Whole Tablet Measurements Using the Spectrum One NTS Tablet Autosampler System
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A P P L I C A T I O N
Whole Tablet Measurements
Using the Spectrum One NTS Tablet
Autosampler System
N O T E
Introduction individual assays by HPLC. The er speeds and also provides more
standard deviation of assay is sample matrix information. It is
Recent advances in NIR technology
intended to provide an idea of also readily automated thus pro-
have changed the ways in which
the uniformity of the blend. This viding the potential for more
both the pharmaceutical industry
measurement is required before and/or faster tablet testing using
and the regulators view the
batch release and can cause seri- less specialized operators. More
current approaches to tablet
ous bottlenecks, especially if out- efficient, more informative
testing in manufacturing.
of-specification results are gener- measurement in this area is a
In 2001, among the FDA’s top 10 ated. The HPLC technique used is key factor in delivering more
reasons for product recall were slow, requires skilled analysts, process understanding; an
problems with sub-potency and provides little or no information objective pursued by industry
tablet dissolution. In addition, on the matrix and destroys the and regulators alike.
recent cases of cGMP violations sample. Analysts are actively
seeking faster, non-destructive This note describes an example
have highlighted issues in tablet
methods which can provide more showing the application of NIR
manufacturing. One area where
information on the sample and tablet transmission measurements
the industry is seeking to improve
are capable of being used by less to determine the active content of
its processes is in the blending
experienced operators. whole tablets
area. After tablet pressing,
measurement of uniformity of
NIR now offers the possibility
content usually involves taking
of performing non-destructive,
a sample (typically 10 tablets)
whole tablet testing at much high-
from the batch and performing
www.perkinelmer.com
Method integration software (AssureID™
version 2) provides simple
The aim of the study was to present
construction of methods which can
whole, coated tablets to the analyser
be easily readied for effective
to determine active level, then to
push-button operation in the plant
perform a series of analyses on a
(Figure 3). Given the method is
batch of tablets to provide informa-
generally used by users in a
tion on the uniformity of the batch.
production environment numerous
Using the system described below,
system design features in both
the samples are presented
software and hardware are oriented
horizontally to the spectrometer and
towards more robust methods – from
a masked beam illuminates each
sample presentation to the software
sample with a spot diameter of
workflows designed to minimize the
6 mm. The power of the beam at the Figure 1: Tablet holder for
likelihood of operational errors.
sample position is relatively low NIR transmission measurements.
(ca 200 mW) in order to avoid
unwanted heating problems in
the tablet, which could interfere
with results.
The tablets to be tested were 350 mg
in weight, ca 12 mm in length and
ca. 5-mm thick. Using the NIR
transmission approach, it is
important to present the sample
to the instrument in such a way as
to minimize stray radiation from the
instrument passing around the side
of the sample and going onto the
detector. To overcome this potential
problem, special custom tablet
holders may be fabricated to ensure
a tight fit between tablet holder and
tablet. An illustration of the sample
holders is shown in Figure 1.
The Spectrum™ One NTS FT-NIR
spectrometer was equipped with the
Tablet Autosampler sampling system. Figure 2: Spectrum One NTS tablet autosampler system.
The system includes detectors for
both transmission and reflectance
measurement, and an automated
sample wheel for batch measurements
(Figure 2). Dedicated detectors allow
for optimized operation for this
potentially demanding measurement.
The method development and system
Figure 3: AssureID software for tablet analysis automation.
Calibration with 68 independent samples, For the batch calculations, 10 tablets
spanning the same concentration were placed into the tablet holders
When setting up the system for
range (validation set) were used. which in turn were mounted onto
analysis, it is necessary to calibrate
Calibration details are shown the wheel. It is also advisable to
the system using a training set of
in Table 1. generate a tablet presentation SOP
samples which span the target assay
to ensure correct positioning of the
value – usually 80-120% of target When the primary property of tablets into the autosampler between
value is chosen. This can sometimes interest is chemical composition different operators. The AssureID
be the slowest part of the system such as active content, there are software allows users to display
implementation as it can be difficult some steps that can be taken to their own SOP prior to analysis.
to obtain samples which are so improve the robustness of the This can contain product-specific
"off-spec," especially for mature method to operator and/or sampling information which is linked to that
processes. Hence it is often most variability. For example, the choice particular method.
effective to implement this technology of using derivative spectra for the
earlier in the product lifecycle in the analysis can considerably improve
formulation development or scale-up the robustness of the calibration with Results and Discussion
stages when a wider range of respect to sampling variations such
calibration tablets is more likely For this analysis, batches of 10
as tablet height position and for this
to be at hand. samples were analysed using the
method it was found that a smoothed
PLS1 method outlined above and
second derivative approach worked
The target concentration for this simple batch statistics including
well. It is a very simple operation
product was 20 mg per 350-mg the mean assay value, standard
in Quant+ to switch-on various
tablet. To generate the calibration, deviation, and minimum and
forms of data pre-treatment and to
samples ranging from 16-mg content maximum batch values were
view the effects on the calibration
to 24-mg content were scanned and calculated and output to the reports
performance. The calibration model
the Quant+ quantitative software and secure database. The database
used and certain sampling precau-
application used to generate the cali- may be queried within the AssureID
tions are key factors in determining
bration equation relating the spectral application to show result trends,
the ultimate robustness of the
changes to the concentration values. revealing important information
method in everyday use and, as a
The Quant+ software offers a full about the process. An example plot
rule, extra care taken at this stage
suite of diagnostics to help optimise is shown in Figure 4. A typical
is easily paid back in terms of the
the calibration before incorporating output from a query is shown in the
reliability of the final method.
the model into the analysis figure below. Individual records may
workflow. For this study, it was Relevant instrument data collection also be examined, tracing calculated
found adequate to use a sample parameters for optimum results for results to associated instrument
training set, a calibration set of this sample set are shown in Table 2. conditions, spectra and system
20 samples and to test the model check results, Figure 5.
Table 2: Instrument details for tablet
Table 1: Quantitative calibration details. assay measurement.
Number of calibration samples 20 Scan range/cm-1 12000-8500
Number of validation samples 68 Resolution/cm-1 16
Calibration algorithm Partial least Scan time/per sample 60 sec
squares (PLS1) Scan time per batch 10 min
Data pre-processing 2nd derivative, Apodization Strong
25 point smooth width
Background reference Open beam
Number of PLS factors 2
Standard error of calibration (20 samples)/mg 0.8
Standard error of prediction (60 samples)/mg 0.9
This kind of display provides useful As the technique becomes more samples. In this case changes in the
information on a number of important accepted by the industry, it is spectra are related directly to some
process issues, assisting the overall expected that more "calibration-free" variability in the process. For
understanding of the process: approaches will be adopted in tablet example, the standard deviation of
analysis. Such methods skip the step an isolated active peak height may
■ Potency drift during the run of the of developing a model relating the be related directly to uniformity of
tablet press spectral changes to properties of a batch thereby eliminating the need
■
interest for a pre-analysed training to calibrate using samples which are
Potency variability between runs
set of samples and applying the already beyond the bounds of normal
on a tablet press
model to predict properties for the process variability. This approach
■ Potency variability between tablet
presses
■ Potency variability with differing
blending conditions
■ Direct comparison with HPLC
assay values. In general due to
the much faster and more
representative NIR analysis it is
possible to obtain trend plots
with far more data points than the
corresponding HPLC trend plots.
This kind of information is beneficial
not only from the point of view of
improved understanding of the
blending/pressing from the point of
view of potency, but can be extended
to provide similar information on
other ingredients, and in favourable
cases some physical properties such
as coating thickness and hardness –
with no significant impact of on
batch analysis time. Figure 4: Trend display showing variation of potency within a batch.
Next, it is envisaged tablet analysis
will be extended to the following:
■ Other matrix components
■ Physical properties such as
hardness and/or coating thickness
■ Powder blends before tablet
pressing. This will be possible by
extracting sample from the blender
using a sample thief and pressing
the blend into wafers prior to NIR
transmission analysis.
■ Other uncoated tablets where
moisture will be measured in
addition to active. Moisture will
be measured by reflectance and
active content by transmission.
Figure 5: Tablet analysis database display.
may be easier for some products, based approach worked better. The Increasing scrutiny from the
where the active absorption in the method can be run in parallel with regulators and the drive for
spectrum is very clearly differentiated the conventional HPLC method improved process understanding will
from the other ingredients in the during the validation stage. ensure the technique will become
spectrum. For other products, more widespread. The
however, the distinction is less clear anticipated development of official
making it necessary to introduce Conclusion guidelines for setting up and testing
more sophisticated data analysis The use of NIR transmission for NIR transmission methods in a
techniques. Figure 6 shows the NIR whole tablet analysis can effectively similar manner to the NIR reflectance
transmission spectra of two different improve the efficiency of the tablet methods will be another factor in the
products. In Figure 6a, the active pressing step by allowing faster growth of this exciting development.
band is not overlapped with those feedback into the process than the
of the other ingredients and simple As the pharmaceutical industry
conventional HPLC method. NIR can
band height measurements can be begins to realize the benefits of
be an order of magnitude faster.
correlated directly with the potency. the new technologies for NIR testing,
More analytical information per
In Figure 6b, the active band is it will then be just a matter of time
sample and more tablet analyses
overlapped with the absorption of before NIR becomes established as a
in a given time greatly increases
the other ingredients and for this standard method used as commonly
process understanding.
particular product, a chemometrics- as mid-IR in pharmacopeial methods.
Figure 6a: NIR transmission spectra where active absorp- Figure 6b: NIR transmission spectra where active
tion is separated from other components in the matrix. absorption is overlapped with other ingredients. The
Spectra from 0-, 10-, 50-, 200-mg strength tablets. two traces show spectra from tablets of two strengths,
ca 5 and 10% active, where the absorption due to the
active indicated.PerkinElmer Life and Analytical Sciences 710 Bridgeport Avenue Shelton, CT 06484-4794 USA Phone: (800) 762-4000 or (+1) 203-925-4602 www.perkinelmer.com © 2003 PerkinElmer, Inc. All rights reserved. PerkinElmer is a registered trademark and AssureID and Spectrum are trademarks of PerkinElmer, Inc. All trademarks depicted are the property of their respective holders or owners. PerkinElmer reserves the right to change this document at any time and disclaims liability for editorial, pictorial, or typographical errors. 006832_02 070300 Printed in USA
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