any disturbance effect on the permanent magnet from the probe or sample temperature.
This methodology will facilitate the application of variable-temperature shielding and, therefore, potentially extend the application of compact NMR instruments to flowing samples at higher temperature than the permanent magnet.