Adoption of Quality by Design (QbD) principles, regulatory support of QbD, process analytical technology (PAT), and continuous manufacturing are major factors effecting new approaches to pharmaceutical manufacturing and bioprocessing. In this review, we highlight new technology developments, data analysis models, and applications of Raman spectroscopy, which have expanded the scope of Raman spectroscopy as a process analytical technology. Emerging technologies such as transmission and enhanced reflection Raman, and new approaches to using available technologies, expand the scope of Raman spectroscopy in pharmaceutical manufacturing, and now Raman spectroscopy is successfully integrated into real-time release testing, continuous manufacturing, and statistical process control. Since the last major review of Raman as a pharmaceutical PAT in 2010, many new Raman applications in bioprocessing have emerged. Exciting reports of in situ Raman spectroscopy in bioprocesses complement a growing scientific field of biological and biomedical Raman spectroscopy. Raman spectroscopy has made a positive impact as a process analytical and control tool for pharmaceutical manufacturing and bioprocessing, with demonstrated scientific and financial benefits throughout a product’s lifecycle.

The aim of this study was to evaluate the suitability of Raman spectroscopy as a Process Analytical Technology (PAT) tool for the in-line determination of the active pharmaceutical ingredient (API) concentration and the polymer-drug solid state during a pharmaceutical hot-melt extrusion process. For in-line API quantification, different metoprolol tartrate (MPT) -Eudragit ® RL PO mixtures, containing 10, 20, 30, and 40% MPT respectively, were extruded and monitored in-line in the die using Raman spectroscopy. A PLS model, regressing the MPT concentrations versus the in-line collected Raman spectra, was developed and validated, allowing real-time API concentration determination. The correlation between the predicted and real MPT concentrations of the validation samples is acceptable (R²=0.997) The predictive performance of the calibration model is rated by the root mean square error of prediction (RMSEP), which is 0.59%. Two different polymer-drug mixtures were prepared to evaluate the suitability of Raman spectroscopy for in-line polymer-drug solid state characterization. Mixture 1 contained 90% Eudragit ® RS PO and 10% MPT, and was extruded at 140°C, hence producing a solid solution. Mixture 2 contained 60% Eudragit ® RS PO and 40% MPT, and was extruded at 105°C, prod ucing a solid dispersion. The Raman spectra collected during these extrusion processes provided two main observations. First, the MPT Raman peaks in the solid solution broadened compared to the corresponding solid dispersion peaks, indicating the presence of amorphous MPT. Secondly, peak shifts appeared in the spectra of the solid dispersion and solid solution compared to the physical mixtures, suggesting interactions between Eudragit ® RS PO and MPT, most likely hydrogen bonds. These shifts were larger in the spectra of the solid solution. DSC analysis confirmed these Raman solid state observations and the interactions seen in the spectra. Raman spectroscopy is a potential PAT-tool for in-line determination of the API-concentration and the polymer-drug solid state during pharmaceutical hot-melt extrusion.

IntrodutionRaman analyzers have matured to the point that they are now viable outside the laboratory environment, and away from highly trained technical personnel. Automated Raman analyzers are currently running continuously in several different chemical production plants around the world as well as in analytical laboratories. This paper introduces analytical Raman spectroscopy and the instrumentation required for the field. We also briefly present the usefulness of Confocal Raman microprobe for the study of polymer crystallinity (PET). Analytical Raman spectroscopyMolecular vibrations shift the wavelength of a small fraction of the light that strikes a substance. This shifted light, called Raman scatter, can be used for quantitative and qualitative analysis. Quantitative analysis is based on the intensity of the Raman scattered light being proportional to concentration. Qualitative analysis is based on the wavelength shifts being different for a wide range of different molecular vibrations.Raman spectroscopy is a scattering process, unlike the absorption process measured by mid-IR or NIR Spectroscopy. Both Raman and mid-IR measure fundamental molecular vibrations resulting in sharp, well-resolved bands. Raman spectral bands arise when a vibration induces a net change in polarizability whereas mid-IR bands occur from a net dipole change. Strong Raman scatterers contain functional groups with highly deformable electron clouds. Examples include alkenes, alkynes, cyano, C-S, C-halogen and a wide range of inorganic species. Raman is very useful for measuring symmetric vibrations from the C-C backbone of polymers, diatomic molecules (N 2 , O 2 , etc.), and S-S bonds in proteins. Raman can be used to measure species dissolved or suspended in aqueous solutions. The Raman spectrum of water is relatively weak in the fingerprint region compared to the high absorption in the mid-IR or NIR. A Raman spectrum typically contains a large amount of information as sharp, well-resolved spectral bands. The band positions, intensities, and shapes provide an interpretable and fairly unique fingerprint for qualitative analysis. Quantitative analysis can often be done by simple band area measurement, but multivariate methods like partial least squares (PLS) often extract more information. The sharp, well-resolved structure typical of Raman spectra increases the robustness of simultaneous multi-component analysis.The main strength of Raman spectroscopy for on line analysis (process control) and/or analytical applications is flexible sampling. Raman probes analyse material a fixed distance from the end of the probe. Transparent materials between the end of the probe and the sample do not hinder the measurement. As a result, Raman analysis can be done through quartz or sapphire windows or through closed transparent containers. The sample does not need to be touched, removed from the process stream, or perturbed in any way. The need for slip streams or grab samples is eliminated.The Raman probe both delivers laser light to the sample and c...

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Micro-Raman spectrometry and Mossbauer spectroscopy have been used to identify the corrosion products on a steel coupon exposed in an industrial environment for 16 years. The Raman analysis was performed on a polished metallographic cross-section in order to map the oxides across the thickness of the coating. The spectra were recorded using a LabRam Micro-Raman spectrograph incorporating a 17 mW HeNe laser (attenuated to 1 mW to prevent oxide transformation), focused to 1 μm spot size, and 1800 g/mm grating. The confocal line-scan imaging enabled 100 spectra to be recorded in one scan at 0.5 um intervals across the thickness of the coating. The Mossbauer analysis was performed using in-situ scattering Mossbauer spectroscopy on the attached corrosion coating and transmission Mossbauer spectroscopy at 300K and 77K on the removed coating, to measure the fraction of each oxide present. Micro-Raman spectrometry showed that the corrosion products had formed in distinct layers as shown in Figure 1.