Classification and Visualization of Physical and Chemical Properties of Falsified Medicines with Handheld Raman Spectroscopy and X-Ray Computed Tomography

Abstract

Analytical methods for the detection of substandard and falsified medical products (SFs) are important for public health and patient safety. Research to understand how the physical and chemical properties of SFs can be most effectively applied to distinguish the SFs from authentic products has not yet been investigated enough. Here, we investigated the usefulness of two analytical methods, handheld Raman spectroscopy (handheld Raman) and X-ray computed tomography (X-ray CT), for detecting SFs among oral solid antihypertensive pharmaceutical products containing candesartan cilexetil as an active pharmaceutical ingredient (API). X-ray CT visualized at least two different types of falsified tablets, one containing many cracks and voids and the other containing aggregates with high electron density, such as from the presence of the heavy elements. Generic products that purported to contain equivalent amounts of API to the authentic products were discriminated from the authentic products by the handheld Raman and the different physical structure on X-ray CT. Approach to investigate both the chemical and physical properties with handheld Raman and X-ray CT, respectively, promise the accurate discrimination of the SFs, even if their visual appearance is similar with authentic products. We present a decision tree for investigating the authenticity of samples purporting to be authentic commercial tablets. Our results indicate that the combination approach of visual observation, handheld Raman and X-ray CT is a powerful strategy for nondestructive discrimination of suspect samples.

Figure 1.

Visual inspection of tablets: T-1; authentic product A (4 mg), T-2; authentic product A (8 mg), T-3 and T-4; generic products from different Chinese manufacturers, T-5; model formulation including API and lactose monohydrate, obtained by direct compression, T-6; model formulation including API and the same excipients as in the authentic product A, obtained by direct compression, T-7 and T-8; counterfeits found in Indonesia. This figure appears in color at www.ajtmh.org.

Figure 2.

The Raman spectra of the active pharmaceutical ingredient (API), lactose monohydrate (excipient) and the tablets. The area surrounded by the dashed line covers the specific peak of API that does not overlap with the peaks of excipients. Other peaks are due to excipients, mainly from lactose monohydrate. The Raman spectra of T-1 to T-6 including both API and lactose monohydrate are similar, but T-7 and T-8 show distinctly different spectra. This figure appears in color at www.ajtmh.org.

Figure 3.

Average P values of authentic products calculated automatically by the handheld Raman device for similarity to the authentic product A (8 mg). Repeatability of the P value was confirmed by ten replicate measurements. The range of the P value from the maximum to the minimum value is shown by a bar. This figure appears in color at www.ajtmh.org.

Figure 4.

X-ray computed tomography images of the internal structure of tablets T-1 to T-8.

Figure 5.

Decision tree of combination approach for nondestructive discrimination between test samples and authentic product A (8 mg). This figure appears in color at www.ajtmh.org.