Analysis of Drugs Illegally Added into Chinese Traditional ...

ANALYTICAL SCIENCES OCTOBER 2013, VOL. 29 985

Introduction

Traditional Chinese medicine (TCM) is now frequently used to cure cancer,1 rheumatoid arthritis,2 leukemia,3 cardiovascular problems4 and many other diseases either alone or in combination with Western medicines.5 From related articles6 we know that more than 60% of Chinese take TCM; in European countries, approximately $5 billion USD worth of over-the-counter herbal medicines was sold in 2003. Chinese traditional patent medicine (CTPM) is a kind of TCM, which usually has slower effect compared to industrial chemical drugs.7 However, for the sake of profit and improving the efficacy of drugs in a short time, illegal manufactures may add some chemicals to CTPM.8 For example, phenformin, metformin and rosiglitazone are often added into hypoglycemic CTPM,9 sildenafil and tadalafil are added for some healthcare products.8 Though we all know that it is dangerous for patients to take unknown amounts of these chemicals,9 the detection of illegally added chemicals in CTPM is difficult. Firstly, the lack of standardization of the herbal products and the complex chemical composition of CTPM are the main obstacles for these analyses. Secondly, the boiling process and the adding of an excipient may complex the target CTPM. Thirdly, equipments for these detections are costly and not readily available, and pretreatment processes are generally

cumbersome. All of these factors make added chemicals difficult to be monitored by conventional methods.

The main methods for these detections include thin-layer chromatography (TLC),10 high-performance liquid chromatography (HPLC),11,12 liquid chromatography–mass spectrometry (LC-MS),9,13,14 ultra-performance liquid chromatography–mass spectrometry (UPLC-MS-MS),15 TLC-MS,16 and GC-MS.17 These methods can provide results with high accuracy and reliability, but almost all require a cumbersome pretreatment and a time-consuming procedure. The instruments are expensive and the experimental conditions are rigorous.

In comparison with other methods, Raman spectroscopy has its own advantages.18,19 It is capable to obtain “fingerprint information” of target molecules, and to provide high information content; it is also possible to analyze aqueous samples. Surface-enhanced Raman scattering (SERS), a surface-sensitive technique, can gain enhancements of 104 – 106 compared to normal Raman spectroscopy, and the enhancement factor can be up to 1014 – 1015 with resonance.20 It can also be used for single-molecule analysis.21

Interest in pharmaceutical analysis by SERS has increased in the past couple of years. The detection of phenolic estrogens,22 tetracycline,23 captopril,24 controlled substances like morphine, codeine, hydrocodone25 and many other drugs have been attempted. Researchers have abtained SERS spectra of amphetamine, diazepam and methadone in saliva,26 Clement Yuen27 detected paclitaxel in blood plasma by SERS with a rather technically prepared substrate.

However, a fast detection method that can use a simple silver

2013 © The Japan Society for Analytical Chemistry

Y. Z. and X. H. contributed equally to this work.† To whom correspondence should be addressed.E-mail: [email protected] (C. C.); [email protected] (L. Y.)

Analysis of Drugs Illegally Added into Chinese Traditional Patent Medicine Using Surface-enhanced Raman Scattering

Yan ZHANG,* Xiaoyan HUANG,** Wenfang LIU,** Zeneng CHENG,** Chuanpin CHEN,**† and Lihui YIN***†

* Hunan Xiangtan Institute for Food and Drug Control, Xiangtan, Hunan 411100, P. R. China ** Department of Pharmaceutics, School of Pharmaceutical Sciences, Central South University, Changsha,

Hunan 410013, P. R. China *** National Institutes for Food and Drug Control, Beijing 100050, P. R. China

Illegal chemicals, which could cause unpredictable side effects, may be added into traditional Chinese medicine (TCM) for a rapid healing effect. In this report, a surface-enhanced Raman scattering (SERS) analysis method for five kinds of illegally added drugs (rosiglitazone maleate, phenformin hydrochloride, metformin hydrochloride, pioglitazone hydrochloride and sibutramine hydrochloride) in Chinese traditional patent medicine (CTPM) has been demonstrated, including simultaneous detections of drug mixtures with CTPM. Silver colloidal, prepared by a sodium citrate reaction, was used as a SERS substrate. The optimum pH condition for each drug has also been explored because of its combined effect on protonation, surface charge, repulsion of an analyte and nanoparticles. Furthermore, the simultaneous detection of two or three kinds of these chemicals has been carried out. Characteristic peaks are employed for qualitative analysis. This is the first research using SERS for the analysis of drug mixtures in CTPM without any separation process.

Keywords Surface-enhanced Raman spectroscopy, Chinese traditional patent medicines, illegal additives

(Received July 24, 2013; Accepted August 27, 2013; Published October 10, 2013)

986 ANALYTICAL SCIENCES OCTOBER 2013, VOL. 29

colloidal as a substrate to analyze drugs in CTPM, and employ little pretreatment to the sample, is still absent. Almost all investigations concerned complex sample with a cumbersome pretreatment or standard sample in simple matrix. Also, all papers published have been limited to the analysis of only one compound.

Here, we describe how to develop a simple SERS method using a portable Raman spectrometer, which can be employed for on-site detection later, for the detection of added chemical drugs in CTPM. This method is also applied for the simultaneous detection of two or three kinds of compounds. Only a little pretreatment process was employed in the study, and the silver colloidal substrate is easily prepared. According to “The list of substance may be illegally added into healthcare products” issued by CFDA (China Food and Drug Administration), we chose five most commonly added drugs and ten kinds of popular CTPM. The aggregation of silver colloidal after the addition of samples, HCl or NaOH, has been investigated for sensitive SERS detection of illegally added drugs in CTPM. The added proportion presently used was as low as 0.1%, and all of the detections were finished without any pretreatment of the samples.

Experimental

Reagents and chemicalsThe reagents used were all analytical-grade chemicals.

Rosiglitazone maleate, phenformin hydrochloride, metformin hydrochloride, pioglitazone hydrochloride and sibutramine hydrochloride reference substances were purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China); the structures of these five chemicals are illustrated in Fig. 1. Standard solutions of the chemical drugs were prepared by deionized water.

CTPM (Jiangtangshu capsule, 300 mg; Tangniaole capsule, 300 mg; Ganluxiaoke capsule, 300 mg; Jiangtangning, 300 mg; Jiangtang capsule, 300 mg; Tangxinsukang capsule, 500 mg; Fengjiaotangtai capsule, 500 mg; Xiaokejiangtang capsule, 300 mg; Meizizi anti obesity capsule, 400 mg; Qiaojiaren capsule, 400 mg) were purchased from the market. Detailed information about these CTPM is available in Supporting Information (Table S1). The CTPM (including the capsule shell) were mixed with a specific amount of target chemicals, and then the mixture was dissolved in deionized water as a working solution.

ApparatusA portable Raman spectrometer (i-Raman, BWTEK, USA)

was employed for the detection. The excitation wavelength was 785 ± 1 nm, SERS spectra were recorded from 175 to 3100 cm–1 with a spectral resolution of 5 cm–1, and the acquisition time was 20 s. A transmission electron microscope (TEM) (JEM-2010, JEOL Ltd., Japan) was employed in our study for obtaining TEM images.

SamplesSilver colloidal was prepared while referring to the method of

citrate reduction.28 Briefly, 900 mg of silver nitrate powder was dissolved in 500 mL of deionized water, and then the aqueous solution was boiled. Ten milliliters of 1% sodium citrate were then added, and the solution was kept boiling for 1 h. After mixing an equal volume of the standard solution and silver colloidal for final detection samples, a fixed amount of HCl or NaOH (0.1 mol/L) was added to adjust the pH value.

Fig. 1　Chemical structures of five target analytes. (A) Rosiglitazone maleate, (B) phenformin hydrochloride, (C) metformin hydrochloride, (D) pioglitazone hydrochloride, (E) sibutramine hydrochloride. Fig. 2　TEM images of: (A) Ag nanoparticles in the original state,

(B) the surface of Ag nanoparticles, (C) Ag nanoparticles of silver colloidal + standard samples, (D) Ag nanoparticles of silver colloidal + standard samples + HCl or NaOH solution.


Results and Discussion

To investigate size and morphology of silver nanoparticles, TEM images (Fig. 2) were obtained to evaluate the variation of silver nanoparticles caused by the addition of standard samples, HCl or NaOH. The colloidal (Fig. 2(A)) was a blend of spherical and rod particles in various shapes; they were well-dispersed in the original silver colloidal at first. It is about 60 – 80 nm diameter for spherical nanoparticles. Figure 2(B) shows the typical metal and polyhedron structure of nanoparticles; this could have importance in any SERS enhancement effect revealed by other authors.29 Then, with the addition of standard samples (Fig. 2(C)), silver nanoparticles started to aggregate together, and after adjusting the pH value, the colloidal was further aggregated, and the clusters became bigger. The inter-particle space of nanoparticles was then down to several nanometers, which is one feature of an ideal SERS

substrate30 (Fig. 2(D)). The generating rate of hot sites, which is a decisive factor for the enhancement, can be improved in this way.31

SERS is sensitive to the pH condition. Thus, the spectra of five chemical drugs (rosiglitazone maleate, phenformin hydrochloride, metformin hydrochloride, pioglitazone hydrochloride and sibutramine hydrochloride) under different pH conditions were obtained. Because the nanoparticles aggregated quickly to the pH meter probe, the pH value can not be measured accurately. Here, using pH paper, the acidic condition represents a pH of about 2, alkaline is 12, and a neutral condition is at 7. The results show that each chemical exhibits significantly different spectra under these three conditions. As shown in Fig. 3(A), rosiglitazone maleate showed the largest response and the least interference under an acidic condition; the peaks here are the strongest and most abundant compared to those in alkaline and neutral conditions. Under an acidic condition, all peaks at 408, 620, 736, 816, 984,

Fig. 3　SERS spectra of drugs on Ag colloidal under different pH conditions. (A) and (B) are the SERS spectra of rosiglitazone maleate and phenformin hydrochloride at a concentration of 1 × 10–5 mol·L–1, respectively. For (A), lines “a to c” represent rosiglitazone maleate in acidic, alkaline and neutral condition, respectively. For (B), lines “a to c” represent phenformin hydrochloride in alkaline, acidic and neutral condition, respectively.

Fig. 4　SERS spectra of rosiglitazone maleate (A) and phenformin hydrochloride (B) in different CTPM; the detections were operated in acidic and alkaline conditions, respectively. For (A), lines “a to e” represent an adding proportion of 1.0% in Jiangtangshu, 0.8% in Tangniaole, 0.5% in Ganluxiaoke, 0.3% in Jiangtangning, 0.1% in Jiangtang. For (B), lines “a to e” represent an adding proportion of 1.0% in Fengjiaotangtai, 0.8% in Tangxinsukang, 0.5% in Xiaokejiangtang, 0.3% in Jiangtangshu, 0.1% in Jiangtang, respectively.


1178, 1254, 1324, 1384, and 1614 cm–1 were the characteristic peaks of rosiglitazone maleate. However, under alkaline and neutral conditions, some peaks, like 736 and 1324 cm–1, were obviously weakened; peaks at 408, 1254, and 1384 cm–1 even could not be found. The results are almost the same for pioglitazone hydrochloride, sibutramine hydrochloride since all of these three compounds need an acidic condition for SERS analysis. This can be explained by the fact that they all are sub-acidic or neutral; deprotonated molecules do exist under an acidic condition, though it is less than in an alkaline condition. However, with further increasing of the pH, the surface potential of silver nanoparticles become more negative, while the rate of ionization of a compound increases. This lead to a hindered adsorption process caused by an increased repulsion between the nanoparticles and the analyte molecules.34

On the contrary, phenformin hydrochloride needs to be detected under an alkaline condition (Fig. 3(B)). No peaks can be found in a neutral condition, but in an alkaline condition, peaks at 998, 1028 and 1200 cm–1 are rather strong; these three peaks together with 620, 770 cm–1 peaks are characteristic peaks of phenformin hydrochloride. Metformin hydrochloride also needs to be detected under an alkaline condition. This is because the biguanide structure makes them strongly alkaline. The pKa value for metformin is 12.4, and for phenformin hydrochloride it is 12.15. They can only be deprotonated under a rather basic condition, and then link to a mental surface to form an Ag–N bonds.

Therefore, we boldly speculate that the pH condition can be selective for different chemicals since it can influence the structures, adsorption and molecular orientation of chemicals in silver colloidal.32 Gao24 proved that the effect of the pH condition on the signal intensity is actually caused by a change of the “hot site”. Each specific chemical has its own most suitable pH conditions, and the nanoparticles undergo appropriate aggregation in this situation. The selectivity of silver colloidal in different pH conditions affects the intensity of the Raman signal and the appearance of the characteristic peaks. In other words, the selectivity affects the accuracy of the fingerprints of chemicals, and each chemical has its own most suitable pH conditions. After a screening of the pH condition, more chemicals can be detected, and high sensitivity can be gained.

To employ this excellent method for the detection of illegal additives in CTPM, under their most suitable pH conditions, the Raman response of the five chemicals, respectively, in several CTPM were investigated. (The spectra of a CTPM control sample under different pH conditions can be available in Supporting Information (Fig. S1), also the standard spectra of metformin hydrochloride, pioglitazone hydrochloride and sibutramine hydrochloride is available in Supporting Information (Fig. S2). Here, we detected several different adding proportion samples, and finally chose one of them. As is shown in Figs. 4 and 5, the characteristic peaks of all the five drugs in CTPM are consistent with their standard spectra, and all of the peaks are very clear. Drugs can be well detected even at a 0.1% adding proportion. Figure 4(A) shows that six characteristic peaks of rosiglitazone maleate at 408, 736, 1178, 1254, 1324, and 1384 cm–1 can be found, and are well separated with the interfering peaks. The red-shift of the peaks at 1254 and 1324 cm–1 may be a result of further aggregation of silver nanoparticles. This is because the adding of a matrix may decrease the inter-particle spacing of the isolated colloidal that did not form aggregates with the adsorbate.33 For phenformin hydrochloride, there were apparent vibration peaks at 928, 998, 1028 and 1200 cm–1 in all five CTPM. As is shown in Fig, 5,

the peak at 820 cm–1 of metformin hydrochloride was submerged by the background peaks. For sibutramine hydrochloride, only in a Tangniaole capsule can the three characteristic peaks be fully detected. However, the characteristic peak at 820 cm–1 of pioglitazone hydrochloride can be well detected in all CTPM.

The simultaneous determinations of two or three kinds of chemical drugs in CTPM were carried out as well. As is shown in Figs. 6 and 7, the best pH conditions for these detections were chosen firstly as mentioned above. For the simultaneous

Fig. 5　SERS spectra of metformin hydrochloride (A), pioglitazone hydrochloride (B) and sibutramine hydrochloride (C), respectively, in different CTPM; the detections were operated in alkaline, acidic and acidic condition respectively. For (A), lines “a to d” represent an adding proportion of 20.0% in Jiangtangshu, 15.0% in Tangniaole, 10.0% in Ganluxiaoke, 5.0% in Jiangtangning. For (B), lines “a to e” represent 1.0% in Tangniaole, 0.8% in Jiangtangning, 0.5% in Tangxinsukang, 0.3% in Jiangtang, 0.1% in Jiangtangshu. For (C), lines “a to d” represent 3.0 and 2.0% in Meizizi anti obesity capsule, 1.0 and 0.5% in Qiaojiaoren respectively.


determinations of phenformin hydrochloride and metformin hydrochloride (Fig. 6), both characteristic peaks of the two chemicals under an alkaline condition can be found in the standard spectra. The peaks at 620, 998, and 1026 cm–1 were the characteristic peaks of phenformin hydrochloride and peaks at 818, 1408, and 1450 cm–1 were the characteristic peaks of metformin hydrochloride. Considering the blue shift of all peaks of metformin hydrochloride, we classify the 998 cm–1 peak into the phenformin hydrochloride group, though 995 cm–1 appeared in the standard spectrum of metformin hydrochloride. Figure 6(B) shows that in the four investigated CTPM, all of the characteristic peaks of phenformin hydrochloride at 998, 1026, and 1200 cm–1 were very distinct. For metformin hydrochloride, peaks at 818, 1408, and 1450 cm–1 can be detected as well, and all were less interfered by the background. Meanwhile, we also attempted simultaneous determinations of three chemical drugs.

Figure 7(A) shows that simultaneous determinations of

rosiglitazone maleate, phenformin hydrochloride and pioglitazone hydrochloride require an acidic condition. In the standard spectra, peaks at 744 and 1332 cm–1 were for rosiglitazone maleate, 998, 1028, and 1202 cm–1 were for phenformin hydrochloride, and 626, 1174 cm–1 were for pioglitazone hydrochloride. In CTPM, peaks at 734 and 1330 cm–1 represent rosiglitazone maleate, 998 and 1030 cm–1 peaks represent phenformin hydrochloride; 626 and 1778 cm–1 peaks represent pioglitazone hydrochloride. In this way, we also finished the simultaneous detection of phenformin hydrochloride mixed with pioglitazone hydrochloride, and phenformin hydrochloride mixed with rosiglitazone maleate. Therefore, we could easily figure out two or three kinds of illegally added chemicals in CTPM simultaneously, depending on these spectra.

Fig. 6　SERS spectra of the simultaneous detection of phenformin hydrochloride (Phe) and metformin hydrochloride (Met). (A) is the SERS spectra of the two chemicals in different pH conditions, and lines “a to c” represents in alkaline, acidic and neutral condition, respectively. (B) is the SERS spectra of the two chemicals in different CTPM in alkaline condition. Lines “a to d”, respectively, represents an adding proportion of Phe 1.0% and Met 15.0% in Tangniaole, Phe 0.8% and Met 10.0% in Jiangtangning, Phe 0.5% and Met 8.0% in Tangxinsukang, Phe 0.3% and Met 5% in Jiangtang.

Fig. 7　SERS spectra of the simultaneous detection of rosiglitazone maleate (Roi), phenformin hydrochloride (Phe), pioglitazone hydrochloride (Pio). (A) is the SERS spectra of the three chemicals in different pH conditions, and lines “a to c” represent in alkaline, acidic and neutral condition respectively. (B) is the SERS spectra of the three chemicals in different CTPM in acidic condition. Lines “a to d” respectively represent an adding proportion of 1.0% in Tangniaole, 0.8% in Jiangtangning, 0.5% in Tangxinsukang, 0.3% in Jiangtang, 0.1% in Jiangtangshu for all three chemicals.


Conclusions

The simultaneous detection of two or three kinds of chemicals in CTPM matrix was demonstrated in the present work after investigating the silver colloidal aggregation and pH conditions. It was found that the pH level was extremely important for the aggregation of nanoparticles and the absorption of the analyte. Meanwhile, this study achieved the simultaneous detection of several drugs in one run. With portable Raman scattering equipment, this convenient detection could provide a rapid method for on-site detection. This study provides an economical and efficient method for such studies and can be easily introduced into daily detection.

If a more detailed study on the aggregation of silver colloidal under subdivided pH conditions can be carried out, it may be helpful to gain a deeper understanding concerning the influence of the pH condition. We are also considering to establish a SERS database similar to an IR fingerprint database. According to this database, people can compare the spectra obtained with the corresponding one in the database to determine the composition of unknown additives. After a systemic study of the pH contribution on SERS, this method could be applied in the fields of foods, health-care products and cosmetics.

Acknowledgements

This work was supported in part by a research grant from the National Natural Science Foundation of China (Grant No. 81202378). We also acknowledge Fundamental Research Funds for the Central Universities (Grant No. 2012QNZT092) and the Major Science and Technology Planning Project of Haikou City, Hainan Province, China.

Supporting Information

Prescription of related CTPM (Table S1), SERS spectra of their control sample in acidic and alkaline condition, respectively (Fig. S1), and standard spectra of metformin hydrochloride, pioglitazone hydrochloride, sibutramine hydrochloride in their corresponding suitable pH condition (Fig. S2). This material is available free of charge on the Web at http://www.jsac.or.jp/analsci/.

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