For Merck internal use only
Abstract
PCA Classification
Summary
Characterization and Classification of Pharmaceutical Tablet Coating by
Laser Induced Breakdown Spectroscopy (LIBS)
Laser Induced Breakdown Spectroscopy (LIBS) has
emerged as an innovative tool for quantitative and
qualitative elemental analysis in pharmaceutical
research. The sampling process, laser ablation (LA),
involves a high-power pulsed laser beam directed and
focused onto a solid sample to convert a finite volume
of the sample into excited vapor and aerosol
constituents. As the plasma cools, the excited
constituents relax to their ground state and emit light at
characteristic wavelengths of the elements present.
LIBS has several advantages including little to no
sample preparation, fast measurement time, broad
elemental coverage, and versatile sampling protocols.
Herein, the potential use of LIBS for rapid
characterization of tablet coatings will be illustrated.
Firstly, the thickness and uniformity of the tablet
coating, which has a significant effect on the coating
performance, were assessed by LIBS. Additionally, the
technique was used to locate contaminants on the
coating, as well as to identify the specific elemental
contaminants present. Further, principle component
analysis (PCA) were utilized to discriminate among
different samples and to visualize differences in tablet
coatings.
Lanfang Zoua, Yong Liu
b, Brittany Kassim
a, Xiaodong Bu
a
a Analytical Research & Development, Merck Research Laboratories, Rahway, NJ 07065, USA
b Analytical Science, Merck Research Laboratories, West Point, PA 19486, USA
Laser induced breakdown spectroscopy (LIBS) was
demonstrated as a means for detecting and mapping
elements on the pharmaceutical tablet coatings,
which illustrates the coating information, including
thickness, uniformity, contamination and
classification. PCA exhibited a clear visual diagnosis
of the different classes of samples and also provides
a physical interpretation of the classification results.
In addition, LIBS can be used as a standalone
technique but also could be coupled with ICP-MS to
quantify more difficult elements.
Laser Ablation
LIBS Spectrum of Coating and Core
Acknowledgements: We would like to thank AR&D
management for their continued support. We would also like
to thank our collaborators for allowing us to be part of the
investigations and stories. We look forward to many more
future collaborations.
Most coating may have various inorganic elements present
as additives or impurities, such as Ti, Fe or Mg. These
elements have clearly identifiable peaks in the LIBS
emission spectrum. In our materials, Ti was identified as a
tag element to represent the tablet coating and the Ti I
emission line at 498.17 nm was selected. In contrast, there
is no Ti in the core of tablets, allowing the ability to clearly
distinguish between coating and core.
The average Ti intensity from 16 different sites was
plotted based on the laser pulse number. The signal
was observed to change as the laser drilled through the
tablet from the surface to the core. The intensity of first
shot is high, then stays high for thirteen laser shots and
eventually decreases as the laser penetrates the
coating. The decrease in signal can be ascribed to the
penetration of coating into the core.
• Micro Analysis – 5 - 250 µm laser spot
• Bulk Analysis – laser is operated in
raster or line scan mode to ablate a
larger area of the sample
• Depth Profiling – ablate a single
location with many laser pulses, each
laser pulse represents characteristic
information about the sample
• 2D Mapping – lateral surface mapping
of a sample
• 3D Mapping – lateral surface + depth
profile analysis
Coating Thickness
Coating Uniformity
Coating Contamination
Blue 1
Blue 2
Mini 1
Mini 2
Big 1
Big 2
The uniformity of the coating has a significant effect on
the coating performance. Layer-by-layer chemical
imaging is a novel strategy to provide important
information on the elemental distribution of materials
as a function of depth, which allows the direct visual
observation of the uniformity of the coating thickness.
The quick location and identification of contaminants
on the tablet coating remains a great challenge
despite the fast development of various analytical
techniques in the pharmaceutical industry. LIBS
provides a simple way to detect the location of
contaminants. The spectrum differences between the
locations with contaminants and without contaminants
are very obvious. Because LIBS can perform micro
analysis down to μm level, the exact location of the
contaminants can be acquired.
Moreover, LIBS can be used to generate 2D mapping
for the contaminated area. Figure a displays the
intensity map for Ti I 498.17 nm and Figure b shows
the Fe I 495.76 nm intensity map for the region that
was analyzed. Fe is main element in the
contaminates. This provides a visual view of where the
contaminants are and what elements they consist of.
Principle component analysis (PCA) is one of the most
extensively used multivariate statistical techniques in
chemometrics. PCA can effectively reduce the high-
dimensional LIBS data onto a lower dimensional
coordinate system, in which the largest variance lies on
the first axis and decreases thereafter for each
successive axis.
The first PC explains 72.7% of the total variance in the
dataset. After incorporating the second and third PCs,
this metric increase to 94.8%. The first three PC scores
were plotted for LIBS analysis of three different classes
of pharmaceutical tablets. Clearly, the tablets of each
class tend to cluster together and are fairly well
separated from the other classes. These results imply
that LIBS spectra can provide vital information to
routinely monitor pharmaceutical tablets as well as to
distinguish different classes of tablets.
MK-8931 tablet with
Iron contamination
Ti Fe