Terahertz Time-of-Flight Tomography Beyond the Axial Resolution Limit: Autoregressive Spectral Estimation Based on the Modified Covariance Method

Zhai, Min, Alexandre Locquet, Cyrielle Roquelet, and D. S. Citrin. "Terahertz Time-of-Flight Tomography Beyond the Axial Resolution Limit: Autoregressive Spectral Estimation Based on the Modified Covariance Method." Journal of Infrared, Millimeter, and Terahertz Waves (2020): 1-14.

Abstract

We present a time-of-flight tomography method for exceeding the naïve axial (i.e., depth) resolution limit of terahertz (THz) deconvolution by autoregressive spectral extrapolation (AR) based on the modified covariance method (AR/MCM). In contrast to Wiener filtering combined with wavelet denoising, AR/MCM does not discard any frequency components in the low signal-to-noise (SNR) regions of the measured data, and unlike the AR approach based on the Burg method (AR/BM), no peak splitting (single peaks in the impulse response function appearing as double peaks) as well as frequency bias (spectral peaks shifted with respect to their correct positions) is observed after deconvolution. After verifying the advantages of AR/MCM over Wiener filtering in conjunction with wavelet denoising as well as over AR/BM, using synthetic data, AR/MCM is employed to reconstruct a single layer of mill scale on a steel coupon from experimental THz time-of-flight tomography data. The reconstruction shows good agreement with the film thickness obtained from destructive cross-sectional measurements. In addition, unlike AR/BM, optimizing the parameters to obtain stable reconstruction is straightforward relying of Akaike’s information criterion suggesting that AR/MCM can be an easier to implement for THz nondestructive characterization of stratigraphy under noisy conditions, particularly when estimates of the stratigraphy may not a priori be available.

Full paper can be found at https://link.springer.com/article/10.1007/s10762-020-00722-1

… that minimizes the AIC. Experiment. The measurement in this work is carried out using a pulsed, broadband THz time domain system from TeraView Ltd. (TPSSpectra 3000), shown schematically in Fig. 1. The GaAs photoconductive …

Comparisons of intra-tablet coating variability using DEM simulations, asymptotic limit models, and experiments

Ben Freireich, Rahul Kumar, William Ketterhagen, Ke Su, Carl Wassgren, J. Axel Zeitler

Abstract

Discrete element method (DEM) computer simulations are used to investigate intra-tablet coating thickness variability. Two new post-processing algorithms are presented. The first algorithm uses an image-based method to track the exposure to a simulated spray of small area panels on each tablet's surface so that the distribution of spray exposure times over the tablet's surface can be determined directly from DEM data. The second algorithm predicts the asymptotic limit of intra-tablet coating uniformity. This second algorithm includes the influence of tablet orientation and shadowing when considering exposure to the spray, averaged over many tablets.

The DEM simulations produce the first direct evidence that non-spherical tablets approach asymptotic intra-tablet coating variability values. The asymptotic limits are predicted well using the new asymptotic prediction model. In general, tablet caps have thicker coatings than tablet bands. Moreover, tablets that have a more elongated shape tend to have less coating on the smaller radius of curvature portions of the bands. Of particular importance in this new asymptotic modeling approach is the inclusion of shadowing effects. When shadowing is not included and only tablet orientation is considered, the predictions over-predict the asymptotic intra-tablet coating variability values and also change the observed rank order of the asymptotic values for different tablet shapes. The asymptotic intra-tablet coating variability values using the new algorithm correlate reasonably well with tablet sphericity, with increasing sphericity improving coating uniformity.

This paper also presents the first attempt to directly compare experimental and simulated coating thickness distributions. The asymptotic coating thickness predictions compare well qualitatively with terahertz thickness measurements made on tablets from coating experiments. Unfortunately, only qualitative comparisons could be made due to the limited number of tablets sampled experimentally and differences in spray zone areas and flux distributions. The tablets in the experiments, however, displayed similar features as those found in the simulations.

This study was performed using TeraView's Spectra 3000 system. (TeraView, Cambridge, UK)

Full Article: http://www.sciencedirect.com/science/article/pii/S0009250915001852

Evaluation of critical process parameters for inter-tablet coating uniformity of active-coated GITS using Terahertz Pulsed Imaging

Daniela Brock, J. Axel Zeitler, Adrian Funke, Klaus Knop, Peter Kleinebudde

Abstract

The aim of this study was the evaluation of critical process parameters (CPP) for inter-tablet coating uniformity in an active pan coating process using nondestructive Terahertz Pulsed Imaging (TPI). Coating uniformity was assessed by calculating the coefficient of variation (CV) of coating thickness measured by TPI, and the CV of API content measured by high performance liquid chromatography (HPLC). A design of experiments (DoE) was performed at pilot scale with drum load, drum speed, spray rate, run duration and spray pressure as factors. Good agreement in the CV of both analytical techniques was shown. The DoE models both revealed the same CPP: a low drum load, high drum speed, low spray rate and high run duration were beneficial for coating uniformity. The spray pressure was only significant in one of the DoE models. It was further shown that the negative impact of a high drum load on the CV cannot only be compensated by high drum speed, but also be compensated by a low spray rate and long run duration. It was demonstrated that TPI is a feasible tool for the measurement of inter-tablet coating uniformity and for the evaluation of CPP in an active pan coating process.

This study was performed using TeraView's Imaga 2000 system. (TeraView, Cambridge, UK)

Full Article: http://www.sciencedirect.com/science/article/pii/S0939641114002203

Non-destructive measurement of polymer coatings on pharmaceutical tablets using X-ray micro CT and terahertz pulsed imaging

Authors: Isabelle-Sophie Russe^1,2, Daniela Brock^1,2, Klaus Knop², Peter Kleinebudde², J. Axel Zeitler¹⁼
1 Department of Chemical Engineering and Biotechnology, University of Cambridge,  Cambridge, UK
2 Institute of Pharmaceutics and Biopharmaceutics, University of Duesseldorf, Duesseldorf, Germany


Full text: http://www.skyscan.be/company/UM2013/15.pdf

Conclusion

We conclude that TPI is a robust technique, and, that due to its very simple measurement  principle, it is an ideal measurement technique to quantify the coating thickness in process control and quality monitoring applications. The method introduced in this paper will be useful to explore whether there is an influence on  the refractive index of a given coating formulation with changes in process conditions during  coating or curing. It furthermore opens the possibility, in pharmaceutical applications and  beyond, to develop metrology standards for coatings that can be used to calibrate TPI  measurements for absolute thickness.
Beyond its use as a calibration technique for TPI the XµCT method has provided some  intriguing insight into the coating properties at extremes of the tablet geometry, at the edges  of tablets where high curvature was thought to typically prevent quantitative TPI  measurements due to strong scattering. The main limitations of the XµCT technique are the  measurement, and in particular, processing time together with the high demands in  computational power and data storage as well as the limited contrast that can be resolved  between coating and core. We therefore envisage that the main impact of this technique is likely to be in research and development and to support techniques such as TPI rather than  in routine quality control or process measurements.

...Samples were measured on a TPI imaga 2000 (Teraview Ltd., Cambridge, UK), using a point spacing grid of 200 x 200 µm and a penetration depth of 1 mm in air...

Quantitative analysis of the layer separation risk in bilayer tablets using terahertz pulsed imaging

International Journal of Pharmaceutics, DOI: 10.1016/j.ijpharm.2013.05.010 May 2013

Authors: Masahiro Niwa^a,Yasuhiro Hiraishi^a, Norio Iwasaki^a, Katsuhide Terada^b
a Pharmaceutical Technology R&D Laboratories, CMC Center, Takeda Pharmaceutical Company Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
b Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan

More details at: http://www.sciencedirect.com/science/article/pii/S0378517313004092

Highlights

• TPI could nondestructively detect cracks between the two layers.
• TPI could quantify adhesion integrity of bilayer tablet by interface index.
• Interface index showed good correlation to the layer separation tendency.
• TPI revealed the relationship between compression pressure and interface quality.

Abstract

Layer separation is a critical defect in many bilayer tablets. Despite its importance for product quality, few studies have investigated its root cause. We evaluated bilayer tablets with varying layer separation tendencies using terahertz pulsed imaging (TPI) in comparison with other analytical methods such as tensile strength measurements, friability testing, scanning electron microscopy (SEM), and X-ray computed tomography (XRCT). The layer separation risk was determined by friability testing and shown to be correlated with the final compression pressure used for bilayer tablet fabrication. TPI could nondestructively detect cracks between the component layers that lead to layer separation. The adhesion integrity of the interface was quantified by the interface index, a unique value derived from the time-domain terahertz waveform. The interface index showed good correlation to the layer separation tendency and could distinguish interface quality among seven batches of bilayer tablets. In contrast, SEM and XRCT detected structural defects but could not distinguish batches with high or low layer separation risk. TPI revealed the relationship between compression pressure and interface quality. Thus, TPI can aid in quality control by providing a precise estimate of the layer separation risk and robust quality of bilayer tablet development with better understanding of layer separation.

... 2.5. TPI. The TPI Imaga 2000 system (TeraView Ltd., Cambridge, UK) was used in this study. ... All data were acquired using the TPI Coating Scan software version 1.7.3 (TeraView) and analyzed using TPIcsView software version 2.3.4 (TeraView). 2.6. Statistical analysis. ... 

Hardness and density distributions of pharmaceutical tablets measured by terahertz pulsed imaging

Journal of Pharmaceutical Sciences
22 Apr 2013; +Wiley Textbooks
DOI: 10.1002/jps.23560

Authors: Robert K. May^1,4, Ke Su¹, Lianghao Han², Shuncong Zhong³, James A. Elliott², Lynn F. Gladden¹, Mike Evans⁴, Yaochun Shen³, J. Axel Zeitler¹
1. Department of Chemical Engineering and Biotechnology,+Cambridge University Press Education, Cambridge CB2 3RA, UK
2. Department of Materials Science and Metallurgy, +Cambridge University Press Education, Cambridge CB2 3QZ, UK
3. Department of Electrical Engineering and Electronics, +University of Liverpool, Liverpool L69 3GJ, UK
4. +TeraView Ltd., St John’s Innovation Park, Cambridge, CB4 0WS, UK

Abstract

We present terahertz pulsed imaging (TPI) as a novel tool to quantify the hardness and surface density distribution of pharmaceutical tablets. Good agreement between the surface refractive index (SRI) measured by TPI and the crushing force measured from diametral compression tests was found using a set of tablets that were compacted at various compression forces. We also found a strong correlation between TPI results and tablet bulk density, and how these relate to tablet hardness. Numerical simulations of tablet surface density distribution by finite element analysis exhibit excellent agreement with the TPI measured SRI maps. These results show that TPI has an advantage over traditional diametral compression and is more suitable for nondestructive hardness and density distribution monitoring and control of pharmaceutical manufacturing processes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci

...Terahertz pulsed imaging reflection measurements of sample tablets were acquired using a TPI Imaga 2000 (TeraView Ltd., Cambridge, UK). A detailed description of the measurement technique was presented earlier. The system has a useful spectral range of 60GHz to 3 THz, corresponding to a wavelength range of 0.09–5mm...


More details at: http://onlinelibrary.wiley.com/doi/10.1002/jps.23560/abstract

Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging

·         European Journal of Pharmaceutics and Biopharmaceutics

Available online 5 January 2012

• Joshua Müller^a, 
• Daniela Brock^a, 
• Klaus Knop^a, 
• J. Axel Zeitler^b, 
• Peter Kleinebudde

• Abstract

  Raman spectroscopy was implemented successfully as a non-invasive and rapid process analytical technology (PAT) tool for in-line quantitative monitoring of functional coating. Coating experiments were performed at which diprophylline tablets were coated with a sustained release formulation based on Kollicoat® SR 30 D. Using PLS a multivariate model was constructed by correlating Raman spectral data with the mean dissolution time as determined by dissolution testing and the coating thickness as measured by terahertz pulsed imaging.
  By performing in-line measurements it was possible to monitor the progress of the coating process and to detect the end point of the process, where the acquired coating amount was achieved for the desired MDT or coating thickness.
  
  Mean dissolution time (MDT) over coating time predicted by Raman spectroscopy (top left) and in correlation to coating thickness measured by terahertz spectroscopy (top right). Layer thickness maps and histograms from TPI measurements after a short (left) and a longer (right) coating time.
  
  
  Terahertz results were acquired on a TeraView's TPI2000 instrument.
  
  
  For more information :
  http://www.sciencedirect.com/science/article/pii/S0939641111003614
  
  

  Keywords

  • Process analytical technology; 
  • Multivariate data analysis; 
  • Raman spectroscopy; 
  • Terahertz pulsed imaging; 
  • Functional coating; 
  • Mean dissolution time