Robert K. May

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.

Hardness and Density Distributions of Pharmaceutical Tablets Measured by Terahertz Pulsed Imaging

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.

Systematic study of terahertz time-domain spectra of historically informed black inks

The potential of terahertz-time domain spectroscopy (THz-TDS) as a diagnostic tool for studies of inks in historical documents is investigated in this paper. Transmission mode THz-TDS was performed on historically informed model writing and drawing inks. Carbon black, bistre and sepia inks show featureless spectra between 5 and 75 cm(-1) (0.15-2.25 THz); however, their analysis still provided useful information on the interaction of terahertz radiation with amorphous materials. On the other hand, THz-TDS can be used to distinguish different iron gall inks with respect to the amount of iron(II) sulfate contained, as sharp spectral features are observed for inks containing different ratios of iron(II) sulfate to tannic or gallic acid. Additionally, copper sulfate was found to modify the structure of iron(II) precipitate. Furthermore, Principal Component Analysis (PCA) applied to THz-TDS spectra, highlights changes in iron gall inks during thermal degradation, during which a decrease in the sharp spectral bands associated with iron(II) sulfate is observed. ATR-FTIR spectroscopy combined with THz-TDS of dynamically heated ink samples indicate that this phenomenon is due to dehydration of iron(II) sulfate heptahydrate. While this research demonstrates the potential of THz-TDS to improve monitoring of the chemical state of historical documents, the outcomes go beyond the heritage field, as it also helps to develop the theoretical knowledge on interactions between terahertz radiation and matter, particularly in studies of long-range symmetry (polymorphism) in complex molecular structures and the role played by the surrounding matrix, and also indicates the potential of THz-TDS for the optimization of contrast in terahertz imaging.

Impact of Processing Conditions on Inter-tablet Coating Thickness Variations Measured by Terahertz In-Line Sensing.

A novel in-line technique utilising pulsed terahertz radiation for direct measurement of the film coating thickness of individual tablets during the coating process was previously developed and demonstrated on a production-scale coater. Here, we use this technique to monitor the evolution of tablet film coating thickness and its inter-tablet variability during the coating process under a number of different process conditions that have been purposefully induced in the production-scale coating process. The changes that were introduced to the coating process include removing the baffles from the coater, adding uncoated tablets to the running process, halting the drum, blockage of spray guns and changes to the spray rate. The terahertz sensor was able to pick up the resulting changes in average coating thickness in the coating drum and we report the impact of these process changes on the resulting coating quality.

Pharmaceutical tablet hardness measurements with thz pulsed imaging

We present the results of terahertz pulsed imaging (TPI) experiments to measure the ‘hardness’ of pharmaceutical solid dosage forms (tablets) compacted at various compression forces. Results of TPI measurements are compared to those from diametric compression tests as well as finite element analysis (FEA) simulations of density distributions on the surface of the tablet. In both cases strong correlation with TPI results was found. In particular, radially symmetric spatial distributions in tablet density due to the shape of the punch used in tablet manufacture were observed. The results of these experiments show that TPI is suitable for non-destructive monitoring and control of pharmaceutical manufacturing processes.

Terahertz pulsed imaging of surface variations on pharmaceutical tablets

We present an analysis of terahertz pulsed imaging (TPI) measurements made on pharmaceutical tablets compacted at a range of compression forces. In particular, we investigate the uniformity and local variations in the refractive index on the surface of tablets of different shapes. Through terahertz imaging it has been possible to observe small-scale deviations on tablet surfaces that may have relevance to the quality of tablet manufacture and performance.

Influence of Particle Size on Optical Constants From Pellets Measured With Terahertz Pulsed Spectroscopy

Particle size is shown to influence both the overall value and the measurement precision of the refractive index and absorption coefficient of a sample diluted with high density polyethylene (HDPE) powder and compressed in a pellet. However, excessive grinding of a sample before it is mixed with HDPE powder can result in the formation of large particle clusters. These aggregates can induce internal scattering of the terahertz pulse within the pellet as well as lead to different mechanical properties of the pellet, which may change the distribution of air pores. These phenomena result in extracted optical constants with low accuracy and precision. The present work introduces a simple experimental procedure to improve the precision and accuracy of optical constants from spectroscopic pellets. This procedure consists of moderately grinding the sample powder in fine HDPE powder with a pestle and mortar. The standard deviation of the refractive index of Prussian blue has been observed to reduce from 0.14 to 0.02 following this procedure.

Near-infrared spectroscopy for non-destructive coating analysis calibrated by Terahertz Pulsed Imaging

Near-infrared (NIR) spectroscopy is a versatile technique for non-destructive analysis of pharmaceutical tablet coating thickness; however, it needs a calibration model and thus the prior knowledge about the coating thickness of each tablet is required. In this work, we demonstrate that Terahertz Pulsed Imaging (TPI) can provide, in a nondestructive fashion, such coating thickness information for building the calibration model needed by the NIR technique.

In-line monitoring of coating thickness of pharmaceutical tablets during production scale film coating by Terahertz imaging

We present preliminary results from in-line Terahertz pulsed imaging (TPI) measurements of coating thickness on pharmaceutical tablets made during production-scale film coating. Results of these real-time TPI measurements are compared to those from off-line TPI measurements, as well as weight-gain measurements made on sample tablets removed at discrete time-intervals during production. The results, and their repeatability, demonstrate that real-time monitoring of pharmaceutical tablet coating is not only possible but provides substantially more information than the standard quality control method.

Neural Network-based non-destructive quantification of thin coating by terahertz pulsed imaging in the frequency domain

Terahertz pulsed imaging (TPI) is a powerful tool for non-destructive quantification of pharmaceutical tablet coatings. In this paper, we present a Neural Network (NN) based method for extracting the coating thickness from the FFT-amplitude of the measured terahertz waveform. We demonstrate that the NN-based frequency domain method outperforms the standard “peak-finding” time-domain method, in terms of quantifying thinner coating thickness, although a learning set of data is necessary.