Porosity, one of the important quality attributes of pharmaceutical tablets, directly affects the mechanical properties, the mass transport and hence tablet disintegration, dissolution and ultimately the bioavailability of an orally administered drug. The ability to accurately and quickly monitor the porosity of tablets during manufacture or during the manufacturing process will enable a greater assurance of product quality. This tutorial systematically outlines the steps involved in the terahertz-based measurement method that can be used to quantify the porosity of a tablet within seconds in a non-destructive and non-invasive manner. The terahertz-based porosity measurement can be performed using one of the three main methods, which are (i) the zero-porosity approximation (ZPA); (ii) the traditional Bruggeman effective medium approximation (TB-EMA); and (iii) the anisotropic Bruggeman effective medium approximation (AB-EMA). By using a set of batches of flat-faced and biconvex tablets as a case study, the three main methods are compared and contrasted. Overall, frequency-domain signal processing coupled with the AB-EMA method was found to be most suitable approach in terms of accuracy and robustness when predicting the porosity of tablets over a range of complexities and geometries. This tutorial aims to concisely outline all the necessary steps, precautions and unique advantages associated with the terahertz-based porosity measurement method.
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Showing posts with label Daniel Markl. Show all posts
Showing posts with label Daniel Markl. Show all posts
Friday, January 17, 2020
Abstract-Terahertz-Based Porosity Measurement of Pharmaceutical Tablets: a Tutorial
Porosity, one of the important quality attributes of pharmaceutical tablets, directly affects the mechanical properties, the mass transport and hence tablet disintegration, dissolution and ultimately the bioavailability of an orally administered drug. The ability to accurately and quickly monitor the porosity of tablets during manufacture or during the manufacturing process will enable a greater assurance of product quality. This tutorial systematically outlines the steps involved in the terahertz-based measurement method that can be used to quantify the porosity of a tablet within seconds in a non-destructive and non-invasive manner. The terahertz-based porosity measurement can be performed using one of the three main methods, which are (i) the zero-porosity approximation (ZPA); (ii) the traditional Bruggeman effective medium approximation (TB-EMA); and (iii) the anisotropic Bruggeman effective medium approximation (AB-EMA). By using a set of batches of flat-faced and biconvex tablets as a case study, the three main methods are compared and contrasted. Overall, frequency-domain signal processing coupled with the AB-EMA method was found to be most suitable approach in terms of accuracy and robustness when predicting the porosity of tablets over a range of complexities and geometries. This tutorial aims to concisely outline all the necessary steps, precautions and unique advantages associated with the terahertz-based porosity measurement method.
Saturday, December 1, 2018
Abstract- In-situ Monitoring of Powder Density Using Terahertz Pulsed Imaging
Daniel Markl, Runqiao Dong, Jingyi Li, J Axel Zeitler
https://ieeexplore.ieee.org/document/8510184
We have developed an approach to investigate density variations in a moving powder bed by means of terahertz pulsed imaging. Terahertz measurements were acquired continuously during the rotation of a container filled with different grades of lactose and microcrystalline cellulose powder. Relative density distributions were resolved for different compaction stages of the powder, which indicated high variations of the powder density.
Saturday, July 14, 2018
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.
Saturday, February 3, 2018
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.
Sunday, December 10, 2017
Abstract-Analysis of anisotropic pore structures using terahertz spectroscopy and imaging
Daniel Markl, Cathy Ridgway, Prince Bawuah, Patrick Gane, Jarkko Ketolainen, Kai-Erik Peiponen, J Axel Zeitler
http://ieeexplore.ieee.org/document/8066929/
This study demonstrates the analysis of anisotropic pore structures of highly porous pharmaceutical powder compacts by combining terahertz time-domain spectroscopy and in-situ measurements of the liquid penetration using terahertz pulsed imaging.
Tuesday, November 21, 2017
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.
Monday, May 22, 2017
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
Monday, April 3, 2017
Abstract-Optics-based compressibility parameter for pharmaceutical tablets obtained with the aid of the terahertz refractive index
Mousumi Chakraborty, Cathy Ridgway, Prince Bawuah, Daniel Markl, Patrick A.C. Gane, Jarkko Ketolainen, J.Axel Zeitler, Kai-Erik Peiponen,
http://www.sciencedirect.com/science/article/pii/S037851731730279X
The objective of this study is to propose a novel optical compressibility parameter for porous pharmaceutical tablets. This parameter is defined with the aid of the effective refractive index of a tablet that is obtained from non-destructive and contactless terahertz (THz) time-delay transmission measurement. The optical compressibility parameter of two training sets of pharmaceutical tablets with a priori known porosity and mass fraction of a drug was investigated. Both pharmaceutical sets were compressed with one of the most commonly used excipients, namely microcrystalline cellulose (MCC) and drug Indomethacin. The optical compressibility clearly correlates with the skeletal bulk modulus determined by mercury porosimetry and the recently proposed terahertz lumped structural parameter calculated from terahertz measurements. This lumped structural parameter can be used to analyse the pattern of arrangement of excipient and drug particles in porous pharmaceutical tablets. Therefore, we propose that the optical compressibility can serve as a quality parameter of a pharmaceutical tablet corresponding with the skeletal bulk modulus of the porous tablet, which is related to structural arrangement of the powder particles in the tablet.
Sunday, February 5, 2017
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.
Sunday, December 25, 2016
Abstract-Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging
- Daniel Markl,
- J. Axel Zeitler,
- Cecilie Rasch,
- Maria Høtoft Michaelsen,
- Anette Müllertz,
- Jukka Rantanen,
- Thomas Rades,
- Johan Bøtke,
Purpose
A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI).
Methods
Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined.
Results
A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 ± 0.75% larger than designed; n = 3).
Conclusions
The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms
Sunday, September 4, 2016
Teraview Blog- Abstract-Pharmaceutical applications of terahertz spectroscopy and imaging
Daniel Markl ; Michael T. Ruggiero and J. Axel Zeitler
http://terahertzspectroscopyandimaging.blogspot.com/2016/08/pharmaceutical-applications-of.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+TerahertzSpectroscopyAndImaging+%28terahertz+spectroscopy+and+imaging%29Terahertz spectroscopy and imaging techniques have advanced the chemical and physical characterisation of active pharmaceutical ingredients (APIs), excipients and final solid dosage forms. Terahertz radiation can be used to investigate both chemical and solid structures, as well as provide information on the bulk morphology of pharmaceutical materials. The penetrating and non-destructive properties of terahertz light, coupled with its high acquisition rate, makes this technology a promising candidate for process analytical technology (PAT) applications.
Terahertz radiation corresponds to frequencies between the microwave and infrared regions of the electromagnetic spectrum (300 GHz to 10 THz, or wavelengths of 1mm to 1μm). For many years the terahertz region had been referred to as the ‘terahertz gap’ because of the difficulties in generating and detecting terahertz light. This has changed over the past few decades due to major advances that have brought down costs and instrument size, from $500,000+ laser systems that can take up an entire laboratory space to sub-$100,000 benchtop – and even hand-held – devices. Such breakthroughs have brought terahertz techniques into the mainstream and have enabled terahertz technologies to be implemented in industrial settings.
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