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Journal of Pharmaceutical and Biomedical Analysis 97 (2014) 24–28

Contents lists available at ScienceDirect

Journal of Pharmaceutical and Biomedical Analysis

j o ur nal ho me page: www.elsev ier .com/ lo cate / jpba

hort communication

dentification and quantitation of the ingredients in a counterfeitietnamese herbal medicine against rheumatic diseases

ohannes Wiesta, Curd Schollmayera, Gabriele Gresserb, Ulrike Holzgrabea,∗

Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Wuerzburg, GermanyPharmaceutical Biology, Julius-von-Sachs-Institute for Biosciences, University of Wuerzburg, Wuerzburg, Germany

r t i c l e i n f o

rticle history:eceived 4 March 2014eceived in revised form 3 April 2014ccepted 9 April 2014vailable online 19 April 2014

a b s t r a c t

Counterfeit and/or illegally manufactured drugs and herbal medicines are becoming an increasing prob-lem throughout the world. Internet sales simplify distribution and payment of these falsified drugs. Herewe report on a Vietnamese herbal medicine, which was advertised for treatment of rheumatic diseasefrom a religious Vietnamese healer. By means of NMR and LC/MS we found 863 mg acetaminophen,262 mg sulfamethoxazole, 42 mg indomethacin and less than 1% trimethoprim in a sachet of 2.617 g

eywords:ntirheumatic herbal medicineC/MSMR

powder content, in addition to some cinnamon bark and phosphate.© 2014 Elsevier B.V. All rights reserved.

Rllegal drug

. Introduction

People suffering from rheumatic diseases are tempted to buyerbal medicines because the antirheumatic therapy with chemicalrugs is accompanied by frequently occurring strong side effects,.g. due to gastro-intestinal bleeding. Visiting the internet reveals

huge selection of herbals against rheumatoid arthritis form Asianountries, such as China, India (TCM, Ayurvedic, Unani or Tibbi), andorea [1–3]. For many Indian herbals, the pharmacological activity

s well-described, e.g. [4]. Other herbals are of low quality and ille-al, and possibly dangerous for the patients [5]. In addition, a lotf so-called herbals, available in the internet, contain chemicallyefined drugs beside herbals [6], e.g. in the field of lifestyle drugsuch as tadalafil [7] and sildenafil [8,9]. Here, the chemical drug isostly not labeled.Counterfeit and/or illegally manufactured drugs and herbal

edicines are becoming an increasing problem throughout theorld. The problem is well documented in the literature [10].nravelling the counterfeiting by identification of the ingredients

f the (herbal) drugs is always a challenge. Mostly a combina-ion of many spectroscopic techniques such as high performanceiquid chromatography hyphenated with mass spectrometry and

Abbreviations: 1H NMR spectroscopy, proton nuclear magnetic resonance;SAID, non-steroidal anti-inflammatory drug.∗ Corresponding author. Tel.: +49 931 3185461; fax: +49 931 3185494.

E-mail address: u.holzgrabe@pharmazie.uni-wuerzburg.de (U. Holzgrabe).

ttp://dx.doi.org/10.1016/j.jpba.2014.04.013731-7085/© 2014 Elsevier B.V. All rights reserved.

NMR spectroscopy is necessary for identification and quantifica-tion of the active pharmaceutical components [11,12] in additionto special techniques as DOSY 1H NMR [13].

Recently, we got such an herbal drug from a female rheumaticpatient who bought the medicine from a religious Vietnamesehealer. It was advertised as 100% natural and accompanied bythe advice to take one sachet per day. A sachet contained 2.6 gof a brownish powder, smelling of cinnamon. Unfortunately, nolabeling was found. For identification and quantification of theingredients HPLC–UV and –MS, NMR and IR experiments as wellas some inorganic tests were applied, in addition light microscopestudies to elucidate the herbal ingredients.

2. Material and methods

2.1. Chemicals

HPLC grade acetonitrile and methanol were purchased fromVWR (Darmstadt, Germany), acetic acid ACS reagent ≥99.7% fromSigma-Aldrich (Schnelldorf, Germany), isopropyl alcohol ≥99.7%from Bernd Kraft (Duisburg, Germany) and hexadeuteriodimethylsulfoxide (DMSO-d6, 99.8% D) from Euriso-top (Saarbrücken,Germany). HPLC grade water was obtained by in-house Milliporesystem from Merck (Darmstadt, Germany). As reference standards,

acetaminophen was purchased from Rhodia Organique (Venis-seux, France), trimethoprim from Procter&Gamble (Cincinnati,USA), sulfamethoxazole from Berlin-Chemie (Berlin, Germany) andindomethacin from Sigma-Aldrich (Schnelldorf, Germany).

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J. Wiest et al. / Journal of Pharmaceutic

.2. NMR spectroscopy

NMR measurements were performed on a Bruker Avance III00 MHz spectrometer (Bruker BioSpin, Karlsruhe, Germany) with

PABBI 1H/D-BB 5 mm probe head, and data processing with theopSpin 3.0 software. Depending on the concentration the num-er of scans varied from 128 to 13k for 1H NMR and 512 to2k for 13C NMR measurements. The standard measurements 1HMR were performed at 300 K, flip angle 30◦, spectral width of0.55 ppm, transmitter offset of 6.175 ppm, acquisition time 3.985 sollowed by a relaxation delay varied from 1 to 20 s. 64k dataoints were collected at a spinning frequency of 20 Hz. Processingarameters were set to an exponential line broadening windowunction of 0.3 Hz, an automatic baseline correction and man-al phasing. The spectra were referenced to the residual solventignal of DMSO (2.5 ppm/39.52 ppm). For structure elucidation aull characterization was performed consisting of standard 1H,3C, distortionless enhancement by polarization transfer (DEPT-35), correlated spectroscopy (H-H-COSY), heteronuclear multipleuantum coherence (HMQC) and heteronuclear multiple bond cor-elation (HMBC) experiments. Standard 5 mm NMR tubes (ST 500)ere purchased from Norell (Landisville, USA).

For a first NMR screen of the entire sample, 20 mg were dis-olved in 700 �l DMSO-d6. For structure elucidation the respectiveractions of 10 preparative HPLC runs (see below) were evaporatedn vacuo and the residue was dissolved in 550 �l DMSO-d6.

.3. HPLC chromatography

Analytical and preparative HPLC analyses were performedsing an Agilent Technologies 1100 series systems (Waldbronn,ermany). The analytical system consisted of a binary pump, aegasser, an autosampler, a column thermostat and a diode-arrayV detector. The preparative system consisted of a binary pump, anutosampler, fraction collector and a diode-array UV detector with-ut an degasser, therefore the solvents were degassed by Sonorexath Bandelin (Berlin, Germany) for 30 min. The LC–MS systemonsisted of a 1100 series HPLC, ESI source and a LC/MSD Trap ofgilent Technologies.

A Nucleodur Sphinx RP (150 × 4.6 mm, 5 �m) column was usedor analytical purposes and the column a Nucleodur Sphinx RP125 × 10 mm, 5 �m) for preparative isolation of the components.PLC vials and caps were purchased from Phenomenex (Aschaf-

enburg, Germany). The samples were centrifuged with 13 000 rpm0 min by an EBA 12 centrifuge of Hettich (Tuttlingen, Germany).

The separation was carried out by means of the method reportedy Panusa et al. [12] using a Nucleodur Sphinx RP column and aradient of water (A) and acetonitrile (B) each with acetic acid 0.1%nd applying a wavelength of 254 nm. The elution started isocratic5:15 (A:B, v/v) for 3 min, to 70:30 (A:B, v/v) in 7 min and from0:30 to 10:90 (A:B, v/v) in 20 min. After each run the column wasashed with 100% B for 5 min and then conditioned with 85:15

A:B, v/v) for 10 min. The injection volume was 5 �l and the columnhermostat was kept at 30 ◦C. This method was scaled up with a flowf 4.6 ml min−1 for preparative HPLC.

For structure elucidation purposes the HPLC – using the Panusaethod – was hyphenated to an ESI–MS detector: the parameter

or positive mode and negative ionization mode was set to 350 ◦Crying temperature, 70.00 psi nebulizer, 12.0 l min−1 drying gasnitrogen) and a scanning range from 50–800 m/z.

.4. IR spectroscopy

For IR studies the test compound was washed with isopropyllcohol to separate the inorganic material and organic molecules.

Biomedical Analysis 97 (2014) 24–28 25

The spectra were conducted on Jasco FT/IR-6100 spectrometer fromJasco (Gross-Umstadt, Germany).

2.5. Spectroscopic data of the ingredients

2.5.1. Acetaminophen1H-NMR (DMSO-d6, ı (ppm) J (Hz)): 9.62 (s, 1H, NH), 9.11 (s, 1H,

OH), 7.33 (m, 2H, H-arom), 6.66 (m, 2H, H-arom), 1.97 (s, 3H, CH3).

2.5.2. Trimethoprim1H-NMR (DMSO-d6, ı (ppm), J (Hz)): 7.52 (s, 1H, H-arom), 6.55

(s, 2H, H-arom), 6.09 (s, 2H, NH2), 5.71 (s, 2H, NH2), 3.72 (s, 6H,2×OCH3), 3.62 (s, 3H, OCH3), 3.53 (s, 2H, CH2).

2.5.3. Sulfamethoxazole1H-NMR (DMSO-d6, ı (ppm), J (Hz)): 10.9 (s, 1H, NH), 7.45

(m, 2H, H-arom), 6.56 (m, 2H, H-arom), 6.09 (d, 1H, 4J = 0.8 Hz,H-oxazole), 6.06 (s, 2H, NH2), 2.28 (d, 3H, 4J = 0.8 Hz, CH3).

2.5.4. Indomethacin1H-NMR (DMSO-d6, ı (ppm), J (Hz): 12.35 (s, 1H, COOH), 7.66 (m,

4H, H-arom), 7.04 (d, 1H, 4J = 2.5 Hz H-arom), 6.93 (d, 1H, 3J = 9.0 Hz,H-arom), 6.70 (dd, 1H, 3J = 9.0 Hz, 4J = 2.5 Hz, H-arom), 3.75 (s, 3H,-OCH3), 3.66 (s, 2H, CH2COOH), 2.20 (s, 3H, CH3).

2.6. Quantification of the active ingredients—Standard addition

One sachet herbal mix contained 2.617 g brownish powder. Thepowder was grounded in a mortar for HPLC and NMR sample prepa-ration.

The concentration of herbal mix was 1 mg ml−1 for pre-liminary HPLC and MS test, 100 mg ml−1 for preparative HPLCand 0.8522 mg ml−1 for analytical HPLC dissolved in methanolby 10 min sonication and then centrifuged at 13 000 rpm for10 min. For standard addition the concentration was 214.79 mgacetaminophen, 68.23 mg sulfamethoxazole and 19.04 mgindomethacin dissolved in 250 ml methanol. To the test solu-tion of 0.8522 mg ml−1 test compound, 100, 200, 300, 400, 500 �lstandard solutions were added.

2.7. Test for phosphate

One hundred milligram test compound was washed with iso-propyl alcohol to separate the inorganic material and organicmolecules. The residue was dried for 24 h over silica gel in vacuoand 20 mg inorganic material was mixed with 1 ml nitric acid 60%and 20 mg ammonium molybdate. The solution was heated up for1 min and after 20 min cooling to room temperature a yellow saltprecipitated.

2.8. Microscopic inspection

The herbal mixture was examined by a CX41 microscopefrom Olympus (Hamburg, Germany), and the microscope imageswere recorded by an EC3 microscope camera from Leica (Nidau,Switzerland).

3. Results and discussion

3.1. Identification

In order to get a general idea about the ingredients of the sachet

the powder was pestle to get a uniform powder. 20 mg of thispowder was dissolved in DMSO-d6 and a 1H NMR spectrum wasmeasured (see Fig. 2). The NMR spectrum was dominated by the sig-nals of acetaminophen (see Fig. 1), i.e. two multiplets ca. at ı = 6.66

26 J. Wiest et al. / Journal of Pharmaceutical and Biomedical Analysis 97 (2014) 24–28

Fig. 1. Structural formula of acetaminophen, trimethoprim, sulfamethoxazole and indomethacin.

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for the methoxy groups and ı = 6.55 ppm from the phenyl proton(2H) of the 1,2,3-trimethoxybenzene moiety, and the protons of thetwo amino groups at ı = 6.09 ppm and 5.71 ppm for the pyrimidine-2,4-diamine group.

Fig. 2. 400 MHz 1H NMR-Spectra of the herbal mixture, acetamino

nd 7.33 ppm indicating a para-substituted aromatic system and ainglet at ı = 1.97 ppm for the CH3 substituent of the N-acetyl group,n addition to two singlets at ı = 9.11 and 9. 62 ppm, which coulde assigned to the OH and NH protons.

For the identification of the other ingredients the mixture wasubjected to a preparative HPLC utilizing the method described byanussa et al. [12]. In the chromatogram (see Fig. 3) 4 peaks coulde identified beside acetaminophen being peak A. An analytical runith mass spectroscopic detection (ESI ion trap) was performed in

rder to determine the molecular mass of each peak. The retentionimes of the compounds A–D are reported in Table 1.

For peak B an m/z of 291 Da was found in ESI–MS positive modus.

ven though only small amount were isolated from the HPLC run,H NMR spectra could be measured and showed the typical signalsf trimethoprim (see Fig. 1) at ı = 3.72 ppm (6H) and 3.62 ppm (3H)

able 1eak, retention time, base peak, m/z, name of the identified substance and contentn one sachet.

Peak tr (min) Base peak m/z Identified substance Content (%)

A 3.1 [M + H]+ 152 Acetaminophen 33B 7.1 [M + H]+ 291 Trimethoprim <1C 12.2 [M − H]− 252 Sulfamethoxazole 10D 21.9 [M − H]− 356 Indomethacin 1.6

, trimethoprim, sulfamethoxazole and indomethacin in DMSO-d6.

Fig. 3. HPLC chromatogram of the herbal mixture dissolved in methanol using a gra-dient of water and acetonitrile each with acetic acid 0.1% and applying a wavelengthof 254 nm.

J. Wiest et al. / Journal of Pharmaceutical and Biomedical Analysis 97 (2014) 24–28 27

Fig. 4. IR spectrum of the inorganic m

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potassium iodide (the inset Fig. 5).

Fig. 5. Light microscope image of the herbal mixture.

For peak C m/z of 252 Da was found in the negative ESI–MS mode.he 1H NMR spectrum was characterized by a para-substitutedhenyl ring with two multiplets at ca. ı = 7.45 and 6.56 ppm, ainglet for an amino group at ı = 6.06 ppm and a singlet for a sul-onamide group at ı = 10.9 ppm, a doublet in the aromatic regiont ı = 6.09 ppm for 1H (J = 0.8 Hz) and a doublet at ı = 2.28 ppm forH (J = 0.8 Hz), typical for a methyl substituted isoxazole group.ogether with the mass data, the NMR spectrum could be assigned

o sulfamethoxazole (see Fig. 1).

The structure of peak D was assumed to be indomethacin,ecause of a broad 1H NMR signal at ı = 12.35 ppm (1H), the sig-al splitting pattern of the aromatic signals, a methoxy group at

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ı = 3.75 ppm (3H) and a methyl group at 2.20 ppm (3H). The assign-ment was supported by a pseudomolecular ion [M − H]− at m/z of356 obtained in the negative ESI spectrum, with the characteristicisotopic distribution of a monochlorinated compound.

The content of Peak E was too low for further characterization(<0.5%).

The NMR data corresponded to the literature [14], how-ever, to confirm the structure elucidation the herbal mix wasstudied by HPLC and spiked with reference standards. Thus,the APIs acetaminophen, sulfamethoxazole, trimethoprim andindomethacin could ambiguously be assigned. The inorganic partcould be assigned to phosphate because of the strong absorptionat 1003 cm−1 in the IR spectrum (see Fig. 4) and a positive test forphosphate with ammonium molybdate.

Since the sample has a characteristic aroma of Cinnamon Bark,light microscopy was used to identify this plant. The genus Cin-namomum includes nearly 250 species, which are mainly nativeto the tropics and subtropics of Asia [15]. In Europe the barkof Cinnamomum verum (syn: C. zeylanicum) is used as herbaldrug [16], meanwhile mainly C. aromaticum (Chinese cinna-mon) and C. burmannii (Padang cinnamon) are used as spice[17].

Using light microscopy the following plant cells and plant tis-sues typical for bark could be detected: Rounded sclereids withmoderately thickened cell walls, fragments of fibers with lignified,channeled cell walls, single or in groups and cell fragments sur-rounded by oil drops (Fig. 5). Parenchyma containing fine calciumoxalate needles or squared crystals could not be found. Abundantstarch granules could be identified using a solution of iodine and

Unfortunately portion of herbal tissue in the sample is very lowand plant tissue fragments are very small, thus it was not possibleto identify one of the three named cinnamon bark.

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8 J. Wiest et al. / Journal of Pharmaceutic

.2. Quantitation

Quantitation of the APIs was performed by the standard addi-ion method using the HPLC method of Panusa et al. [12]. Calculatedn the standard addition plots (Fig. 6) one sachets of 2.617 gonsisted of 863 mg acetaminophen, 262 mg sulfamethoxazole and2 mg indometacin. The content of trimethoprim was less than 1%nd was not exactly quantified (Table 1). Thus, about 1200 mg ofhe powder could be attributed to chemically defined drugs andhe remaining powder might be of herbal origin and inorganic

aterial.

.3. Pharmacological assessment of the mixture

The typical daily dosage of acetaminophen for grownups rangesetween 325 and 1000 mg with a maximum dosage of 4000 mg

n 24 h [18]. If the patient takes the entire sachet, the mixtureontains the right dosage. The same holds true for indomethacinhose recommended dosage ranges between 25 and 100 mg with

maximum dosage of 200 mg [19]. About 40 mg were found in theachets. Sulfamethoxazole and trimethoprim are always applieds a fixed combination of 40, 80 and 160 mg trimethoprim and00, 400 and 800 mg sulfamethoxazole, respectively, called co-rimoxazole [20]. Again the sachet contained the amount necessaryor an anti-infective therapy.

Even though the dosages of all ingredients are suitable theuestion arises whether such a combination of an analgesic, aon-steriodal anti-inflammatory drug (NSAID) and an antibiotic

s reasonable. Whereas indomethacin belongs to the standardherapy of rheumatic diseases, albeit better NSAIDS are availableow, acetaminophen, being analgesic with no anti-inflammatoryroperties, is normally not applied in the antirheumatic treat-ent. Moreover, rheumatism is not necessarily associated with

bacterial infection. Thus, co-trimoxazole should not be admin-stered; moreover the unnecessary application of an antibiotican induce resistances which can spread out and make thentibiotics inefficient. At last, rheumatic patients may take therugs against their disease on a regular basis in addition to theherbal-containing” sachet; therefore a possible overdose cannote excluded and may increase the risk for side effects e.g. intestinalleeding.

. Conclusion

The herbal Vietnamese sachet advertised as an antirheumaticedicine and purchased from a religious Vietnamese healer

onsisted of acetaminophen, indomethacin, sulfamethoxazole andrimethoprim in addition to certain amounts of herbal and inor-anic material. Although the daily dosage of this sachet does notxceed the daily maximum uptake, the application is not recom-ended. The medicine could be obtained without any prescription

ven though indomethacin and co-trimoxazole are prescriptionrugs. Thus, purchasing these sachets is illegal.

onflict of interest

The authors declare no conflict of interest.

[

Biomedical Analysis 97 (2014) 24–28

Acknowledgment

We thank Dr. Michael Tuerk, University of Wuerzburg, for estab-lishing the contact to the rheumatic patient and for supplying thesachets.

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