Analytical and Bioanalytical Chemistry

, Volume 410, Issue 25, pp 6489–6495 | Cite as

Spectrofluorometric determination of berberine using a novel Au nanocluster with large Stokes shift

  • Aoli Wen
  • Xiaoxiao Peng
  • Pingping Zhang
  • Yunfei LongEmail author
  • Huiming Gong
  • Qingru Xie
  • Ming Yue
  • Shu ChenEmail author
Research Paper


Berberine hydrochloride (BHC), a natural isoquinoline alkaloid, is widely applied as a an agent in traditional Chinese medicine. Almost all the traditional methods for BHC detection require complicated preprocessing steps or expensive instruments. In this article, we report a simple, rapid, sensitive, and selective method for BHC detection using fluorescent gold nanoclusters (F-AuNCs) as the fluorescent probe with a large Stokes shift of 237 nm. The F-AuNCs prepared with citrate-stabilized stannous chloride and hydrogen tetrachloroaurate(III) as raw materials in an aqueous medium display strong and stable fluorescence at 566 nm. When F-AuNCs are mixed with BHC, the fluorescence of F-AuNCs is effectively quenched. Under optimized conditions, this method allows sensitive and selective measurements of BHC in a concentration ranging from 1.0 × 10-6 to 1.0 × 10-4 mol L-1 with a detection limit of 7.5 × 10-8 mol L-1, which is relatively low among reported spectral methods. This method provides excellent selectivity for the detection of BHC against inorganic anions and natural amino acids. In addition, the BHC content in two different types of berberine tablets was successfully determined by this method and the results showed high accuracy.

Graphical Abstract


Berberine hydrochloride Gold nanoclusters Fluorescent Stokes shift 


Berberine hydrochloride (BHC) is an isoquinoline alkaloid isolated from Rhizoma coptidis, Berberis aquifolium, Berberis vulgaris, and other Chinese herbs [1]. Because of BHC’s antibacterial, antilipid peroxidation, antiatherosclerotic, and neuroprotective properties as well as its property of relieving polycystic ovary syndrome [2, 3, 4, 5, 6], its quantification is crucial in the fields of clinic medical assay and optical probes [7, 8, 9]. Many analytical methods, including chromatography [10, 11], mass spectrometry [12], capillary electrophoresis [13], chemiluminescence [14], electrochemical analysis [15, 16], light scattering spectrometry [17, 18], colorimetric assay [19, 20] fluorescence spectra [21, 22, 23], and optical fiber sensing [24, 25, 26], for the quantification of BHC have been established. These methods have certain advantages, such as sensitivity and selectivity, but require expensive instruments or complicated procedures. On the basis of these methods, sensing methods using fluorescence, scattering, and the fluorescence spectrum have been rapidly developed in recent years [27, 28, 29], possessing simplicity in approach, shortened response time, and cost-effectiveness.

Recently, fluorescent probes using metal nanoclusters (NCs) with small particle size have drawn considerable research interest in the fields of analytical chemistry owing to their special characteristics, such as good biocompatibility, large surface area, low toxicity, and exceptional fluorescent properties [30, 31, 32]. By choosing different capping and stabilizing agents, researchers have developed various approaches to synthesize NCs and have applied them in chemosensing/biosensing [33]. However, the development of high-quality NCs (e.g., relatively narrow size distributions, high quantum yield, and large Stokes shift) remains a challenge [34]. A large Stokes shift is beneficial in reducing spectral overlap [35] and mitigating reabsorption losses [36], as well as for signal detection in fluorescence imaging [37]. More importantly, these benefits are helpful in reducing interference when the analyte is being determined. Therefore, many researchers are trying to develop new probes with a large Stokes shift for use in spectrofluorometric determination.

In this work, we demonstrate a novel fluorescent probe using fluorescent gold NCs (F-AuNCs) with a Stokes shift as large as 237 nm to detect BHC. Because BHC can strongly quench the fluorescence of F-AuNCs, BHC can be determined at low levels. Furthermore, the decrease in the fluorescence intensity shows a good linear relationship with the concentration of BHC. Thus, a sensitive and selective method for the determination of BHC has been established, and its analytical application has been investigated in compound berberine tablets and BHC tablets.



All the fluorescence spectra and fluorescence intensities were obtained with an RF-5301PC fluorescence spectrophotometer (Shimadzu, Japan) equipped with a 1-cm quartz cell. The absorption spectra were measured with a Lambda 35 UV–vis spectrophotometer (PerkinElmer, USA). Transmission electron microscopy (TEM) images were obtained with a Tecnai G20 electron microscope (FEI, USA). A ZF-7 (black box-type) three-wavelength UV analyzer (JiaPeng, China) at 365 nm as the light source and a Nikon Coolpix 4500 digital camera were used to obtain images of the F-AuNCs. Resonance light scattering (RLS) intensities were measured with the same fluorescence spectrophotometer. The sample was scanned synchronously with the same excitation and emission wavelengths from 240 to 650 nm with use of the fluorescence spectrophotometer. The BHC content was characterized by high-performance liquid chromatography (HPLC) using a liquid chromatograph (LC2010AT, Japan) equipped with a UV detector (TSP, USA). The detection wavelength was 265 nm and the chromatographic column was an AcclaimTM 120 C18 column (4.6 mm × 250 mm, 5 μm). The separation was performed at 30 °C, and the isocratic elution at a flow rate of 1.0 mL/min used a mobile phase of 30:70 acetonitrile and KH2PO4 (0.03 mol L-1). The injection volume was 20 μL.


All reagents were of analytical grade, including stannous chloride (SnCl2; AR, Sigma-Aldrich), hydrogen peroxide (H2O2; AR, Xilong Chemical Co.), phosphoric acid (H3PO4; AR, Xihuang Chemical Co.), trisodium citrate (C6H5Na3O7·2H2O; AR, J&K Scientific), hydrogen tetrachloroaurate(III) tetrahydrate (HAuCl4·4H2O; AR, Aladdin), and BHC (E. Merck). BHC tablets and compound berberine tablets were purchased from a local drugstore, and were manufactured by Jiangsu Aipusen Pharmaceutical Co. Britton–Robinson buffer solution was used to control the acidity of the system, and double-deionized and double-distilled water was used to prepare all solutions. The Sn2+ stock solution was prepared by addition of solid SnCl2 to 1.2 × 10-2 mol L-1 trisodium citrate solution. The trisodium citrate was dissolved in double-distilled water and then deoxidized with nitrogen gas for 30 min before addition of SnCl2 to prevent oxidation of Sn(II). Trisodium citrate acts as a stabilization reagent to prevent the hydrolysis of Sn2+.

Synthesis of F-AuNCs

F-AuNCs were synthesized according to our previously reported hydrothermal method with minor modification [38]. First, 30.0 mL of citrate-stabilized SnCl2 (1.2 × 10-2 mol L-1), 30.0 mL of 0.005% HAuCl4·4H2O, 315 μL of 3% H2O2 and 560 μL of H3PO4 (1.0 mol L-1) were mixed and heated for 2 h at 150 °C until a pale yellow solution of F-AuNCs was obtained. Then the solution was naturally cooled to room temperature and kept in a refrigerator (about 4 °C). The solution was stable for at least 3 months.

Spectral detection procedures

Typically, 1.0 mL F-AuNC solution, 200 μL Britton–Robinson buffer (pH 2.87), and a certain volume of BHC solution or sample solution were successively added to a 2.5-mL test tube. Then the mixture was diluted to 2.0 mL with water and maintained for 2 min at room temperature. The fluorescence spectra were measured with slit widths of 5 nm at the excitation and emission maxima of 329 and 566 nm, respectively. The degree of fluorescence quenching of F-AuNCs was determined by the relative fluorescence intensity ratio Q: Q = (IFoIF)/IF, where IFo and IF are the fluorescence intensities of F-AuNCs in the absence and presence of BHC, respectively. For the detection of BHC in tablets, BHC tablets and compound berberine tablets were pretreated as follows: 20 slices of tablets were ground to a uniform powder after removal of the sugar coating from the tablets. Then 40 mg powder was weighed accurately and then dissolved in boiling water in a 100-mL beaker, and the resulting mixture was cooled to room temperature. The resulting solution was then diluted to 100 mL.

Results and discussion

Characterization of F-AuNCs

The fluorescence excitation and emission spectra of the synthesized F-AuNCs are shown in Fig. 1 (spectra a and b). When the excitation wavelength was 329 nm, strong emission of the F-AuNCs was observed around 566 nm, the Stokes shift of which was 237 nm. Among previous studies, there were only a small number of reported cases with a Stokes shift of more than 200 nm [39, 40, 41, 42]. A large Stokes shift is beneficial in reducing spectral overlap and background signal interference. As can be seen in spectrum a in Fig. 1, the F-AuNC solution is pale yellow under visible light and fluorescences orange-red under 365-nm excitation.
Fig. 1

The excitation (a), emission (b) and UV–vis absorption (c) spectra of fluorescent gold nanoclusters (F-AuNCs). Pictures of F-AuNCs taken with and without illumination by a UV lamp (365 nm) are shown in the inset

The F-AuNCs exhibit UV–vis absorption in the wavelength range from 200 to 400 nm (Fig. 1, spectrum c). The absence of a surface plasmon peak at approximately 520 nm, which is the typical absorption wavelength of large gold nanoparticles as reported in the literature [43], indicates the relatively small diameter of the as-prepared F-AuNCs. Moreover, it is fascinating that the F-AuNCs have low-energy emission at 566 nm when the excitation wavelength is 329 nm. The Stokes shift is 237 nm, which can be very attractive for sensor applications.

TEM images and the size distribution analysis of F-AuNCs are shown in Fig. 2, and indicate that the F-AuNC clusters are well dispersed, with an average diameter of approximately 2.7 nm. This result is consistent with the absorption spectra. The inset in Fig. 2a of the high-resolution TEM image shows that the lattice fringes of F-AuNCs are consistent with metallic gold with a lattice spacing of 2.3 Å and the (111) crystal plane of face-centered cubic gold [44]. The results indicate that the small gold NCs are fluorescent.
Fig. 2

a Transmission electron microscopy (TEM) image (the inset shows the high-resolution TEM image) and b particle size distribution histogram of fluorescent gold nanoclusters

Interaction between F-AuNCs and BHC

Fluorescence spectra (Fig. 3a) of F-AuNCs in the presence of BHC in the pH 2.78 Britton–Robinson buffer were obtained with an excitation wavelength of 329 nm. As can be seen in Fig. 3a, the fluorescence intensity of F-AuNCs progressively decreases with increase of the BHC concentration. Meanwhile the maximum emission peak remains stable without an obvious change in position or shape. BHC (curve 9) exhibits only very weak fluorescence in aqueous solution when excited at 329 nm. To understand the factors that cause the fluorescence quenching in the presence of BHC, we measured the UV–vis and RLS spectra of BHC. Figure 3b displays the absorption spectra of BHC. The center of the BHC absorption band is at 345 nm, which is near the maximum excitation of F-AuNCs (at approximately 329 nm). Thus, the inner filter effect [23, 45] of BHC may be the main reason for the quenching of the fluorescence of F-AuNCs. However, the inner filter effect is not the only reason for the fluorescence quenching, since the experimental fluorescence intensities (curve 1 in the inset graph in Fig. 3b) obtained with different BHC concentrations are relatively higher than the corrected fluorescence intensities (curve 2 in the inset graph in Fig. 3b), which are corrected from the absorption spectra for different BHC concentrations. Another reason for the quenching of the fluorescence may be F-AuNC aggregation, as can be seen from the RLS intensity of the mixture of F-AuNCs and BHC (curve 2 in Fig. 3c) being higher than that of the F-AuNCs (curve 1 in Fig. 3c). When BHC was added to the acidic F-AuNC solution, the F-AuNCs could aggregate into large-diameter particles. These deductions are supported by the RLS spectral data in Fig. 3c.
Fig. 3

a Fluorescence spectra of fluorescent gold nanoclusters (F-AuNCs) in the presence of various concentrations of berberine hydrochloride (BHC) and b the absorption spectra obtained with various concentrations of BHC. The inset in b shows the experimental (line 1) and corrected (line 2) fluorescence intensities of F-AuNCs in the presence of various concentrations of BHC. a 1–8 F-AuNCs plus Britton–Robinson buffer (pH 2.87) plus BHC; 9 BHC. b 1–8 BHC. cBHC for spectra 1–8 in a and b, 0, 1.0 × 10-6, 5.0 × 10-6, 10 × 10-6, 30 × 10-6, 50 × 10-6, 70 × 10-6, and 100 × 10-6 mol L-1); cBHC for spectrum 9 in a, 1.0 × 10-4 mol L-1. c Resonance light scattering (RLS) spectra of F-AuNCs (curve 1) and in the presence of BHC (curve 2). The concentration of BHC is 1.0 × 10-4 mol L-1

As seen from the fluorescence spectra, the interaction between BHC and F-AuNCs can result in great quenching of the fluorescence of F-AuNCs. The different quenching mechanisms are usually classified as either dynamic or static. To distinguish these two mechanisms, observation of the absorption spectra of the fluorophore is a basic method [46, 47, 48]. Dynamic quenching affects only the excited fluorophore because of the interaction between the quencher and the excited fluorophore, and thus no changes in the absorption spectra are expected. In contrast, static quenching involves the perturbation of the absorption spectra caused by the nonluminous complex generated from the interaction between the quencher and the ground-state fluorophore. To confirm the mechanism of fluorescence quenching of F-AuNCs by BHC, the system’s absorption spectra were measured.

Curve 4 in Fig. S1 was obtained by our subtracting curve 2 (the absorption spectrum of F-AuNCs) from curve 1 (the absorption spectrum of the mixture of F-AuNCs and BHC). From comparison with the absorption spectrum of BHC (curve 3 in Fig. S1), it is obvious that a hypochromic effect [49] appears in the absorption spectrum of BHC in the presence of F-AuNCs, and the wavelength range for this is from 240 to 500 nm.

Optimization of the detection conditions for F-AuNCs

The optimum conditions of the reaction, the effect of foreign substances, and the analytical application of F-AuNCs were investigated. We found that the fluorescence intensity of the mixture of F-AuNCs and BHC changed with the reaction time (within 16 min); the results are shown in Fig. S2a. The fluorescence intensity of the mixture of F-AuNCs and BHC decreased with increase of the reaction time to 200s. The fluorescence intensity reached a minimum and the fluorescence intensity difference (IFoIF) reached a maximum after reaction for 400s. Thus the following determination was performed after the reaction had occurred for 2 min.

The effect of pH on the fluorescence intensity of F-AuNCs was examined with the concentration of BHC fixed at 5.0 × 10-5 mol L-1. As shown in Fig. S2b, the fluorescence intensity difference (IFoIF) (Fig. S2b, curve 3) reached a maximum at pH 2.87. Therefore, 2.87 was chosen as the most appropriate pH.

The influence of the incubation temperature on the fluorescence intensity of F-AuNCs was also examined with the concentration of BHC fixed at 5.0 × 10-5 mol L-1. As also shown in Fig. S2c, BHC caused strong fluorescence quenching of F-AuNCs (Fig. S2c, curve 3). Furthermore, with the rise of temperature, the fluorescence of F-AuNCs decreased obviously. This shows that the fluorescence intensity difference (IFoIF) (Fig. S2c, curve 3) is relatively high when the temperature is in the range from 0 to 20 °C, but decreases evidently when the temperature is above 25 °C. Considering both the accuracy and the convenience, the following test was conducted at 20 °C.

Effect of coexisting substances

Some ions and other species, including Ba2+(Cl-), Ca2+(NO3-), Fe3+(SO42-), K+(Cl-), Mg2+(F-), Na+(NO3-), Zn2+(SO42-), dl-methionine, l-arginine, l-cystine, l-histidine, l-lysine, l-proline, l-threonine, l-tyrosine, glucose, and maltose, that commonly exist in biological samples were chosen as the control group for study of the selectivity of BHC according to previous literature [23, 50, 51]. As shown in Fig. 4, BHC is the only substance that has a distinct signal response, whereas the relative fluorescence intensity ratio (IFoIF)/IF of the control group is negligible. The good selectivity is attributed to the special interaction between BHC and F-AuNCs (e.g., the inner filter effect) that was discussed in “Interaction between F-AuNCs and BHC.” Thus, on account of these advantages, F-AuNCs can be applied for the quantitative determination of BHC in compound berberine tablets.
Fig. 4

Selectivity of berberine hydrochloride (BHC) toward other substances. The concentrations of BHC and the other species are 1.0 × 10-5 mol L-1

Sensitivity for BHC detection

Figure 5a shows the fluorescence intensity of F-AuNCs decreases when the concentration of BHC increases. Also, the fluorescence intensity has a good linear relationship (Fig. 5b) with the concentration of BHC in the range from 1.0 × 10-6 to 1.0 × 10-4 mol L-1 under the optimum conditions. The relationship between the fluorescence intensity and the concentration of BHC can be fitted as the linear regression equation (IFoIF)/IF = −0.1130 + 0.0769c (where c is concentration in micromoles per liter), with the correlation coefficient r = 0.9995. The detection limit (3σ/k) is 7.5 × 10-8 mol L-1.
Fig. 5

a Fluorescence spectra of fluorescent gold nanoclusters in the presence of various concentrations of berberine hydrochloride: 0, 1.0 × 10-6, 5.0 × 10-6, 10 × 10-6, 30 × 10-6, 50 × 10-6, 70 × 10-6, and 100 × 10-6 mol L-1for spectra 1–8. b (IF0 − IF)/IF against concentration of berberine hydrochloride

BHC detection in a composite sample

The method developed was applied to the determination of BHC in compound berberine tablets and BHC tablets. We also used HPLC to ensure the veracity. The results are shown in Table 1. Each compound berberine tablet was found to contain 28.20 mg BHC. This value is consistent with the reference value of 30.00 mg (relative standard deviation 1.97%). Each BHC tablet was found to contain 104.85 mg BHC, which is consistent with the reference value of 100 mg (relative standard deviation 1.75%). The HPLC results are presented in Table 2. Each compound berberine tablet was found to contain 32.38 mg BHC, which is consistent with the reference value of 30.00 mg (relative standard deviation 2.54%). Therefore, this method may be used in the quality control of berberine tablets.
Table 1

Results obtained from fluorescence (n = 3)


Detection value (mg/slide)

Average value (mg/slide)

Reference value (mg/slide)

RSD (%)

Compound berberine tablets







Berberine hydrochloride tablets









RSD relative standard deviation

Table 2

Results obtained by high-performance liquid chromatography (n = 3)


Detection value (mg/slide)

Average value (mg/slide)

Reference value (mg/slide)

RSD (%)

Compound berberine tablets







RSD relative standard deviation


Novel water-soluble F-AuNCs with a large Stokes shift were developed as a spectrofluorometric probe for the determination of berberine. The F-AuNCs were prepared with citrate-stabilized stannous chloride and hydrogen tetrachloroaurate(III) tetrahydrate as raw materials. The properties of the F-AuNCs were characterized by their fluorescence, their absorption spectra, and TEM. With the F-AuNCs used as a probe, a simple and rapid method was developed for BHC detection based on the strong fluorescence quenching of F-AuNCs. The fluorescence intensity had a good linear relationship with the concentration of BHC, with a relatively low detection limit (7.5 × 10-8 mol L-1). Moreover, the method was further applied in the determination of two different tablets (compound berberine tablets and BHC tablets) and displayed outstanding feasibility and precision. This novel strategy is expected to be a good choice in future pharmaceutical analysis.



This work was supported by the National Natural Science Foundation of China (nos 51502088, 21275047, 21445008), the Hunan Provincial Natural Science Foundation of China (nos 2016JJ3058, 2016JJ5005), the Research Foundation of Education Department of Hunan Province (no. 17B091), the Graduate Innovation Project of the Hunan University of Science and Technology (CX2017B619), and the Foundation of Science and Technology on Transient Impact Laboratory (No. 614260601010317).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

216_2018_1246_MOESM1_ESM.pdf (225 kb)
ESM 1 (PDF 224 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Aoli Wen
    • 1
  • Xiaoxiao Peng
    • 1
  • Pingping Zhang
    • 1
  • Yunfei Long
    • 1
    Email author
  • Huiming Gong
    • 1
  • Qingru Xie
    • 1
  • Ming Yue
    • 1
  • Shu Chen
    • 1
    Email author
  1. 1.Key Laboratory of Theoretical Organic Chemistry and Function Molecule of Ministry of Education, Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan Provincial Key Lab of Advanced Materials for New Energy Storage and Conversion, School of Chemistry and Chemical EngineeringHunan University of Science and TechnologyXiangtanChina

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