Closing the terahertz gap: Tiny laser is an important step toward new sensors

A new imaging technology rapidly measures the chemical compositions of solids. A conventional image of a sample pill is shown at left; at right, looking at the same surface with terahertz frequencies reveals various ingredients as different colors. Such images would aid quality control and development in pharmaceutical manufacturing, as well as medical diagnosis and treatment.

https://www.eurekalert.org/multimedia/pub/207021.php

In a major step toward developing portable scanners that can rapidly measure molecules in pharmaceuticals or classify tissue in patients' skin, researchers have created an imaging system that uses lasers small and efficient enough to fit on a microchip.

The system emits and detects electromagnetic radiation at terahertz frequencies -- higher than radio waves but lower than the long-wave infrared light used for thermal imaging. Imaging using terahertz radiation has long been a goal for engineers, but the difficulty of creating practical systems that work in this frequency range has stymied most applications and resulted in what engineers call the "terahertz gap."

"Here, we have a revolutionary technology that doesn't have any moving parts and uses direct emission of terahertz radiation from semiconductor chips," said Gerard Wysocki, an associate professor of electrical engineering at Princeton University and one of the leaders of the research team.

Terahertz radiation can penetrate substances such as fabrics and plastics, is non-ionizing and therefore safe for medical use, and can be used to view materials difficult to image at other frequencies. The new system, described in a paper published in the June issue of the journal Optica, can quickly probe the identity and arrangement of molecules or expose structural damage to materials.

The device uses stable beams of radiation at precise frequencies. The setup is called a frequency comb because it contains multiple "teeth" that each emit a different, well-defined frequency of radiation. The radiation interacts with molecules in the sample material. A dual-comb structure allows the instrument to efficiently measure the reflected radiation. Unique patterns, or spectral signatures, in the reflected radiation allow researchers to identify the molecular makeup of the sample.

While current terahertz imaging technologies are expensive to produce and cumbersome to operate, the new system is based on a semiconductor design that costs less and can generate many images per second. This speed could make it useful for real-time quality control of pharmaceutical tablets on a production line and other fast-paced uses.

"Imagine that every 100 microseconds a tablet is passing by, and you can check if it has a consistent structure and there's enough of every ingredient you expect," said Wysocki.

As a proof of concept, the researchers created a tablet with three zones containing common inert ingredients in pharmaceuticals -- forms of glucose, lactose and histidine. The terahertz imaging system identified each ingredient and revealed the boundaries between them, as well as a few spots where one chemical had spilled over into a different zone. This type of "hot spot" represents a frequent problem in pharmaceutical production that occurs when the active ingredient is not properly mixed into a tablet.

The team also demonstrated the system's resolution by using it to image a U.S. quarter. Fine details like the eagle's wing feathers, as small as one-fifth of a millimeter wide, were clearly visible.

While the technology makes the industrial and medical use of terahertz imaging more feasible than before, it still requires cooling to a low temperature, a major hurdle for practical applications. Many researchers are now working on lasers that will potentially operate at room temperature. The Princeton team said its dual-comb hyperspectral imaging technique will work well with these new room-temperature laser sources, which could then open many more uses.

Because it is non-ionizing, terahertz radiation is safe for patients and could potentially be used as a diagnostic tool for skin cancer. In addition, the technology's ability to image metal could be applied to test airplane wings for damage after being struck by an object in flight.

In addition to Wysocki, the paper's Princeton authors are former visiting graduate student Lukasz Sterczewski (currently a postdoctoral scholar at NASA's Jet Propulsion Laboratory) and associate research scholar Jonas Westberg. Other co-authors are Yang Yang, David Burghoff and Qing Hu of the Massachusetts Institute of Technology; and John Reno of Sandia National Laboratories. Support for the research was provided in part by the Defense Advanced Research Projects Agency and the U.S. Department of Energy.

Abstract-A quantitative comparison of in-line coating thickness distributions obtained from a pharmaceutical tablet mixing process using discrete element method and terahertz pulsed imaging

Chunlei Pei, Hungyen Lin, Daniel Markl, Yao-ChunShen, J.Axel Zeitler, James A.Elliott,

https://www.sciencedirect.com/science/article/pii/S0009250918304172

The application of terahertz pulsed imaging (TPI) in the in-line configuration to monitor the coating thickness distribution of pharmaceutical tablets has the potential to improve the performance and quality of the spray coating process. In this study, an in-line TPI method is used to measure coating thickness distributions on pre-coated tablets during mixing in a rotating pan, and compared with results obtained numerically using the discrete element method (DEM) combined with a ray-tracing technique. The hit rates (i.e. the number of successful coating thickness measurements per minute) obtained from both terahertz in-line experiments and the DEM/ray-tracing simulations are in good agreement, and both increase with the number of baffles in the mixing pan. We demonstrate that the coating thickness variability as determined from the ray-traced data and the terahertz in-line measurements represents mainly the intra-tablet variability due to relatively uniform mean coating thickness across tablets. The mean coating thickness of the ray-traced data from the numerical simulations agrees well with the mean coating thickness as determined by the off-line TPI measurements. The mean coating thickness of in-line TPI measurements is slightly higher than that of off-line measurements. This discrepancy can be corrected based on the cap-to-band surface area ratio of the tablet and the cap-to-band sampling ratio obtained from ray-tracing simulations: the corrected mean coating thickness of the in-line TPI measurements shows a better agreement with that of off-line measurements.

Abstract-Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy

Daniel Markl, Prince Bawuah, Cathy Ridgway, Sander van den Ban, Daniel J.Goodwin, Jarkko Ketolainen, Patrick Gane, Kai-Erik Peiponen,  J. Axel Zeitler

https://www.sciencedirect.com/science/article/pii/S0378517317311730

Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, Sa, to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The Sa parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The Sa parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product.

Abstract-A non-destructive method for quality control of the pellet distribution within a MUPS tablet by terahertz pulsed imaging

Anna Novikova, Daniel Markl, J. Axel Zeitler, Thomas Rades, Claudia S.Leopold

http://www.sciencedirect.com/science/article/pii/S0928098717305845


Terahertz pulsed imaging (TPI) was applied to analyse the inner structure of multiple unit pellet system (MUPS) tablets. MUPS tablets containing different amounts of theophylline pellets coated with Eudragit® NE 30 D and with microcrystalline cellulose (MCC) as cushioning agent were analysed. The tablets were imaged by TPI and the results were compared to X-ray microtomography. The terahertz pulse beam propagates through the tablets and is back-reflected at the interface between the MCC matrix and the coated pellets within the tablet causing a peak in the terahertz waveform. Cross-section images of the tablets were extracted at different depths and parallel to the tablet faces from 3D terahertz data to visualise the surface-near structure of the MUPS tablets. The images of the surface-near structure of the MUPS tablets were compared to X-ray microtomography images at the same depths. The surface-near structure could be clearly resolved by TPI at depths between 24 and 152 μm below the tablet surface. An increasing amount of pellets within the MUPS tablets appears to slightly decrease the detectability of the pellets within the tablets by TPI. TPI was shown to be a non-destructive method for the detection of pellets within the tablets and could resolve structures thicker than 30 μm. In conclusion, a proof-of-concept was provided for TPI as a method of quality control for MUPS tablets.

Abstract-On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient

• Cathy Ridgway,  
• Prince Bawuah, 
• Daniel Markl, 
• J. Axel Zeitler, 
• Jarkko Ketolainen, 
• Kai-Erik Peiponen, 
• Patrick Gane, 

• ^a Omya International AG, CH-4665 Oftringen, Switzerland
• ^b Institute of Photonics, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland
• ^c Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom
• ^d School of Pharmacy, Promis Centre, University of Eastern Finland, P.O. Box 1617, FI-70211, Kuopio, Finland
• ^e Aalto University, Chemical Engineering, Bioproducts and Biosystems, FI-00076 Aalto, Helsinki, Finland
• 
  

http://www.sciencedirect.com/science/article/pii/S0378517317303393

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties

Abstract-Non-destructive Prediction of Enteric Coating Layer Thickness and Drug Dissolution Rate by Near-infrared spectroscopy and X-ray computed tomography

Aoi Ariyasu, 

Yusuke Hattori, 

Makoto Otsuka

http://www.sciencedirect.com/science/article/pii/S0378517317302983

The coating layer thickness of enteric-coated tablets is a key factor that determines the drug dissolution rate from the tablet. Near-infrared spectroscopy (NIRS) enables non-destructive and quick measurement of the coating layer thickness, and thus allows the investigation of the relation between enteric coating layer thickness and drug dissolution rate. Two marketed products of aspirin enteric-coated tablets were used in this study, and the correlation between the predicted coating layer thickness and the obtained drug dissolution rate was investigated. Our results showed correlation for one product; the drug dissolution rate decreased with the increase in enteric coating layer thickness, whereas, there was no correlation for the other product. Additional examination of the distribution of coating layer thickness by X-ray computed tomography (CT) showed homogenous distribution of coating layer thickness for the former product, whereas the latter product exhibited heterogeneous distribution within the tablet, as well as inconsistent trend in the distribution between the tablets. It was suggested that this heterogeneity and inconsistent trend in layer thickness distribution contributed to the absence of correlation between the layer thickness of the face and side regions of the tablets, which resulted in the loss of correlation between the coating layer thickness and drug dissolution rate. Therefore, the predictability of drug dissolution rate from enteric-coated tablets depended on the homogeneity of the coating layer thickness. In addition, the importance of micro analysis, X-ray CT in this study, was suggested even if the macro analysis, NIR spectroscopy (NIRS) in this study, are finally applied for the measurement.

Abstract-Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

Daniel Markl, Johanna Sauerwein, Daniel J. Goodwin, Sander van den Ban, J. Axel Zeitler

http://link.springer.com/article/10.1007/s11095-017-2108-4

The aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.

Non-invasive screening method reveals important properties of pharmaceutical tablets

Information on significant properties of pharmaceutical tablets, such as their mechanical strength and dissolution, can now be obtained without resorting to the conventional, time-consuming and destructive testing methods, according to a new study completed at the University of Eastern Finland. A new structural descriptive parameter based on terahertz (THz) time-domain techniques allow for a non-invasive detection of pharmaceutical tablet parameters, constituting a research breakthrough in the field of pharmacy

https://www.sciencedaily.com/releases/2017/01/170110091904.htm

The study focused on non-contact quality inspection of pharmaceutical tablets using terahertz time-domain techniques. Terahertz radiation represents the far end of the infrared band and it has unique properties that permit a quick and safe identification of pharmaceutical tablet properties. Using THz radiation, which is invisible and safe for human beings, it is possible to determine what a tablet is made of, including the nature of its constituents and how they are arranged. To this effect, the study has developed a novel structural descriptive parameter for pharmaceutical tablets, addressing the orientation of their microscopic structure. The parameter provides information on the pattern of arrangement of the various particulates as well as air pores within a tablet.

This fast and non-destructive screening method has significant applications in the inspection of the quality of individual tablets during production, providing information on the amount of active pharmaceutical ingredient, tablet porosity and weight, among other things. Another important application is that this method can detect counterfeit and substandard tablets (for example fake antimalarial tablets) flooding the markets in developing countries, where counterfeit drugs are a major cause of mortality.

The parameter constitutes a research breakthrough in the field of pharmacy, as in-depth understanding of its behaviour gives information on, e.g., the mechanical strength, content uniformity and dissolution of pharmaceutical tablets.

By utilising training sets of pharmaceutical tablets, scientists at the University of Eastern Finland in collaboration with scientists at the University of Cambridge, UK, and in Switzerland have successfully demonstrated the ability to non-invasively detect the porosity, weight and height of tablets.. Based on these promising results, the researchers believe that an alternative non-destructive approach for quality screening of tablets can, in the future, replace the conventional destructive techniques such as mercury intrusion porosimetry. Hence, pharmacists and pharmaceutical scientists can now screen individual tablets even in the production line.

Since the majority (about 80%) of administered drugs are tablets, there is a significant need for a process analytical technology (PAT) tool that will permit the screening of individual pharmaceutical tablets before they reach end users. The methods were presented by Prince Bawuah, MSc, in his doctoral dissertation, and the findings were originally published in the International Journal of Pharmaceutics, European Journal of Pharmaceutics and Biopharmaceutics and Optical Review. The findings serve not only the pharmaceutical industry, but also pharmaceutical research.

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Materials provided by University of Eastern Finland. Note: Content may be edited for style and length.

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Journal Reference:

1. Prince Bawuah, Mousumi Chakraborty, Tuomas Ervasti, J.Axel Zeitler, Jarkko Ketolainen, Patrick A.C. Gane, Kai-Erik Peiponen. A structure parameter for porous pharmaceutical tablets obtained with the aid of Wiener bounds for effective permittivity and terahertz time-delay measurement. International Journal of Pharmaceutics, 2016; 506 (1-2): 87 DOI: 10.1016/j.ijpharm.2016.04.026