Raman quantitative processing

The qualitative analysis of inorganic substances in the solid state or in aqueous solution was the object of numerous Raman investigations, especially within the aim of the assignment of main lines to vibrational modes. Much less attention was devoted to the identification and quantitative determination of the content of each species in a mixture. The demand of new techniques and instruments for the real-time and on line monitoring of substances in water requires more reliable quantitative processes. Simultaneously the progress in the development of more compact transportable or portable Raman instruments has made possible the availability of appropriate Raman sensors. ... 

Because of its insensitivity to quenching (the lifetime of the virtual state is -lO s), Raman spectroscopy is of considerable interest for quantitative measurements on combustion processes. Further, important flame species such as O2, N2 and H2 that do not exhibit IR transitions (Sect.4.2.2) can be readily studied with the Raman technique. However, because of the inherent weakness of the Raman scattering process (Sect.4.3) only non-lumi-nous (non-sooting) flames can be studied. 

In polymer/additive deformulation (of extracts, solutions and in-polymer), spectroscopic methods (nowadays mainly UV, IR and to a lesser extent NMR followed at a large distance by Raman) play an important role, and even more so in process analysis, where the time-consuming chromatographic techniques are less favoured. Some methods, as NMR and Raman spectrometry, were once relatively insensitive, but seem poised to become better performing. Quantitative polymer/additive analysis may benefit from more extensive use of 600-800 MHz 1-NMR equipped with a high-temperature accessory (soluble additives only). 

Raman spectroscopy is emerging as a powerful analytical tool in the pharmaceutical industry, both in PAT and in qualitative and quantitative analyses of pharmaceuticals. Reviews of analyses of pharmaceuticals by Raman spectroscopy have been published.158 159 Applications include identification of raw materials, quantification of APIs in different formulations, polymorphic screening, and support of chemical development process scale-up. Recently published applications of Raman spectroscopy in high-throughput pharmaceutical analyses include determination of APIs in pharmaceutical liquids,160,161 suspensions,162 163 ointments,164 gel and patch formulations,165 and tablets and capsules.166-172... 

Raman spectroscopy is particularly well suited for use in process monitoring and conttol. This chapter discusses Raman spectroscopy s attractive features as well as alerts the reader to aspects that may present ehallenges. The fundamental principles of the technique are reviewed. The reader will learn about instrumentation and options in order to make the most appropriate choices. Special aspects of performing quantitative Raman spectroscopy are discussed since these are required in many installations. Apphcations from many diverse fields are presented. The reader is encouraged to examine aU of the areas since there are good lessons and stimulating ideas in aU. 

Quantitative Raman spectroscopy is an established technique used in a variety of industries and on many different sample forms from raw materials to in-process solutions to waste streams, including most of the applications presented here [1]. Most of the applications presented in the next section rely on quantitative analysis. Similar to other spectroscopic techniques, many factors influence the accuracy and precision of quantitative Raman measurements, but high quality spectra from representative samples are most important. 

Raman spectroscopy was discovered over 75 years ago but has only been a viable process tool for 10-15 years. However, there has been an astounding increase in process Raman spectroscopy examples in the last five years. The United States Food and Drag Administration s (US FDA) endorsement of process analytical technology clearly set off an explosion of activity. Problems that sometimes sidelined Raman in the past, such as fluorescence or highly variable quantitative predictions from samples that were too small to be representative, are being re-examined and leading to new technology. In turn, that helps open, or perhaps reopen, new application areas. The availabihty of easy to use Raman instrumentation at many prices also helps with that. 

T.R.M. De Beer, W.R.G. Baeyens, J. Ouyang, C. Vervaet and J.R Remon, Raman spectroscopy as a process analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension. Analyst, 131, 1137-1144 (2006). 

J. Cornel, C. Lindenberg and M. Mazzotti, Quantitative application of in situ ATR-FTIR and Raman spectroscopy in crystallization processes, Ind. Eng. Chem. Res., 47, 4870 882 (2008). 

The Raman effect has also been broadly applied to online and bench-top quantitative applications, such as determination of pharmaceutical materials and process monitoring [4-6], in vivo clinical measurements [7], biological materials [8, 9], to name only a few. Because the absolute Raman response is difficult to measure accurately (sample presentation and delivered laser power can vary), these measurements are almost always calculated as a percentage with respect to the response from an internal standard. This standard is typically part of the sample matrix in a drug product, the standard may be an excipient in a biological sample, it is commonly water. 

NIR, Raman would be expected to offer advantages such as ease of use for quantitative analysis. The reason for less widespread use of process Raman spectroscopy is due in part to more expensive equipment, relative to NIR. A broader implementation of process Raman spectroscopy in the pharmaceutical industry has previously also been hampered by inherent weaknesses in sampling in remote measurements on solids. This is discussed further in Section 10.3. 

Additional source of information for UHMWPE acetabular cups arises from the quantitative analysis of polarized Raman spectra. Figure 17.6 shows photographs and the outcome of such analysis for two acetabular cups, which were retrieved after substantially different in vivo lifetimes. The retrieved acetabular cups were both belonging to male patients and sterilized by y-rays, but produced by different processes. One acetabular component (manufactured in 2002 by Biomet Inc.) was prepared by isostatic compression molding and sterilized before implantation by a dose of 33 kGy of y-rays. It was retrieved due to infection after 2 years 5 months. This cup will be referred to as the short-term retrieval. The other retrieval (manufactured in 1995 by Zimmer Inc.) was prepared by Ram-extruded molding and sterilized in air by a dose of 25-37 kGy of y-rays. For this latter cup, the follow-up pe-... 

The decision to use a Raman analyzer depends on the availability and practicality of alternative analyzer technologies. Similar to mid-IR, Raman bands represent fundamental modes of vibration. Bands are narrow and molecule specific, and they provide quantitative chemical analysis. The technology is equally amenable to the analysis of gases, liquids, slurries, emulsions, powders, and solids, including samples with particulates and bubbles. Noninvasive probes can be used and are a key feature in many applications where the process must not be breached. 

Dh is the frequency of the normal vibration k and a p the change of the components of the molecular polarizability with the normal coordinate (see Secs. 2.4, 3.4.5 and 3.5.4). In both cases, N is the number of molecules per unit volume involved in the process. IR as well as Raman spectroscopy can therefore be applied in quantitative analysis. 

The use of laser Raman spectrometry in order to quantitatively investigate the urea synthesis under process conditions has been reported by Van Eck et al. (1983). Only Raman spectroscopy seems to suit the problem, since the visible radiation which is used to excite and detect Raman transitions can easily be directed to a measuring cell. Furthermore, water, which is an acceptable solvent, and all compounds involved in the synthesis show characteristic Raman bands. In order to compensate for many of the instrumental factors relative intensities were used instead of absolute intensities. Reproducible window mountings are a necessity. The effect of pressure and temperature on the Raman intensity have to be taken into account if measurements are to be carried out in situ (Sec. 6.8). The effect of the temperature is moderated by using an internal standard. 

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