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