Real-Time NIR

First and most importantly, real-time NIR monitoring enabled real-time control of the process. For a given product, the molecular weight and end-group balance in the prepolymer exiting the front end or melt part of the process must be controlled at specified levels in order for the back end or solid-phase part of the process to successfully produce the intended polymer composition. In addition, the variability in prepolymer composition must be controlled with very tight tolerances to keep the variation in final product composition within specification limits. Since the process dynamics in the front end were more rapid than those in conventional PET processes, the conventional analytical approach involving off-line analysis of samples obtained every 2-A hours was not sufficient to achieve the desired product quality. 

Finally, real-time NIR monitoring, once validated to the satisfaction of the process engineers and operators, significantly reduced the need for hot process sampling (with its attendant safety concerns) and lab analysis by allowing the sampling frequency to be greatly reduced (to near zero for some process points). 

In summary, it appears that roller compaction pre- and postblends can be NIR monitored during scale-up, independent of batch size and blender type. Using real time NIR monitoring would advance blender unit operations knowledge and provide continuous information and assurance about specific unit operations such as roller compaction, a key FDA Process Analytical Technology goal. 

The system hardware of a real-time NIR SI system is very much reliant on methodology, wavelength range and application requirements. Apart from the materials that have to be detected, sample size, required spatial resolution and the necessary throughput influence the design of an SI sensor unit. The following concentrates on the description of the most common case in NIR real-time material analysis and classification, a spatial-scanning SI system in DR mode. 

The contribution of equipment drift is very smalt as discussed in the chemometrics section. To illustrate this, consider the variability of a real-time NIR signal from a ribbon as it is compacted on the Fitzpatrick IRS20 as shown in Figure 22. The variation in slope is on the order of 0.5 units introducing only a small error in the measurement. Of course once quantified this contribution can be corrected for in the data. 

An ingenious multichannel instrument for tissue imaging was developed at the University of Illinois [162], The thrust of the research was to develop a frequency-domain instrument for noninvasive, real-time NIR optical tomography of tissue in... 

The application of near-IR spectroscopy for real-time monitoring of glucose, lactic acid, acetic acid and biomass in liquid cultures of microorganisms of the genera Lactobacillus and Staphylococcus has been recently published [76]. The NIR spectrum acquired by the optical-fibre probe immersed in the culture is exploited using a partial least squares (PLS) calibration step, a classical method for IR techniques. 

Fig. 6.13. Comparison of rates of sampling for a bioprocess (fermentation) the ability of NIR to measure in real time is compared with discrete sampling techniques.

The squaraine rotaxane tetracarboxylic acid 15a is soluble in aqueous solution at physiological pH and acts as an excellent fluorescent marker with extremely high photostability, which allows trafficking processes in cells to be monitored in realtime, with constant sample illumination, over many minutes. This type of real-time monitoring cannot be done with other available NIR fluorescent probes, such as the amphiphilic styryl dye KM4-64 and water-soluble dextran-Alexa 647 conjugate, because they are rapidly photobleached. 

The potential applications of NIR OFCD determination of metal ions are numerous. The detection of metal contaminants can be accomplished in real-time by using a portable fiber optical metal sensor (OFMD). Metal probe applications developed in the laboratory can be directly transferred to portable environmental applications with minimal effort. The response time of the NIR probe is comparable to its visible counterparts and is much faster than the traditional methods of metal analysis such as atomic absorption spectroscopy, polarography, and ion chromatography. With the use of OFMD results can be monitored on-site resulting in a significant reduction in labor cost and analysis time. 

Lactic acid fermentation was the topic of a paper by Vaccari et al.35 In this work, lactic acid, glucose, and biomass were determined over the course of the reaction. The measurements were made in real time, using a bypass pump and flow-through cell for the NIR measurements. Instead of using normal chemomet-ric statistics, the authors used correlation coefficients, mean of differences, standard deviation, student s t-test, and the student test parameter of significant difference to evaluate the results. Under these restrictions, the results appeared fairly good, with the biomass having the best set of statistics. 

In some manufacturing process analysis applications the analyte requires sample preparation (dilution, derivatization, etc.) to afford a suitable analytical method. Derivatization, emission enhancement, and other extrinsic fluorescent approaches described previously are examples of such methods. On-line methods, in particular those requiring chemical reaction, are often reserved for unique cases where other PAT techniques (e.g., UV-vis, NIR, etc.) are insufficient (e.g., very low concentrations) and real-time process control is imperative. That is, there are several complexities to address with these types of on-line solutions to realize a robust process analysis method such as post reaction cleanup, filtering of reaction byproducts, etc. Nevertheless, real-time sample preparation is achieved via an on-line sample conditioning system. These systems can also address harsh process stream conditions (flow, pressure, temperature, etc.) that are either not appropriate for the desired measurement accuracy or precision or the mechanical limitations of the inline insertion probe or flow cell. This section summarizes some of the common LIF monitoring applications across various sectors. 

On-line MRS contributed to process control by quantitatively predicting the moisture content. MRS also provided process understanding within this study where the authors note that PCA was able to discriminate amongst various hydration states. The target end point of 5-8% w/w HjO was chosen because the trihydrate was the desired form. Using on-line NIRS to monitor this drying process was ideal since end point was determined in real-time prior to the formation of an undesired lower hydrate form. ... 

Chabot et al. at Atofina Chemicals (King of Prussia, PA, USA) used in-line NIR to monitor monomer conversion in real time in a batch emulsion polymerization process. The business value of this monitoring... 

The results indicate that NIR does indeed have both the resolution (specificity) and the sensitivity needed for this application. The NIR method was successfully implemented in the plant, replacing the conventional GC method and allowing real-time control and optimization of the PDEB separation process. 

To control the CCD, the anthors chose a closed-loop control strategy with in-line NIR used to measure the monomer concentrations. The closed-loop control strategy nses the NIR in-line measurement to provide close to real-time information abont the concentration of both reactants and prodncts in the reactor. One prerequisite of this control strategy is that the sampling rate be faster than the kinetics of the reaction. 

The study was then extended to monitor the scale-up of a pharmaceutical blend containing an active pharmaceutical ingredient. A binary mixture of acetaminophen (APAP) with microcrystalline cellulose was selected as the model formulation. The ability of NIR spectroscopy to monitor real-time content uniformity in addition to the aforementioned compact attributes, during roller compaction was also tested. 

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