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Journal of Food and Drug Analysis, Vol. 20, No. 4, 2012, Pages 872-878 doi:10.6227/jfda.2012200417

Simultaneous Determination of Sesquiterpene Lactones in chinensis by HPLC

QINGHU WANG*, WULIJI AO, XIN YING, GENXIAO MENG, XIAOLAN WU AND WENQUAN TAI

College of Traditional Mongolian Medicine, Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia, China

(Received: February 15, 2012; Accepted: July 18, 2012)

ABATRACT

A reversed-phase high-performance liquid chromatographic method is described for the simultaneous determination of six sesqui-

terpene lactones: 3β-[3-(4-hydroxyphenyl)acetyl-β-D-glucopyranosyloxy]-8β-hydroxy-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR1) 3β-[3-(4-hydroxyphenyl)acetyl-β-D-glucopyranosyloxy]-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR2), 3β-(β-D-glucopyranosyloxy)- 8β-(4-hydroxyphenyl)acetoxy-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR3), 3β-(β-D-glucopyranosyloxy)-8β-(2-hydroxy-3- methylbutanoyloxy)acetoxy-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR4), 3β-(β-D-glucopyranosyloxy)-4(15),10(14)11(13)- guaiatrien-12,6-olide (AR5), and 3β-hydroxy-4(15),10(14)11(13)- guaiatrien-12,6-olide (AR6) in the whole of Ixeris chinensis. The separation by gradient elution was performed on Hypersil ODS-2 column (250 mm × 4.6 mm, 5 µm) at 30°C with acetonitrile and water as the mobile phase, and monitored by absorbance at 238 nm. The parameters of linearity, precision, accuracy, and specificity of the method were evaluated. The recovery of the method is 95.85-98.19%, and linearity (r > 0.9993) was obtained for all sesquiterpene lactones. A high degree of specificity as well as repeatability and reproducibility (relative standard deviation values less than 2.0%) were also achieved. This assay was successfully applied to the determination of six sesquiterpene lactones in ten samples. The results indicated that the developed assay method was rapid, accurate, reliable and could be readily utilized as a quantitative analysis method for I. chinensis.

Key words: HPLC, simultaneous determination, sesquiterpene lactones, Ixeris chinensis

INTRODUCTION 8β-hydroxy-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR1) 3β-[3-(4-hydroxyphenyl)acetyl-β-D-glucopyranosyloxy]- Ixeris chinensis Nakai (Compositae) is a 4(15),10(14)11(13)-guaiatrien-12,6-olide (AR2), 3β-(β- perennial plant found in various areas in China and used as D-glucopyranosyloxy)-8β-(4-hydroxyphenyl)acetoxy- a folk medicine for the treatment of bronchitis, pneumonia, 4(15),10(14)11(13)-guaiatrien-12,6-olide (AR3), 3β-(β-D- pharyngitis, dysentery, and poisonous indigestion on the glucopyranosyloxy)-8β-(2-hydroxy-3-methylbutanoyloxy) (1) basis of its antifebrile, antidotal, and analgesic effects . The acetoxy-4(15),10(14)11(13)-guaiatrien-12,6-olide (AR4), known constituents of this plant include triterpenes(2), and 3β-(β-D-glucopyranosyloxy)-4(15),10(14)11(13)-guaiatrien- (3) flavonoids . Studies on some other species of this 12,6-olide (AR5), and 3β-hydroxy-4(15),10(14)11(13)- revealed the presence of sesquiterpene lactones such as guaiatrien-12,6-olide (AR6) whose structures are shown guaianolides, eudesmanolides, germacranolides, and their in Figure 1. Unfortunately, to date, except the report on glycosides(4-6). Recently a series of sesquiterpene lactones determination of luteolin in I. chinensis by reversed-phase identified from the whole plant of I. chinensis(7-9) and the high-performance liquid chromatography (RP-HPLC)(12), diverse biological activity reported for guaianolides(10,11) there is no literature giving an accurate quality evaluation of prompted us to undertake a further investigation of the I. chinensis because of unavailability of commercial refer- guaianolides in this plant. In our phytochemical investigation, ence standards. several sesquiterpene lactones were isolated including In the present study, a novel HPLC method was devel- 3β-[3-(4-hydroxyphenyl)acetyl-β-D-glucopyranosyloxy]- oped to determine the six sesquiterpene lactones in ten * Author for correspondence. Tel: +86-0475-8314242; samples of I. chinensis simultaneously. The established Fax: +86-0475-8314242; E-mail [email protected] method has the advantage of adequate sensitivity, precision, 873

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14 14 14 14 accuracy and is also suitable for the quality control of I. 10 O 2 1 2 10 chinensis. R2 1 OH 24 5 10 7 HO 5 10 O O1'' 1 R 24 1 7 15 5 2 HO 5 OH O 2''1'' 4 7 15 4 7 6'' 4'' OH 13 13 15 O 11 15 O 11 MATERIALS AND METHODS 2'' OH 13 13 6'' 4'' O12 11 12 HO OR1 O 11 12 O 12 O OR AR6 HO 1 O O AR6 I. Reagents and Samples 5' 4' 2' 1' 5' 4' 3' AR1 :R = R = OH 1 HO 7' 3' CH2' 2CO1' 2 LC-grade acetonitrile was purchased from Merck (Darm- AR :R OH 1 1 = HO 7' CH2CO R2 = stadt, Germany); deionized water was purified by Milli-Q AR : R H 2 1 = HO CH2CO R2 = system (Millipore, Bedford, MA, USA); all other solvents AR : R H 2 1 = HO CH2CO R2 = were of analytical grade from Yuwang Industry Co. Ltd. AR H (Dezhou, China). Ten samples were obtained from different 3 :R1 = R2 = HO CH2CO AR H 3 :R1 = R2 = HO CH2CO habitats in China, and identified by Prof. Bateer (College of 1' 3' CH AR :R H C CH CH 3 Mongolian Medicine and Pharmacy, Inner Mongolia Univer- 4 1 = R2 = 1' 3' CH AR H CH 3 4 :R1 = R2 = OC CHOH CH 3 sity for Nationalities, China). Samples were deposited at the CH AR :R H R H O OH 3 Herbarium of Inner Mongolia University for Nationalities. 5 1 = 2 = (4-6) AR :R H H Sesquiterpene lactones (AR , AR , AR , AR , AR , Figure5 1. Chemical1 = structuresR2 = of six sesquiterpene lactones used in the 1 2 3 4 5 study. AR6) were isolated and purified from the I. Chinensis. Their

1 Table 1. H-NMR (600 MHz, J in Hz) spectral data for compounds AR1- AR6 in CD3OD

No. AR1 AR2 AR3 AR4 AR5 AR6 1 3.02 (1H, t, 9.6) 2.98 (1H, t, 9.6) 2.95 (1H, t, 9.6) 3.03 (1H, t, 9.6) 2.97 (1H, t, 9.3) 2.98 (1H, t, 9.3) 2 2.28 (1H, m) 2.37 (1H, m) 2.43 (1H, m) 2.41(1H, m) 2.33 (1H, m) 2.37 (1H, m) 1.89 (1H, m) 1.94 (1H, m) 1.98 (1H, m) 2.02 (1H, m) 1.98 (1H, m) 1.91 (1H, m) 3 4.62 (1H, t,7.2) 4.65 (1H, t,7.2) 4.64 (1H, t,7.2) 4.64 (1H, t, 9.6) 4.65 (1H, t,7.0) 4.60 (1H, t,7.0) 5 2.81 (1H, m) 2.80 (1H, m) 2.80 (1H, m) 2.86 (1H, m) 2.82 (1H, t, 9.3) 2.83 (1H, t, 9.3) 6 4.23 (1H, t, 9.6) 4.16 (1H, t, 9.6) 4.46 (1H, t, 9.6) 4.64 (1H, t, 96) 4.18 (1H, t, 9.3) 4.16 (1H, t, 9.3) 7 2.88(1H, m) 2.90 (1H, m) 3.34 (1H, m) 3.34 (1H, m) 2.91 (1H, m) 2.90 (1H, m) 8 3.98 (1H, m) 2.24 (1H, m) 5.49 (1H, m) 5.64 (1H, m) 2.23 (1H, m) 2.27 (1H, m) 1.48 (1H, m) 1.45 (1H, m) 1.49 (1H, m) 9 2.27 (1H, m) 2.20 (1H, m) 2.65 (1H, m) 2.62 (1H, m), 2.25 (1H, m) 2.26 (1H, m) 2.74 (1H, m) 2.52 (1H, m) 2.52 (1H, m) 2.52 (1H, m) 2.58 (1H, m) 2.54 (1H, m) 13 6.01 (1H, d, 3.0) 6.08 (1H, d, 3.0) 6.03 (1H, d, 3.6) 6.21 (1H, d, 3.6) 6.04 (1H, d, 3.3) 6.05 (1H, d, 3.3) 5.04 (1H, d, 3.0) 5.57 (1H, d, 3.0) 5.44 (1H, d, 3.6) 5.61 (1H, d, 3.6) 5.54 (1H, d, 3.3) 5.55 (1H, d, 3.3) 14 5.08 (1H, s) 5.01 (1H, s) 5.06 (1H, s) 5.16 (1H, s) 5.01 (1H, s) 5.06 (1H, s) 4.90 (1H, s) 4.93 (1H, s) 4.77 (1H, s) 4.95 (1H, s) 4.97 (1H, s) 4.79 (1H, s) 15 5.38 (1H, s) 5.42 (1H, s) 5.48 (1H, s) 5.48 (1H, s) 5.46 (1H, s) 5.44 (1H, s) 5.31 (1H, s) 5.34 (1H, s) 5.33 (1H, s) 5.38 (1H, s) 5.33 (1H, s) 5.30 (1H, s) 2′ 3.56 (2H, s) 3.60 (2H, s) 3.46 (2H, s) 3.88 (1H, m) 3′ 1.98 (1H, m) 4′ 7.04 (1H, d, 8.4) 7.08 (1H, d, 8.4) 7.00 (1H, d, 8.4) 0.95 (3H, d, 6.0) 5′ 6.73 (1H, d, 8.4) 6.75 (1H, d, 8.4) 6.70 (1H, d, 8.4) 0.88 (3H, d, 6.0) 6′ 7′ 6.73 (1H, d, 8.4) 6.75 (1H, d, 8.4) 6.70 (1H, d, 8.4) 8′ 7.04 (1H, d, 8.4) 7.08 (1H, d, 8.4) 7.00 (1H, d, 8.4) 1″ 4.54 (1H, d, 7.2) 4.60 (1H, d, 7.2) 4.46 (1H, d, 7.2) 4.46 (1H, d, 7.2) 4.47 (1H, d, 7.5) 2″ 3.35 (1H, m) 3.38 (1H, m) 3.18 (1H, m) 3.18 (1H, m) 3.20 (1H, m) 3″ 4.92 (1H, m) 5.02 (1H, m) 3.42 (1H, m) 3.34 (1H, m) 3.43 (1H, m) 4″ 3.50 (1H, m) 3.52 (1H, m) 3.30 (1H, m) 3.30 (1H, m) 3.32 (1H, m) 874

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Table 1. Continued

No. AR1 AR2 AR3 AR4 AR5 AR6 5″ 3.41 (1H, m) 3.43 (1H, m) 3.71 (1H, m) 3.40 (1H, m) 3.71 (1H, m) 6″ 3.86 (1H, m) 3.88 (1H, m) 3.85 (1H, m) 3.86 (1H, m) 3.84 (1H, m) 3.67 (1H, m) 3.66 (1H, m) 3.68 (1H, m) 3.68 (1H, m) 3.69 (1H, m)

13 Table 2. C-NMR (150MHz) spectral data for compounds AR1-AR6 (Shimadzu, Japan), Shimadzu SPD-M10Avp photodiode in CD3OD array detector, Shimadzu SCL-10Avp software for data

No. AR1 AR2 AR3 AR4 AR5 AR6 processing, and a Shimadzu DGU-12A online deaerator. 1 46.6 44.8 45.3 45.7 44.6 44.9 The chromatographic separation was performed on Hypersil ODS-2 analytical column (250 mm × 4.6 mm, 5 µm). The 2 38.9 37.6 38.5 38.7 37.7 37.3 binary gradient elution system consisted of water (A) and 3 81.4 80.6 81.5 81.6 80.9 80.1 acetonitrile (B) and separation was achieved using the 4 150.3 150.2 150.8 151.0 150.4 150.3 following gradient: 0-5 min, 18% B; 5-10 min, 18-45% B; 5 52.4 50.3 51.0 51.4 50.1 50.5 10-20 min, 45-65% B; 20-32 min, 65% B and finally, recon- 6 79.5 83.7 80.2 80.3 83.4 83.1 ditioning steps of the column was 18% B isocratic for 18 7 51.6 45.3 49.0 49.8 45.0 45.6 min. The column temperature was kept constant at 30°C. The flow-rate was 1 mL/min and the injection volume was 20 µL. 8 72.3 30.9 69.3 69.8 31.2 30.4 9 42.6 34.2 41.4 41.0 34.8 34.3 III. Preparation of Standard Solutions 10 145.4 149.2 144.4 144.6 148.7 149.7

11 140.6 141.0 136.3 136.9 140.8 140.2 Standard stock solutions of AR1 (1.2 mg/mL), AR2 12 170.8 170.2 169.0 171.3 169.2 170.3 (1.0 mg/mL), AR3 (1.6 mg/mL), AR4 (1.4 mg/mL), AR5 13 122.5 119.9 122.3 122.4 120.1 122.6 (1.2 mg/mL), and AR6 (2.0 mg/mL) were prepared with methanol. From the stock solution, a series of working stan- 14 117.1 113.6 117.7 118.0 113.8 115.0 dard solutions containing each of the six compounds were 15 114.9 112.5 112.5 113.0 112.1 112.8 prepared by dilution with methanol to the proper concentra- 1′ 172.4 172.0 172.9 174.6 tions. The standard stock and working solutions were all 2′ 40.9 40.2 40.0 76.6 prepared in calibrated flasks and stored at 4°C. 3′ 126.2 125.4 126.1 33.1 IV. Sample Preparation 4′ 131.5 130.6 131.4 19.3 5′ 116.2 115.2 116.3 17.1 All samples of I. chinensis were kept in a desiccator. 6′ 157.7 156.4 157.6 About 1.0 g of dried samples were ground into powder accu- 7′ 116.2 115.2 116.3 rately weighed, soaked in 40 mL MeOH : water solution (90 8′ 131.5 130.6 131.4 : 10, v/v) for 60 min at room temperature, and then sonicated 1″ 102.4 102.5 103.9 104.3 100.8 for 30 min. The MeOH solution was filtered and evaporated in a rotary evaporator, and then made up to exactly 10 mL 2″ 73.3 72.6 75.3 75.1 75.0 with MeOH in a volumetric flask. The solutions were filtered 3″ 79.1 78.8 78.1 78.1 78.6 through a 0.45 µm membrane filter before subjecting 20 µL 4″ 70.1 69.8 71.7 71.7 70.9 to LC analysis. 5″ 77.3 76.8 77.9 77.9 77.2 6″ 62.7 62.0 62.8 62.8 62.3 V. Validation Procedure

Calibration curves were constructed using working stan- dard solutions of all six reference compounds as described structures were identified by comparison of their spectral above. Each calibration curve contained six different concen- data (Table 1 and Table 2) with the literature data(4-7). The trations and was performed in triplicate. The regression purity of each compound was determined to be above 98% by parameters of slope, intercept, and correlation coefficient normalization of the peak areas detected by HPLC. were calculated by the peak-area of the analytes (y) against the concentrations of the calibration standards (x) (Table 3). The II. Instrument and Chromatographic Conditions stock solutions of the six reference compounds were further diluted to a series of concentrations with MeOH to determine The LC system consisted of an LC10-Atvp pump the limit of detection (LOD) and limit of quantitation (LOQ). 875

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Table 3. The results of optimization of extraction conditions in Ixe2 Content of six sesquiterpene lactones (mg/g) (Mean ± SD, n = 3) Extraction procedure AR1 AR2 AR3 AR4 AR5 AR6 Methanol 0.456 ± 0.008 0.367 ± 0.005 1.038 ± 0.015 0.705 ± 0.011 0.388 ± 0.005 2.878 ± 0.051 90% methanol 0.508 ± 0.009 0.483 ± 0.007 1.322 ± 0.018 0.813 ± 0.012 0.486 ± 0.008 2.958 ± 0.054 Solvent* 75% methanol 0.491 ± 0.010 0.476 ± 0.006 1.298 ± 0.016 0.778 ± 0.010 0.385 ± 0.007 2.011 ± 0.038 90% ethanol 0.487 ± 0.008 0.472 ± 0.006 1.124 ± 0.014 0.689 ± 0.009 0.347 ± 0.005 1.908 ± 0.032 75% ethanol 0.501 ± 0.009 0.481 ± 0.005 1.209 ± 0.016 0.774 ± 0.010 0.364 ± 0.007 1.687 ± 0.028

Extraction Ultrasonic 0.504 ± 0.010 0.480 ± 0.006 1.327 ± 0.020 0.817 ± 0.011 0.482 ± 0.009 2.953 ± 0.058 method** Reflux 0.484 ± 0.010 0.392 ± 0.007 1.302 ± 0.021 0.702 ± 0.012 0.364 ± 0.006 3.021 ± 0.060

10 mL 0.412 ± 0.006 0.366 ± 0.007 1.068 ± 0.017 0.762 ± 0.013 0.360 ± 0.006 2.004 ± 0.036

Solvent 20 mL 0.445 ± 0.008 0.414 ± 0.008 1.306 ± 0.021 0.802 ± 0.013 0.407 ± 0.008 2.243 ± 0.042 volume*** 40 mL 0.507 ± 0.009 0.485 ± 0.006 1.330 ± 0.023 0.811 ± 0.016 0.489 ± 0.010 2.960 ± 0.057

60 mL 0.506 ± 0.010 0.482 ± 0.006 1.325 ± 0.022 0.813 ± 0.015 0.490 ± 0.009 2.958 ± 0.055

20 min 0.468 ± 0.006 0.423 ± 0.005 1.124 ± 0.021 0.756 ± 0.013 0.411 ± 0.008 2.006 ± 0.040 Extraction 30 min 0.505 ± 0.009 0.487 ± 0.008 1.326 ± 0.024 0.814 ± 0.017 0.485 ± 0.010 2.954 ± 0.059 time**** 40 min 0.505 ± 0.008 0.480 ± 0.007 1.329 ± 0.025 0.813 ± 0.016 0.489 ± 0.009 2.953 ± 0.058 * Solvent: 90% MeOH. ** Extraction method: ultrasonic treatment. *** Solvent volume: 40 mL. **** Extraction time: 30 min.

Table 4. Calibration curve for six sesquiterpene lactones Compound Calibration Curvea r Linear range (mg/mL) LOD (mg/mL) LOQ(mg/mL) 6 AR1 y = 1.31 × 10 x ‒ 10186 0.9996 1.20-0.012 0.004 0.012 6 AR2 y = 1.30 × 10 x ‒ 8059 0.9997 1.00-0.020 0.007 0.020 6 AR3 y = 1.19 × 10 x ‒ 27928 0.9995 1.60-0.032 0.010 0.032 6 AR4 y = 1.00 × 10 x ‒ 20194 0.9993 1.40-0.028 0.009 0.028 6 AR5 y = 1.28 × 10 x ‒ 10314 0.9997 1.20-0.012 0.004 0.012 6 AR6 y = 1.02 × 10 x ‒ 23297 0.9998 2.00-0.040 0.014 0.040 a y = peak area and x = concentration (mg/mL)

Table 5. Precision, repeatability and stability of the six sesquiterpene lactones

Intra-day Inter-day Repeatability Stability Compound RSD (%, n = 5) RSD (%, n = 5) RSD (%, n = 5) RSD (%, n = 6)

AR1 1.08 1.34 1.86 1.13

AR2 1.20 1.28 1.76 1.16

AR3 1.64 1.68 1.94 1.47

AR4 1.34 1.46 1.72 1.42

AR5 1.18 1.24 1.48 1.26

AR6 1.51 1.82 1.98 1.58 876

Journal of Food and Drug Analysis, Vol. 20, No. 4, 2012

Table 6. Recovery of the six sesquiterpene lactones (n = 6) 80 AR3 Compound Added (mg) Found (mg) Recovery (%) RSD(%) 60 AR 0.252 0.495 96.43 2.04 AR6 1 40 AR4 AR1 mAU

AR2 0.241 0.472 95.85 1.94 AR5

20 AR2 AR3 0.663 1.314 98.19 1.67 0 AR 0.409 0.805 96.82 2.08 4 80

AR5 0.242 0.477 97.11 2.15 AR6

60 AR3 AR6 1.478 2.927 98.04 1.85 40 AR4 mAU

20 AR5 AR1 AR2

The LOD and LOQ under the present chromatographic condi- 0 80 tions were determined at S/N ratio of 3 and 10, respectively. The intra-day precision, presented as relative standard 60 AR3 deviation (RSD), was determined for calibration sample by 40 AR6 mAU analyzing the five replicates on the same day, while the inter- AR4

20 AR1 AR2 day values were carried out over five consecutive days. In AR5 order to evaluate the repeatability of the developed assay, five 0 different working solutions prepared from the same sample 5 10 15 20 25 30 (Ixe2; Tongliao, Neimenggu) were analyzed. The RSD was Minutes taken as a measure of precision and repeatability. The sample Figure 2. Representative HPLC chromatograms of mixed standards stability test was performed with one sample at 0, 3, 6, 12, (AR1 0.05 mg/mL, AR2 0.04 mg/mL, AR3 0.15 mg/mL, AR4 0.08 mg/ 24, and 48 h within 2 days. During this period, the solution mL, AR5 0.04 mg/mL, AR6 0.10 mg/mL) and methanol extract of I. was stored at room temperature. Variations were expressed in chinensis. (a Mixed standards, b Ixe2, c Ixe9.) RSD (Table 4). The average recoveries were calculated by the following equation: recovery (%) = (amount found - amount contained)/ to be 1.0 mL/min. based on the UV–VIS spectra of the six amount added ×100%, and RSD (%) = (SD/mean) ×100%. sesquiterpene lactones recorded by (PDAD) in the range of The results are listed in Table 5. 190-800 nm, they all have the same UV absorption peaks of Samples from different regions of China were prepared near 238 nm, so that 238 nm was chosen for monitoring. The as described above. An aliquot (20 µL) of the filtrate was chromatograms of six standards and samples are shown in directly subjected to HPLC analysis. Each sample was deter- Figure 2. mined in triplicate. Chromatographic peaks of the samples Figure 2 showed the representative chromatograms were quantified by the external standard method. of mixed standards of the six sesquiterpene lactones and MeOH extract of I. chinensis. The six sesquiterpene lactones were well separated under the described chromatographic RESULTS AND DISCUSSION conditions.

I. Optimization of Chromatographic Conditions II. Optimization of Extraction Conditions

The selection of the LC conditions was guided by the Selection of an extraction method suitable for the type of requirements of chromatograms with better resolution of samples is always important. In this study (Table 3), variables adjacent peaks within a short time. In this study, mobile phase, involved in the procedure such as solvent, extraction method, the gradient mode and the operating conditions were opti- solvent volume and extraction time were optimized. Pure and mized through several trials to achieve good resolution and aqueous MeOH or EtOH solutions were selected as extraction symmetric peak shapes of analytes. Preliminary researches solvents. The best solvent was found to be 90% MeOH, which indicated that better separation and results were obtained allowed the complete extraction of all the six sesquiterpene using a mobile phase of water and acetonitrile rather than lactones at higher yields. Comparing to refluxing extraction water and MeOH. Therefore, in this work, water and acetoni- and ultrasonic extraction, the ultrasonic treatment procedure trile were chosen as the mobile phase. Further studies found was found more effective and simple for six sesquiterpene that many interfering compounds were present in the plant lactones and thus selected as the optimum extraction method. material. Thus, gradient elution program was carried out to In order to investigate the solvent volume, 1.0 g of dried separate these components in samples. The optimum eluting sample (Ixe2; Tongliao, Neimenggu) was extracted with 10, procedure was described above. The effect of temperature 20, 40, 60 mL of 90% MeOH, and the results showed that 40 on the separation was investigated in the range of 25-40°C, or 60 mL of 90% MeOH had the highest yield with almost 30°C being optimal. The most suitable flow rate was found equal extraction capacities. Therefore, 40 mL was selected 877

Journal of Food and Drug Analysis, Vol. 20, No. 4, 2012 as the solvent volume and the highest amounts of sesqui- the analytes concerned. Therefore, the HPLC method was terpene lactones were obtained with the extraction time of precise, accurate and sensitive enough for simultaneously 30 min after soaking with 90% MeOH for 60 min at room quantitative evaluation of six major active sesquiterpene temperature. lactones in Ixeris chinensis.

III. Method Validation V. Sample Analysis

Under the chromatographic conditions adopted in This newly developed HPLC assay method was subse- this study, all calibration curves exhibited good linearity quently applied to the simultaneous determination of the six (r > 0.9993) in a relatively wide. According to the results active sesquiterpene lactones in Ixeris chinensis obtained of the tests of precision, repeatability and stability of the from different geographic locations. Their contents were six analytes, it was indicated that the RSD of the overall listed in Table 7. All six compounds could be well detected intra- and inter-day variations were less than 2.0% for all six in the ten analyzed samples. The content of a sesquiterpene analytes. Further, validation studies of this method proved lactone compound varied markedly dependent on the produc- that this assay had good reproducibility with RSD also less tion places, for example, the content of AR3 varied from than 2.0% for all the analysis and the sample solutions were 0.827 to 2.550 mg/g in the 10 samples. The higher degree stable during 48 h at room temperature with an RSD less of variability in the sesquiterpene lactone content (total or than 1.6%. The developed analytical method had goodac- individuals) in samples from different geographical locations curacy with the overall recovery from 95.85 to 98.19% for could be due to various factors, such as geographical source,

Table 7. Quantitative analytical results of various samples Collection source Content of six sesquiterpene lactones (mg/g) (Mean ± SD, n = 3) Sample no. Time Amount AR1 AR2 AR3 AR4 AR5 AR6 Hailaer, Neimenggu Ixe1 2010.5.12 1.108 ± 0.013 0.611 ± 0.012 1.711 ± 0.020 0.802 ± 0.013 0.576 ± 0.011 2.081 ± 0.027 200 g

Tongliao, Neimenggu Ixe2 2010.4.20 0.505 ± 0.010 0.482 ± 0.005 1.326 ± 0.018 0.818 ± 0.010 0.483 ± 0.007 2.955 ± 0.042 5000 g

Ameng, Neimenggu Ixe3 2010.5.24 0.359 ± 0.005 0.273 ± 0.005 0.827 ± 0.016 0.307 ± 0.006 0.406 ± 0.007 1.080 ± 0.017 300 g

Qingdao, Shandong Ixe4 2010.4.15 0.766 ± 0.012 0.541 ± 0.010 1.012 ± 0.015 0.615 ± 0.009 0.357 ± 0.005 2.817 ± 0.039 200 g

Baqu, Xingjiang Ixe5 2010.6.10 1.369 ± 0.021 1.111 ± 0.015 2.443 ± 0.034 1.320 ± 0.016 0.774 ± 0.013 3.505 ± 0.037 300 g

Xining, Qinghai Ixe6 2010.6.22 1.254 ± 0.022 0.899 ± 0.010 1.185 ± 0.030 1.423 ± 0.017 0.930 ± 0.017 2.505 ± 0.026 300 g

Zengzhou, Henan Ixe7 2010.4.14 0.634 ± 0.011 0.404 ± 0.007 1.010 ± 0.013 0.588 ± 0.005 0.389 ± 0.004 1.218 ± 0.015 500 g

Fuxin, Liaoning Ixe8 2010.5.20 1.015 ± 0.013 0.708 ± 0.008 1.520 ± 0.015 0.684 ± 0.011 0.425 ± 0.006 2.028 ± 0.021 300 g

Changchun, Jilin Ixe9 2010.5.26 0.488 ± 0.006 0.404 ± 0.007 1.010 ± 0.017 0.615 ± 0.011 0.307 ± 0.005 1.732 ± 0.029 500 g Hanshen, Neimenggu Ixe10 2010.6.05 1.460 ± 0.026 1.236 ± 0.024 2.550 ± 0.037 1.119 ± 0.017 0.883 ± 0.013 3.346 ± 0.042 1000 g Average 0.896 0.667 1.522 0.829 0.553 2.327 878

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