Analysis online

Further improvements on typical signal distance rules will certainly reduce the tremendous workload of online analysis. This new approach will lead to a reduction of the on-site analyst team. 

It is worth briefly pointing out the difference between in-line and online analysis. In-line analysis does not involve removal of the sample from the reaction vessel, for example in determining water or oxygen content. On-line analysis does involve removing a sample, usually as a side stream, which adds to the complexity of the plant since the sample off-take equipment will often need to be built to the same integrity as the plant. There are four common techniques employed ... 

Hener, U., Brand, W. A., Hilkert, A. W., Juchelka, D., Mosandl, A. and Podebrad, F. (1998) Simultaneous online analysis of 180/160 and 13C/12C ratios of organic compounds using GC pyrolysis IRMS. Zeitschrift fur Lebensmittel Untersuchung und Forschung 206, 230 232. 

The heatpipe reformer process concept for hydrogen-rich syngas production. (Reproduced from Karellas, S., Metz, T., Kuhn, S., and Karl, J., Online analysis of the tar content of the product gas from biomass gasification. Application on the BIOHPR. 14th European Biomass Conference Exhibition, Biomass for Energy, Industry and Climate Protection, ETA-Renewable Energies, Paris, 2005. With permission.)... 

The chemical characterization of aerosol particles currently is of great interest in the field of atmospheric chemistry. A major goal is the development of a method for continuous elemental analysis of aerosols, especially for the elements C, N, and S. Chemiluminescence reactions described in this chapter have adequate sensitivity and selectivity for such analyses. In fact, considering that a 1- j.m-diameter particle has a mass of =0.5-1.0 pg, online analysis of single aerosol particles should be achievable, especially for larger particles. 

Ayrton J. et al., 1998. Optimisation and routine use of generic ultra-high flow-rate liquid chromatography with mass spectrometric detection for the direct online analysis of pharmaceuticals in plasma. J Chromatogr A 8282 199. 

Automatization of all stages of the analytical process is a trend that can be discerned in the development of modern analytical methods for chemical manufacture, to various extents depending on reliability and cost-benefit considerations. Among the elements of reliability one counts conformity of the accuracy and precision of the method to the specifications of the manufacturing process, stability of the analytical system and closeness to real-time analysis. The latter is a requirement for feedback into automatic process-control systems. Since the investment in equipment for automatic online analysis may be high, this is frequently replaced by monitoring a property that is easy and inexpensive to measure and correlating that property with the analyte of interest. Such compromise is usually accompanied by a collection of samples that are sent to the analytical laboratory for determination, possibly at a lower cost. 

With the development of sophisticated ionization techniques including electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI), HPLC-MS techniques have been successfully applied to the online analysis of ginsenosides in extracts and biological fluids (Fuzzati, 2004). In terms of sensitivity and specificity, an MS detector is better than UV or ELSD. Among the various MS methods, the HPLC-MS-MS (or just LC-MS-MS) technique is to date the most sensitive method for detection and quantification of ginsenosides. 

With current commercially available equipment the ideal set-up for online analysis would be an HPLC-SPE system, a cryogenic flow probe (30 p,l active volume) that is in permanent use within an actively shielded magnet operating at 500 MHz or higher. The system would offer the optimum LC-NMR sensitivity (no dependency on LC peak volumes), and complex impurities as low as 0.1% could be identified by one- and two-dimensional NMR experiments, provided that the impurities are sufficiently stable to permit isolation on the SPE cartridges,... 

The analytical strategy for a continuous process is necessarily predominantly online, as summarised in Figure 8.3. However, the correlations between continuous process development and online analysis on the one hand and batch process development and off-line analysis on the other are not simple. For example, many aspects of batch process development would benefit from the availability of online analysis and monitoring. Similarly, some of the early development stages of a continuous process will utilise data from batch (i.e. non-continuous) experiments. 

All process development starts with chemistry. The selection criteria for the most suitable chemistry for a continuous process do not suffer from the same constraints as those for a large-scale batch process. For example, highly exothermic reactions are not only possible in a flow reactor, but are in fact preferred [47]. As operator exposure will be low and so will stock levels, different safety considerations come into play that may allow utilisation of otherwise intolerably toxic reagents. Process telescoping is a necessity to minimise the number of intermediate isolations. Examination of all these factors is facilitated by online analysis because of its speed and maintenance of experimental integrity (i.e. no requirement for sampling). 

Chemistry route-scouting and optimisation is increasingly carried out using parallel synthesis equipment [48], for which online analysis is a given, simply because the demands on off-line laboratory analyses would be overwhelming. 

De Mello et al. have constructed a so-called pSYNTAS (miniaturized synthesis and total analysis system). The system was used to perform an Ugi-type reaction to form several a-aminoacetamides from amines, isocyanates and formaldehyde in the presence of water (Scheme 25) [56-58]. The reported system consists of a glass/silicon nanoreactor [59] in connection to a TOF-MS for the real-time online analysis of the reaction stream. Reactions were conducted in the 600 nl volume chip under continuous flow of 20-2 pl/min flow rate. Reduced flow rates resulted in increased outputs. The analyzed outlet flow showed high yields of the desired products with small quantities of starting materials and intermediates (no exact yields were reported). 

Zimmerman, R., Heger, H.J., Kettrup, H.J., Boesl, U. (1997) A mobile resonance-enhanced multiphoton ionization time-of-flight mass spectrometry device for online analysis of aromatic pollutants in waste incinerator flue gases first results. Rapid Commun. Mass Spectrom. 11 1095-1102. 

The Tandem system (Bruker Optics) is available for use during tablet production to measure tablet weight, thickness, hardness, and diameter, as well as online NIR content uniformity. The system can provide online analysis for drug substance uniformity, moisture content, and excipients. The advantage of systems like this is that the necessary data are available immediately to make adjustments to the production parameters in order to improve product rmiformity. Therefore, adjustments can be made to tablet weight in real time in order to achieve 100% of the label claim. 

Online analysis processing mainly comprises the interactive exploration of multidimensional data sets, or data cubes, which are manipulated by operations from matrix algebra, for example, slice-and-dice, roll-up, and drill-down. Computing performance is related to data warehouse size and also data quality, for example, missing data, unsharpness, and redundancy. The multidimensionality issue is critical for extracting pertinent information and selecting the results to be stored and visualized. 

Further Developments Online Analysis by Hyperspectral Imaging... 

J. D. Hearn and G. D. Smith, A Chemical Ionization Mass Spectrometry Method for the Online Analysis of Organic Aerosols, Anal. Chem. 2004,... 

The catalysts were tested in the dehydrogenation of tetrahydrothiophene (DHN of THT), the hydrodesulphurization of thiophene (HDS of thiophene) and the hydrogenation of biphenyl (HN of BP). The reactions were carried out in the vapor phase using dynamic flow microreactors equipped with an automatic online analysis. Reaction conditions are given in Table 1. 

Significant advances have occurred during the past decade to miniaturize the size of the measurement system in order to make online analysis economically feasible and to reduce the time delays that often are present in analyzers. Recently, chemical sensors have been placed on microchips, even those requiring multiple physical, chemical, and biochemical steps (such as electrophoresis) in the analysis. This device has been called lab-on-a-chip. The measurements of chemical composition can be direct or indirect, the latter case referring to applications where some property of the process stream is measured (such as refractive index) and then related to composition of a particular component. 

Acquisition speeds need to be increased in order to provide improved time resolution. In addition, there is a need to provide more online analysis capabilities to improve the efficiency of imaging by allowing more directed investigations of samples. 

Figure 3.82 Internal set-up of a 48-fold rotary valve for the delivery of product gas to a sequential online analysis such as gas chromatography [38] (by courtesy ofVDI-Verlag GmbH).

Analytical interfaces are integrated into the AuMpRes set-up for at-line analysis by sampling and subsequent chromatography (HPLC) [108], Moreover, this allows online analysis by infrared or Raman spectroscopy. Real-time monitoring of the chemical processes can be achieved via spectroscopic measurements, for which suitable optical flow-through cells have to be installed at selected positions of the micro reaction system. 

In their pioneering work, Jensen et al. demonstrated that photochemical transformation can be carried out in a microfabricated reactor [37]. The photomicroreactor had a single serpentine-shaped microchannel (having a width of 500 pm and a depth of 250 or 500 pm, and etched on a silicon chip) covered by a transparent window (Pyrex or quartz) (Scheme 4.25). A miniature UV light source and an online UV analysis probe were integrated to the device. Jensen et al. studied the radical photopinacolization of benzophenone in isopropanol. Substantial conversion of benzophenone was observed for a 0.5 M benzophenone solution in this microflow system. Such a high concentration of benzophenone would present a challenge in macroscale reactors. This microreaction device provided an opportunity for fast process optimization by online analysis of the reaction mixture. 

The microreactor plant will be equipped with the process control and online analysis [47]. The Suzuki coupling reaction is investigated as a common synthetic route for polymeric semiconductors. The transfer of the developed microflow process into chemical production is accompanied by economic and ecologic evaluations. 

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