FIG 5 - uploaded by Neil J Everall
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Plot of X and Y resolutions versus sample thickness assuming a 100 3 2000 lm collection zone and a 500 lm beam diameter. The working measure of resolution was twice the standard deviation of the X and Y distributions.
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Picosecond time-resolved transmission Raman data were acquired for 1 mm thick powder samples of trans-stilbene, and a Monte Carlo model was developed that can successfully model the laser and Raman pulse profiles. Photon migration broadened the incident (approximately 1 ps) probe pulse by two orders of magnitude. As expected from previous studies o...
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... The fact that the distribution was symmetrical and centered at the mid-point of the sample is encouraging; if too high a probability of Raman generation is used in the code, the Zgen distribution becomes biased towards the z ¼ 0 surface, for obvious reasons of fast laser photon depletion. Figure 5 plots the computed Raman resolution (2r(Xgen) and 2r(Ygen)) versus sample thickness assuming a 100 3 2000 lm rectangular collection zone, a 500 lm probe beam, and l t ¼ 40 lm. The distribution is close to normal, so the 61r range accounts for approximately 68% of the total Raman intensity, while 95% of the detected photons originate within 62r about the collection axis. ...
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... resolution is expected to depend on the dimensions of the collection zone, but Fig. 5 is limited to the specific case of a fixed high-aspect ratio slit. sample thickness assuming a circular collection zone, in order to model the sampling geometry of practical transmission Raman instruments, which employ fiber-optic collection systems with bundles of circular fibers. (For example, Srinivasan et al. 37 carried out ...
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... value of T/l t ¼ 10 should give only a 10% difference between observed and transmitted pulse profiles, which is adequate for our work. 41 Figure 6 shows that the predicted resolution (taken as the average of 2r(Xgen) and 2r(Ygen)) worsened linearly from ;450 to 1900 lm as the thickness increased from 1 to 4 mm. It confirms the result from Fig. 5 that even though the lateral resolution is a very small fraction of the total flight path, it is a large fraction (;50%) of the sample thickness. The resolution did not depend strongly on the transport length, presumably because in each case l t was sufficiently small compared with the sample thickness to satisfy the diffusion ...
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Citations
... As with any other Raman based technology TRS tends to be non-destructive. The transmission geometry adds favourable characteristics of bulk sampling [13,14] and the ability to measure the whole intact final dosage form avoids sample preparation steps. Solvation states and polymorphic forms have been extensively studied using Raman based technologies [15,16]. ...
In this feasibility study Transmission Raman spectroscopy (TRS) has been used to build quantitative models for warfarin sodium and warfarin sodium clathrate. The type of warfarin present in manufactured tablets may affect product quality. Models were used to predict warfarin sodium in commercially available tablets at extremely low dosage levels (0.5% w/w). The laboratory made calibration samples used in the modelling varied in amorphous sodium, crystalline clathrate warfarin forms, excipients and dye. This application was highly challenging due to the low level of API and high level of a Raman-active colourant which varied significantly between production batches. A photon recycling optic, known as a Beam Enhancer, was utilised to improve the signal to noise of the Raman spectra to attain a low limit of quantification of 0.19% w/w.
... Related research has been conducted on pharmaceutical tablets, studying the spatial origin of measured Raman signals changes when both in spatial and time-resolved transmission Raman measurements 5,10 and in respective Monte Carlo simulations. 11 However, because of the great difference between biological tissue and pharmaceutical formulations (e.g. ...
... These studies demonstrated a maximum signal originating from the centre of pharmaceutical tablets. 10,11,42 This study shows promise for future applications of transmission Raman, either in the breast or applied through fibre probes, to the prostate. It has advanced the understanding of how the distribution of collected Raman scattering signals change in relation to a range of expected optical properties of tissues. ...
In this study we employed large volume liquid tissue phantoms, consisting of a scattering agent (Intralipid), an absorption agent (Indian ink) and a synthesized calcification powder (calcium hydroxyapatite (HAP)) similar to that found in cancerous tissues (eg breast and prostate), to simulate human tissues. We studied experimentally the magnitude and origin of Raman signals in a transmission Raman geometry as a function of optical properties of the medium and the location of calcifications within the phantom. The goal was to inform the development of future noninvasive cancer screening applications in vivo. The results provide insight into light propagation and Raman scattering distribution in deep Raman measurements, exploring also the effect of the variation of relative absorbance of laser and Raman photons within the phantoms. Most notably when modeling breast and prostate tissues it follows that maximum signals is obtained from the front and back faces of the tissue with the central region contributing less to the measured spectrum.
... In comparison, owing to the recent interest in the use of transmission Raman spectrometry for the analysis of pharmaceutical dosage forms, 20,21 there have been a number of theoretical and experimental studies examining the variation of the transmission Raman signal with depth in turbid media. [22][23][24][25][26] It was suggested in a recent paper that the variation in the transmission Raman signal with depth would also be exhibited by transmission NIR spectrometry. 22 While transmission Raman spectrometry can be employed with non-absorbing and weak to moderately absorbing materials, 22 it is inherent to NIR spectrometry that at least weakly absorbing materials are present to give rise to a signal. ...
... 17 These observations are also consistent with those noted for the Raman signal from an interlayer containing TiO 2 as it was moved through a stack of the eight Avicel disks. 22 In previous Raman studies, [22][23][24][25][26] the lower Raman signal observed when the interlayer occupied a surface position was attributed to loss of photons to the air at the air-sample interface. This results in a reduction in the number of Raman photons generated and subsequently detected when the interlayer occupies a near-surface position. ...
... The present study has confirmed that the variation in transmission NIR signal with depth is consistent with that observed previously for the transmission Raman signal. [22][23][24][25][26] The lower NIR absorbance and Raman intensity observed for the interlayer when positioned at the surface can in both cases be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a nearsurface position. ...
Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different positions as it was moved through a stack of eight 0.5 mm thick disks of microcrystalline cellulose (Avicel). The magnitude of the first derivative of absorbance for the aspirin interlayer at 8934 cm(-1) was lower when the disk was placed at the top or bottom of the stack of Avicel disks, with the largest signal observed when the aspirin was positioned at the central positions. The variation in signal with depth is consistent with that observed previously for transmission Raman spectrometry. In both cases, the trend observed can be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a near-surface position.
... We especially emphasize the importance of signal detection with radial offset from excitation as a feature to discover buried species not only by diffuse reflectance absorption but also by Raman emission, for example. 25,26 The theory of radial absorption is not yet fully developed and we experimentally contribute to this field by the analysis of radial-resolved reflectance spectra. In addition, we contribute to the description of sources of errors like multiple surface reflection of samples in glass cells or deflectance (sideway loss) of radiation in small samples such as pharmaceutical tablets. ...
In continuation of our contribution to "The Axial Transfer" (Appl. Spectr. 2012. 66(8): 934-943), this paper describes the distribution of localized incident radiation in multiple scattering layers of arbitrary thickness and analyzes the lateral intensity profiles of radiation leaving the sample from its illuminated and non-illuminated surfaces. The theoretical profiles are calculated with different approximations of the equation of transfer. We derive for both non-absorbing and absorbing layers simple analytical expressions and verify their accuracy and range of applicability by comparison with Monte Carlo simulations. Particular emphasis is given to the analysis of the radial absorption, an under-theorized and under-investigated feature that can help to identify weak or hidden absorbers. In addition, we contribute to the description of how the radial reflectance is affected by anisotropy or by error sources like multiple surface reflection for samples in glass cells or deflectance (sideway loss) of radiation in small samples. Finally, the theoretical results are compared with experimental data of radial reflectance for quasi non-absorbing and absorbing powder layers.
... This type of detection was worked out already in 1967 by Schrader and Bergmann [18] and received its revival in 2006 by Matousek and Parker [19]. The transmitted Raman signal averages over the whole sample depth with weight maximum in the center of the sample [20,21]. The weak signal strength of transmitted Raman radiation can be enhanced by a dielectric mirror system [22]. ...
... Most of the results agree with the model calculations of Fig. 9 and Eqs. (18)- (20) for diffuse incidence. The increase from case V to case VI can be explained only with normal incidence where, according to Eq. (21), the deep layer produces somewhat higher signals than the layer directly exposed to the surface. ...
Raman intensities from reflection (X ( R )) and transmission (X ( T )) setups are compared by calculations based on random walk and analytical approaches with respect to sample thickness, absorption, and scattering. Experiments incorporating strongly scattering organic polymer layers and powder tablets of pharmaceutical ingredients validate the theoretical findings. For nonabsorbing layers, the Raman reflection and transmission intensities rise steadily with the layer thickness, starting for very thin layers with the ratio X ( T )/X ( R ) = 1 and approaching for thick layers, a lower limit of X ( T )/X ( R ) = 0.5. This result is completely different from the primary irradiation where the ratio of transmittance/reflectance decays hyperbolically with the layer thickness to zero. In absorbing materials, X ( R ) saturates at levels that depend strongly on the absorption and scattering coefficients. X ( T ) passes through a maximum and decreases then exponentially with increasing layer thickness to zero. From the calculated radial intensity spreads, it follows that quantitative transmission Raman spectroscopy requires diameters of the detected sample areas be about six times larger than the sample thickness. In stratified systems, Raman transmission allows deep probing even of small quantities in buried layers. In double layers, the information is independent from the side of the measurements. In triple layers simulating coated tablets, the information of X (T) originates mainly from the center of the bulk material whereas X ( R ) highlights the irradiated boundary region. However, if the stratified sample is measured in a Raman reflection setup in front of a white diffusely reflecting surface, it is possible to monitor the whole depth of a multiple scattering sample with equal statistical weight. This may be a favorable approach for inline Raman spectroscopy in process analytical technology.
... Given the intended use of this technique to interrogate freshly excised samples during an operation, such an approach does not seem practical. Although one could also imagine using transmission Raman spectroscopy (TRS) to provide some tumor geometry information while eliminating the need for a truly multi-modal approach, the spatial resolution of TRS is currently insufficient [187] given the typical size of the specimens removed during BCS (>5 cm cuboids). ...
This dissertation focuses on the development and implementation of several novel mathematical models of light transport in biological tissue for use as quantitative diagnostic tools to assess tissue viability and detect diseased tissue. This work includes semi-empirical models of reflectance and fluorescence for pancreatic cancer diagnostics, computational models of inelastic (Raman) scattering in layered tissues for non-invasive bone tissue assessment and breast tumor margin detection during surgery, and computational models of light propagation for tissues with irregular geometries.
A novel photon-tissue interaction (PTI) model of reflectance and fluorescence was developed and employed to extract biophysically-relevant tissue parameters (mean size of cell nuclei, percentage contribution of collagen to fluorescence) from measured optical spectra of freshly-excised human pancreatic tissues. The mean cellular nuclear size was statistically significant for distinguishing adenocarcinoma sites from non-cancerous (pancreatitis and normal) sites. The percentage contribution of collagen was statistically significant for distinguishing between all three tissue types included in the study (adenocarcinoma, pancreatitis, normal). When these parameters were included in a statistically-rigorous tissue classification algorithm that accounted for intra-patient correlations in the data, adenocarcinoma was distinguished from the non-cancerous tissues with an area of 0.906 under the receiver operating characteristic (ROC) curve and a sensitivity, specificity, positive predictive value, and negative predictive value of 87.5%, 89.0%, 77.8%, and 94.2%, respectively.
A novel Monte Carlo (MC) model of inelastic (Raman) scattering in layered tissues was developed and employed to characterize the effects of tissue and fiber-probe properties on the detected Raman signal. This MC model was employed to assist with two biomedical applications: bone tissue diagnostics and breast tumor margin assessment. For the tumor margin assessment application, it was predicted that the smallest detectable tumor thickness using spatially-offset Raman spectroscopy would be 100 microns under a 0.5 mm margin or 1 mm under a 2 mm margin.
The models described in this dissertation provide accurate, versatile, and quantitative analysis of the effects of fiber-optic probe design and biophysical tissue properties on the detected optical signal and can be employed in a wide range of tissue diagnostic applications.
... Shih et al. used a MC model to validate their method to correct Raman spectra for the influence of scattering and absorption [25]. The MC calculation of spatial resolution and sensitivity with focus on non-absorbing samples was shown by Everall et al. [26]. Recently, Keller et al. adapted a fluorescence code for the prediction of SORS measurements [27], where the sensitivity for detected Raman photons originating from a certain depth was calculated. ...
We present a Monte Carlo model, which we use to calculate the depth dependent sensitivity or sampling volume of different single fiber and multi-fiber Raman probes. A two-layer skin model is employed to investigate the dependency of the sampling volume on the absorption and reduced scattering coefficients in the near infrared wavelength range (NIR). The shape of the sampling volume is mainly determined by the scattering coefficient and the wavelength dependency of absorption and scattering has only a small effect on the sampling volume of a typical fingerprint spectrum. An increase in the sampling depth in nonmelanoma skin cancer, compared to normal skin, is obtained.
... Everall et al. [27] further investigated theoretically the spatial resolution of transmission Raman spectroscopy in both lateral and depth dimensions from a standpoint of tomographic applications. Apart from looking at the spatial origin of the measured Raman signals, the research investigated homogeneity of the probing as a function of experimental geometry. ...
... The resolution was also shown to be much better for objects near either surface, being determined by the diameter of the probe beam and collection aperture irrespective of sample thickness. The objects in the bulk yielded higher signals than those at the surfaces in line with the preceding numerical simulations [27] and experimental findings [25][26][27]. The observations were also shown to be insensitive to the choice of transport length in the studied deep diffusion regime implying that a simple model can be used to predict instrument performance for given experimental conditions. ...
... The resolution was also shown to be much better for objects near either surface, being determined by the diameter of the probe beam and collection aperture irrespective of sample thickness. The objects in the bulk yielded higher signals than those at the surfaces in line with the preceding numerical simulations [27] and experimental findings [25][26][27]. The observations were also shown to be insensitive to the choice of transport length in the studied deep diffusion regime implying that a simple model can be used to predict instrument performance for given experimental conditions. ...
This article reviews recent advances in transmission Raman spectroscopy and its applications, from the perspective of pharmaceutical analysis. The emerging concepts enable rapid non-invasive volumetric analysis of pharmaceutical formulations and could lead to many important applications in pharmaceutical settings, including quantitative bulk analysis of intact pharmaceutical tablets and capsules in quality and process control.
An analytical formula to the depth-of-origin profile of transmission Raman spectroscopy in turbid media was derived from the one-dimensional (1D) Kubelka–Munk model. The depth-of-origin profile of the transmitted Raman is proportional to the excitation intensity profile and the transmittance profile, which are two functions of similar forms. The effect of scattering, absorption, and signal-enhancing reflectors are incorporated into the formula. Depth-of-origin profile of a model sample was measured at better than 0.2 mm resolution and fits the formula reasonably well. Conical reflective cavities placed at the front and/or back of the sample enhanced the signal significantly; the relationship among the enhancement functions is verified by the formula. Optical parameters derived from the fitting are compared to theoretical value predicted by optical ray tracing and direct measurements; discrepancies are related to deficiency of the 1D Kubelka–Munk model.
A spatial heterodyne Raman spectrometer (SHRS) was used to measure transmission Raman spectra of highly scattering compounds. Transmission Raman spectral intensities of ibuprofen were only 2.4 times lower in intensity than backscatter Raman spectra. The throughput was about eight times higher than an f/1.8 dispersive spectrometer, and the width of the area viewed was found to be seven to nine times higher, using 50.8 mm and 250 mm focal length collection lenses. However, the signal-to-noise (S/N) ratio was two times lower for the SHRS than the f/1.8 dispersive spectrometer, apparently due to high levels of stray light.
