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Year |
Ref |
Paper
title |
Abstract |
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2021 |
Terahertz time-domain spectroscopy for powder
compact porosity and pore shape measurements: An error analysis of the
anisotropic bruggeman model |
Terahertz time-domain spectroscopy (THz-TDS)
is a novel technique which has been applied for pore structure analysis and
porosity measurements. For this, mainly the anisotropic Bruggeman (AB-EMA)
model is applied to correlate the effective refractive index (neff) of a
tablet and the porosity as well as to evaluate the pore shape based on the
depolarisation factor L. This paper investigates possible error sources of
the AB-EMA for THz-TDS based tablet analysis. The effect of absorption and
tablet anisotropy – changes of pore shape with porosity and density
distribution – have been investigated. The results suggest that high tablet
absorption has a negligible effect on the accuracy of the AB-EMA. In regards
of tablet anisotropy the accuracy of the porosity determination is not
impaired significantly. However, density distribution and variations in the
pore shape with porosity resulted in an unreliable extraction of the tablet
pore shape. As an extension of the AB-EMA a new concept was introduced to
convert the model into bounds for L. This new approach was found useful to
investigate tablet pore shape but also the applicability of the AB-EMA for an
unknown set of data. |
|
|
2021 |
A Fast and Non-destructive Terahertz Dissolution
Assay for Immediate Release Tablets |
There is a clear need for a robust process
analytical technology tool that can be used for on-line/in-line prediction of
dissolution and disintegration characteristics of pharmaceutical tablets
during manufacture. Tablet porosity is a reliable and fundamental critical
quality attribute which controls key mass transport mechanisms that govern
disintegration and dissolution behavior. A measurement protocol was developed
to measure the total porosity of a large number of tablets in transmission
without the need for any sample preparation. By using this fast and
non-destructive terahertz spectroscopy method it is possible to predict the
disintegration and dissolution of drug from a tablet in less than a second
per sample without the need of a chemometric model. The validity of the
terahertz porosity method was established across a range of immediate release
(IR) formulations of ibuprofen and indomethacin tablets of varying geometries
as well as with and without debossing. Excellent correlation was observed
between the measured terahertz porosity, dissolution characteristics (time to
release 50% drug content) and disintegration time for all samples. These
promising results and considering the robustness of the terahertz method pave
the way for a fully automated at-line/on-line porosity sensor for real time
release testing of IR tablets dissolution. |
|
|
2020 |
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. |
|
|
2020 |
Review of Terahertz Pulsed Imaging for
Pharmaceutical Film Coating Analysis |
Terahertz pulsed imaging (TPI) was introduced
approximately fifteen years ago and has attracted a lot of interest in the
pharmaceutical industry as a fast,
non-destructive modality for quantifying film coatings on pharmaceutical
dosage forms. In this topical review, we look back at the use of TPI for analysing
pharmaceutical film coatings, highlighting the main contributions made and
outlining the key challenges ahead. |
|
|
2018 |
A quantitative comparison of in-line coating
thickness distributions obtained from a pharmaceutical tablet mixing process
using discrete element method and terahertz pulsed imaging |
The application of terahertz pulsed imaging (TPI) in
an 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 the 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 the off-line measurements. |
|
|
2018 |
Fast and non-destructive pore structure analysis
using terahertz time-domain spectroscopy |
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. |
|
|
2018 |
A non-destructive method for quality control of
the pellet distribution within a MUPS tablet by terahertz pulsed imaging |
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. |
|
|
2017 |
Non-destructive Determination of Disintegration
Time and Dissolution in Immediate Release Tablets by Terahertz Transmission
Measurements |
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. |
|
|
2017 |
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 |
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. |
[i]
Anuschek, Moritz, Prince Bawuah, and J. Axel Zeitler. "Terahertz
time-domain spectroscopy for powder compact porosity and pore shape
measurements: An error analysis of the anisotropic bruggeman model."
International Journal of Pharmaceutics: X (2021): 100079.
[ii]
Bawuah, Prince, Daniel Markl, Alice Turner, Mike Evans, Alessia Portieri,
Daniel Farrell, Ralph Lucas, Andrew Anderson, Daniel J. Goodwin, and Axel
Zeitler. "Data supporting'A Fast and Non-destructive Terahertz Dissolution
Assay for Immediate Release Tablets'." (2021).
[iii]
Bawuah,
Prince, Daniel Markl, Daniel Farrell, Mike Evans, Alessia Portieri, Andrew
Anderson, Daniel Goodwin, Ralph Lucas, and J. Axel Zeitler.
"Terahertz-based porosity measurement of pharmaceutical tablets: a tutorial." Journal
of Infrared, Millimeter, and Terahertz Waves (2020): 1-20.
[iv]
Alves-Lima,
Décio, Jun Song, Xiaoran Li, Alessia Portieri, Yaochun Shen, J. Axel Zeitler,
and Hungyen Lin. "Review of Terahertz Pulsed Imaging for Pharmaceutical
Film Coating Analysis." Sensors 20, no. 5 (2020): 1441.
[v]
Pei, Chunlei, Hungyen Lin, Daniel Markl, Yao-Chun Shen, J. Axel Zeitler, and
James A. Elliott. "A quantitative comparison of in-line coating thickness
distributions obtained from a pharmaceutical tablet mixing process using
discrete element method and terahertz pulsed imaging." Chemical
Engineering Science 192 (2018): 34-45.
[vi]
Markl, Daniel, Prince Bawuah, Cathy Ridgway, Sander van den Ban, Daniel J.
Goodwin, Jarkko Ketolainen, Patrick Gane, Kai-Erik Peiponen, and J. Axel
Zeitler. "Fast and non-destructive pore structure analysis using terahertz
time-domain spectroscopy." International journal of pharmaceutics 537, no.
1-2 (2018): 102-110.
[vii]
Novikova, Anna, Daniel Markl, J. Axel Zeitler, Thomas Rades, and Claudia S.
Leopold. "A non-destructive method for quality control of the pellet
distribution within a MUPS tablet by terahertz pulsed imaging." European
Journal of Pharmaceutical Sciences 111 (2018): 549-555.
[viii]
Markl, Daniel, Johanna Sauerwein, Daniel J. Goodwin, Sander van den Ban, and J.
Axel Zeitler. "Non-destructive determination of disintegration time and
dissolution in immediate release tablets by terahertz transmission
measurements." Pharmaceutical research 34, no. 5 (2017): 1012-1022.
[ix]
Ridgway, Cathy, Prince Bawuah, Daniel Markl, J. Axel Zeitler, Jarkko
Ketolainen, Kai-Erik Peiponen, and Patrick Gane. "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."
International journal of pharmaceutics 526, no. 1-2 (2017): 321-331.
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