Terahertz Pulsed Imaging Research Articles

Terahertz In-Line Sensor for Direct Coating Thickness Measurement of Individual Tablets During Film Coating in Real-Time

We present a new in-line measurement technique to determine the coating thickness of individual pharmaceutical tablets during film coating in a pan coating unit using pulsed terahertz technology. Results of these real-time terahertz measurements acquired during a production scale coating run are validated using both off-line high-resolution terahertz pulsed imaging of the whole dosage form as well as weight-gain measurements made on sample tablets removed at discrete time intervals during the process run. The terahertz measurements provide a direct method of determining the coating thickness, and no chemometric calibration models are required for the quantification. The results, and their repeatability, demonstrate that real-time monitoring of pharmaceutical tablet coating is not only possible but also provides substantially more information of the coating quality than the standard quality control method. Rather than providing the average coating thickness of a large number of tablets, the terahertz sensor provides the thickness of up to 100 individual tablet coatings per minute. Using this information, the operator can get additional information about the thickness distribution in the coating pan and adjust the process accordingly. At present, a minimum coating thickness of 40 μm is required to determine the coating thickness. The technique is applicable for coatings up to 1 mm in thickness. Within that range, it provides thickness measurements of sub-micron resolution. Terahertz in-line coating process measurements show considerable potential for applications in real-time release, process analytical technology and quality by design.

Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: A review

The terahertz region of the electromagnetic spectrum spans the frequency range between the infrared and the microwave. Traditionally the exploitation of this spectral region has been difficult owing to the lack of suitable source and detector. Over the last ten years or so, terahertz technology has advanced considerably with both terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) instruments now commercially available. This review outlines some of the recent pharmaceutical applications of terahertz pulsed spectroscopy and imaging. The following application areas are highlighted: (1) discrimination and quantification of polymorphs/hydrates, (2) analysis of solid form transformation dynamics, (3) quantitative characterisation of tablet coatings: off-line and on-line, (4) tablet coating and dissolution, (5) spectroscopic imaging and chemical mapping. This review does not attempt to offer an exhaustive assessment of all anticipated pharmaceutical applications; rather it is an attempt to raise the awareness of the emerging opportunities and usefulness offered by this exciting technology.

Terahertz pulsed imaging study to assess remineralization of artificial caries lesions

We compare terahertz-pulsed imaging (TPI) with transverse microradiography (TMR) and microindentation to measure remineralization of artificial caries lesions. Lesions are formed in bovine enamel using a solution of 0.1 M lactic acid/0.2% Carbopol C907 and 50% saturated with hydroxyapatite adjusted to pH 5.0. The 20-day experimental protocol consists of four 1 min treatment periods with dentifrices containing 10, 675, 1385, and 2700 ppm fluoride, a 4-h/day acid challenge, and, for the remaining time, specimens are stored in a 50:50 pooled human/artificial saliva mixture. Each specimen is imaged at the focal point of the terahertz beam (data-point spacing = 50 μm). The time-domain data are used to calculate the refractive index volume percent profile throughout the lesion, and the differences in the integrated areas between the baseline and post-treatment profiles are used to calculate ΔΔZ((THz)). In addition, the change from baseline in both the lesion depth and the intensity of the reflected pulse from the air/enamel interface is determined. Statistically significant Pearson correlation coefficients are observed between TPI and TMR/microindentation (P < 0.05). We demonstrate that TPI has potential as a research tool for hard tissue imaging.

Total variation deconvolution for terahertz pulsed imaging

In terahertz pulsed imaging (TPI), a deconvolution process is usually applied as an inverse operation to extract the sample impulse function for further imaging or spectroscopic analysis. Often, such deconvolution is achieved by direct inverse filtering (IF) or IF with a coupled low-pass or double Gaussian filter. However, the low-pass or double Gaussian filter cannot cope well with both suppressing noise and retrieving localized terahertz pulses and they often result in over-smoothing. Here, we apply the iterative total variation method to the deconvolution process in TPI with a view to enhance the sample impulse function and generate better terahertz images. Experiments with both simulated and raw data validate a better performance for the proposed approach.

Investigating the use of terahertz pulsed time domain reflection imaging for the study of fabric layers of an Egyptian mummy

This paper reports the first use of terahertz time domain reflection imaging involving textiles on part of a complete human mummy, still in original wrapping. X-ray technique has been used extensively to investigate anatomical features, since X-ray pass through the wrapping. Terahertz waves, on the other hand, can penetrate into non-metallic materials and its reflection depends on the refractive index of materials at the interface, such as textiles and the air. The mummy of Kharushere (ca. 945-712 B.C.) was examined by using Terahertz time domain reflection imaging in the Egyptian galleries of The Metropolitan Museum of Art. Experimental results suggest that the Terahetz imaging is a promising technique for probing the fabric layers surrounding Egyptian mummies, although it is still very limited in its current state. In the future it could become a useful complement to CT scanning when materials with low radiographic density and contrast are being investigated.

Non-destructive quantification of pharmaceutical tablet coatings using terahertz pulsed imaging and optical coherence tomography

Optical coherence tomography (OCT) and terahertz pulsed imaging (TPI) are two powerful techniques allowing high quality cross-sectional images from within scattering media to be obtained non-destructively. In this paper, we report experimental results of using OCT and TPI for quantitatively characterizing pharmaceutical tablet coatings in the thickness range of 10–140 μm. We found that the spectral OCT system developed in-house has an axial resolution of 0.9 μm, and is capable of quantifying very thin coatings in the range of 10–60 μm. The upper limit of 60 μm within the tablet coating and core is owed to the strong scattering of OCT light, which has relatively short wavelengths in the range of 0.5–1.0 μm. On the other hand, TPI utilizes terahertz radiation that has substantially long wavelengths in the range of hundreds of microns, and thus is less prone to the scattering problem. Consequently TPI has been demonstrated to be able to quantify thicker coatings in the range of 40–140 μm and beyond. We concluded that OCT and TPI are two complementary analytical techniques for non-destructive and quantitative characterization of pharmaceutical tablet coatings.

Terahertz spectroscopy of liver cirrhosis: investigating the origin of contrast

We have previously demonstrated that terahertz pulsed imaging is able to distinguish between rat tissues from different healthy organs. In this paper we report our measurements of healthy and cirrhotic liver tissues using terahertz reflection spectroscopy. The water content of the fresh tissue samples was also measured in order to investigate the correlations between the terahertz properties, water content, structural changes and cirrhosis. Finally, the samples were fixed in formalin to determine whether water was the sole source of image contrast in this study. We found that the cirrhotic tissue had a higher water content and absorption coefficient than the normal tissue and that even after formalin fixing there were significant differences between the normal and cirrhotic tissues’ terahertz properties. Our results show that terahertz pulsed imaging can distinguish between healthy and diseased tissue due to differences in absorption originating from both water content and tissue structure.

Terahertz pulsed imaging of knee cartilage

Osteoarthritis (OA) is a common form of arthritis caused by cartilage degeneration. In this paper, we investigate the potential use of terahertz (THz) pulsed imaging to quantitatively measure the early symptoms of OA in an animal model. THz images of excised rabbit femoral condyles were taken. We observe THz waves reflected off different layers within samples and demonstrate that the optical delay between reflections can give a quantitative measure of the thicknesses of particular tissues within cartilage.

Technical note: Terahertz imaging of ancient mummies and bone

Ancient mummified soft-tissues are a unique source to study the evolution of disease. Diagnostic imaging of such historic tissues is of foremost interest in paleoanthropology or paleopathology, with conventional x-ray and computed tomography (CT) being the gold-standard. Longer wavelength radiation in the far-infrared or Terahertz region allows diagnostic close-to-surface tissue differentiation of bone morphology while being harmless to human cells. The aim of this study is to show the feasibility and the morpho-diagnostic impact of THz imaging of historic remains. Images of an artificially embalmed ancient Egyptian human mummy hand, an artificially embalmed ancient Egyptian mummified fish and a macerated human lumbar vertebra were obtained by THz-pulse imaging and compared with conventional X-ray and CT images. Although conventional x-ray imaging provides higher spatial resolution, we found that THz-imaging is well-suited for the investigation of ancient mummified soft tissue and embalming-related substances / wrappings. In particular, bone and cartilaginous structures can be well differentiated from surrounding soft-tissues and bandage-wrappings by THz imaging. Furthermore, THz-pulse imaging also measures the time-delay of the pulsed signal when passing through the sample, which provides supplementary information on the optical density of the sample that is not obtained by X-ray and CT. Terahertz radiation provides a completely non-invasive diagnostic imaging modality for historic dry specimens. We anticipate this modality also to be used for detection of hidden objects in historic samples such as funerary amulets still in situ in wrapped mummies, as well as potentially for the identification of spectral signatures from chemical substances, e.g., in embalming essences.

Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting - a review

Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques for the physical characterization of pharmaceutical drug materials and final solid dosage forms, utilizing spectral information in the far infrared region of the electromagnetic spectrum. This review focuses on the development and performance of pharmaceutical applications of terahertz technology compared with other tools for physical characterization. TPS can be used to characterize crystalline properties of drugs and excipients. Different polymorphic forms of a drug can be readily distinguished and quantified. Recent developments towards a better understanding of the fundamental theory behind spectroscopy in the far infrared have been discussed. Applications for TPI include the measurement of coating thickness and uniformity in coated pharmaceutical tablets, structural imaging and 3D chemical imaging of solid dosage forms.

Refraction losses in terahertz computed tomography

Terahertz pulsed imaging has been used to perform computed tomography of three-dimensional objects inducing high refraction losses. We were able to obtain cross-sectional images of the targets by using a computed tomographic analysis of the terahertz signal based on a multi-peak averaging procedure. Some examples are presented of objects with complex shape such as a Teflon cylinder and a dried chicken bone.

Investigating dissolution performance critical areas on coated tablets: A case study using terahertz pulsed imaging

During the process development of coated tablets, knowledge on the formation and the location of film coating ‘weak spots’ is a key factor to the success of the process and the resulting product batch. It is understood that the performance of the product batch may be greatly limited, and often compromised, by weak spots on the tablet film coat. This study uses circular, biconvex tablets to investigate the ability of terahertz pulsed imaging (TPI) to identify the affected areas on the tablet film coat that are critical for dissolution performance. From the TPI analysis we determined that the tablet central band exhibited the thinnest film coating, lowest coating density and highest surface roughness and thus was the performance limiting area of the film coating. Dissolution tests confirmed that the film coating on the tablet central band was indeed dissolution rate determining, with a faster mean dissolution time (MDT) of 7.4 h in comparison to 10.4 h for the convex top/bottom surface. TPI, as a nondestructive analytical technique, showed potential to be employed as a process analytical tool to probe film coating weak spots during film coating development and to assess the effect on the subsequent dissolution performance. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:392–402, 2010

Terahertz pulsed spectroscopic imaging using optimized binary masks

We report the development of a terahertz pulsed spectroscopic imaging system based on the concept of compressive sensing. A single-point terahertz detector, together with a set of 40 optimized two-dimensional binary masks, was used to measure the terahertz waveforms transmitted through a sample. Terahertz time- and frequency-domain images of the sample comprising 20×20 pixels were subsequently reconstructed. We demonstrate that both the spatial distribution and the spectral characteristics of a sample can be obtained by this means. Compared with conventional terahertz pulsed imaging, no raster scanning of the object is required, and ten times fewer terahertz spectra need be taken. It is therefore ideal for real-time imaging applications.

Monitoring the Film Coating Unit Operation and Predicting Drug Dissolution Using Terahertz Pulsed Imaging

Understanding the coating unit operation is imperative to improve product quality and reduce output risks for coated solid dosage forms. Three batches of sustained-release tablets coated with the same process parameters (pan speed, spray rate, etc.) were subjected to terahertz pulsed imaging (TPI) analysis followed by dissolution testing. Mean dissolution times (MDT) from conventional dissolution testing were correlated with terahertz waveforms, which yielded a multivariate, partial least squares regression (PLS) model with an R2 of 0.92 for the calibration set and 0.91 for the validation set. This two-component, PLS model was built from batch I that was coated in the same environmental conditions (air temperature, humidity, etc.) to that of batch II but at different environmental conditions from batch III. The MDTs of batch II was predicted in a nondestructive manner with the developed PLS model and the accuracy of the predicted values were subsequently validated with conventional dissolution testing and found to be in good agreement. The terahertz PLS model was also shown to be sensitive to changes in the coating conditions, successfully identifying the larger coating variability in batch III. In this study, we demonstrated that TPI in conjunction with PLS analysis could be employed to assist with film coating process understanding and provide predictions on drug dissolution. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4866–4876, 2009

Ex vivo terahertz pulsed imaging to differentiate malignant from normal breast tissue

Ex vivo terahertz pulsed imaging to differentiate malignant from normal breast tissue

Effects of film coating thickness and drug layer uniformity on in vitro drug release from sustained-release coated pellets: A case study using terahertz pulsed imaging

Film coating thickness and terahertz electric field peak strength (TEFPS) were determined using terahertz pulsed imaging (TPI) and employed for the analysis of sustained-release coated pellets (theophylline layered sugar cores coated with Kollicoat ® SR:Kollicoat ® IR polymer blends). The effects of coating thickness, drug layer uniformity and optional curing were investigated using eight batches of pellets. Ten pellets from each batch were imaged with TPI to analyse the coating morphology (depicted in TEFPS) and thickness prior to release measurements. The results showed TEFPS values of 15.8% and 14.5% for pellets with a smooth drug layer coated at 8.2 and 12.5% (w/w) polymer weight-gain, respectively. Whereas 6.7% was derived for pellets with a coarse drug layer coated at both weight-gains. Although there were major differences in TEFPS, the resulting drug release kinetics were very similar. It was also shown that a 36 μm coating thickness difference was not drug release rate determining. These results suggested that drug release for the pellets studied was not predominately governed by drug diffusion through the polymeric film coating but probably to a large extent limited by drug solubility. TPI proved to be highly suitable to detect non-homogeneities in the drug layer and polymeric film coating.

Terahertz pulsed spectroscopy of freshly excised human breast cancer

The complex refractive indices of freshly excised healthy breast tissue and breast cancers collected from 20 patients were measured in the range of 0.15 - 2.0 THz using a portable terahertz pulsed transmission spectrometer. Histology was performed to classify the tissue samples as healthy adipose tissue, healthy fibrous breast tissue, or breast cancers. The average complex refractive index was determined for each group and it was found that samples containing cancer had a higher refractive index and absorption coefficient. The terahertz properties of the tissues were also used to simulate the impulse response functions expected when imaging breast tissue in a reflection geometry as in terahertz pulsed imaging (TPI). Our results indicate that both TPS and TPI can be used to distinguish between healthy adipose breast tissue, healthy fibrous breast tissue and breast cancer due to the differences in the fundamental optical properties.

Tissue characterization using terahertz pulsed imaging in reflection geometry

Terahertz pulsed imaging (TPI™) is a non-ionizing and non-destructive imaging technique that has been recently used to study a wide range of biological materials. The severe attenuation of terahertz radiation in samples with high water content means that biological samples need to be very thin if they are to be measured in transmission geometry. To overcome this limitation, samples could be measured in reflection geometry and this is the most feasible way in which TPI could be performed in a clinical setting. In this study, we therefore used TPI in reflection geometry to characterize the terahertz properties of several organ samples freshly harvested from laboratory rats. We observed differences in the measured time domain responses and determined the frequency-dependent optical properties to characterize the samples further. We found statistically significant differences between the tissue types. These results show that TPI has the potential to accurately differentiate between tissue types non-invasively.

Terahertz pulsed imaging and near infrared imaging to monitor the coating process of pharmaceutical tablets

Terahertz pulsed imaging (TPI) and near infrared (NIR) imaging were used to non-destructively monitor the coating process of film-coated tablets. Samples that were taken from a pan coater at different time points were analyzed by both methods. TPI provided coating thickness maps over the whole surface of the tablets, determining the thickness of the coating at each point of the sample surface in μm, this way also giving information about the coating uniformity. The growth of the coating during the coating process was shown. NIR imaging did not provide direct thickness values, but by different absorbance values, inter- and intra-tablet differences were shown. Thus, coating thickness information was also obtained in a way that different tablets could be compared. The growth of the coating layer during the process was shown as well. Both methods provided comparable results; and they were able to detect small defects in the coating. With TPI, the whole tablet surface could be scanned; with NIR imaging information about the tablet ends at the center-band was not obtained due to the strong curvature. NIR imaging proved to be better at thinner coating layers and had a higher spatial resolution whereas TPI had the clear advantage that it provided direct thickness values.

Terahertz pulsed imaging, a novel process analytical tool to investigate the coating characteristics of push–pull osmotic systems

The aim of this study was to investigate coating characteristics of push–pull osmotic systems (PPOS) using three-dimensional terahertz pulsed imaging (3D-TPI) and to detect physical alterations potentially impacting the drug release. The terahertz time-domain reflection signal was used to obtain information on both the spatial distribution of the coating thickness and the coating internal physical mapping. The results showed that (i) the thickness distribution of PPOS coating can be non-destructively analysed using 3D-TPI and (ii) internal physical alterations impacting the drug release kinetics were detectable by using the terahertz time-domain signal. Based on the results, the potential benefits of implementing 3D-TPI as quality control analytical tool were discussed.