Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy

Abstract

The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.

Figure 1.

Comparison of assay for the samples collected in China and Myanmar. Two vertical dashed lines show the acceptance criteria of 95.0–105.0% assay. This figure appears in color at www.ajtmh.org.

Figure 2.

Comparison of dissolution rate (%) for the samples collected in China and Myanmar. The vertical dashed line shows the acceptance criteria should be more than 75% dissolution rate at 45-minute sampling time. This figure appears in color at www.ajtmh.org.

Figure 3.

Raman spectra of candesartan cilexcetil tablets and the falsified products (before multiplicative scattering correlation preprocessing of Raman spectra). This figure appears in color at www.ajtmh.org.

Figure 4.

Raman spectra of candesartan cilexetil tablets and the falsified products (after multiplicative scattering correlation preprocessing of Raman spectra). This figure appears in color at www.ajtmh.org.

Figure 5.

Comparison between the calibration model and validation result in principal component analysis model. This figure appears in color at www.ajtmh.org.

Figure 6.

Principal component analysis score plot derived from the Raman spectra of candesartan cilexetil tablets, including the falsified tablets, collected in China, Indonesia, Japan, and Myanmar. This figure appears in color at www.ajtmh.org.

Figure 7.

Loading on PC 1, PC 2, and PC 3 in the principal component analysis model calculated by using Raman spectra of candesartan cilexetil tablets. This figure appears in color at www.ajtmh.org.