Research article Received: 13 January 2014,
Revised: 27 March 2014,
Accepted: 3 April 2014
Published online in Wiley Online Library: 16 May 2014
(wileyonlinelibrary.com) DOI 10.1002/bio.2698
Flow-injection chemiluminescence method to detect a β2 adrenergic agonist Guangbin Zhang,a,b Yuhai Tang,b Jian Shang,b Zhongcheng Wang,a Hua Yu,a Wei Dua and Qiang Fua* ABSTRACT: A new method for the detection of β2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of β2 adrenergic agonist with potassium ferricyanide–luminol CL. The effect of β2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide– luminol was discovered. Detection of the β2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1 mmol/L of potassium ferricyanide, 10 μmol/L of luminol, 1.2 mmol/L of sodium hydroxide, a flow speed of 2.6 mL/min and a distance of 1.2 cm from ‘Y2’ to the flow cell. The linear ranges and limit of detection were 10–100 and 5 ng/mL for isoprenaline hydrochloride, 20–100 and 5 ng/mL for salbutamol sulfate, 8–200 and 1 ng/mL for terbutaline sulfate, 20–100 and 4 ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three β2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8–98.5%. The possible CL reaction mechanism of potassium ferricyanide–luminol–β2 adrenergic agonist was discussed from the UV/vis spectra. Copyright © 2014 John Wiley & Sons, Ltd. Additional supporting information may be found in the online version of this article at the publisher’s web site. Keywords: flow injection (FI); chemiluminescence (CL); β2 adrenergic agonist
Introduction
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β2 adrenergic agonists, such as isoproterenol, salbutamol, terbutaline and ractopamine, can bind to receptors on cell membranes to produce physiological effects such as increasing heart rate and relaxation of muscle tissues in the bronchi, uterus or intestinal wall. β2 adrenergic agonists were originally developed to treat pulmonary diseases. However, they have also been used illegally as a growth promoter in cattle, rabbits, poultry, pigs and other livestock. In addition, many incidences of poisoning (1,2) involving these drugs have happened recently. Therefore, the detection of a β2 adrenergic agonist is critical to food safety and public health. Many methods have been developed to detect β2 adrenergic agonists successfully, such as spectrophotometry (3), microemulsion high-performance liquid chromatography (MELC) (4), liquid chromatography–tandem mass spectrometry (LC-MS/MS) (5,6), high-performance liquid chromatography with fluorescence detection (7), electrochemical analysis (8–11), immunoassays (12–16), electrochemiluminescence (17,18), Raman spectroscopy (19) and chemiluminescence (20,21). However, low sensitivity and a narrow linear range were obtained using spectrophotometric methods. Detection of β2 adrenergic agonist by fluorospectrophotometry requires sample derivatization, which is time-consuming and error-prone. The electrochemical method has the advantage of a low limit of detection (LOD), but it is limited by electrode life. Immunoassays with high specificity are commonly used to detect biological samples, however, this method limited by the reaction of antibody and antigen. A MS detector has high sensitivity and specificity, but requires expensive equipment. So a new method is needed that is rapid, sensitive and of low cost for the detection of β2 adrenergic agonists.
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Recently, extremely sensitive chemiluminescence (CL)-based detection techniques have been developed and have attracted considerable attention. Coupled with flow injection (FI) techniques, FI–CL analysis has the advantage of being rapid, sensitive and economical, with a wide linear range, and has been applied in various fields, especially in pharmaceutical analysis. Recently, several reports have described the application of FI–CL analysis to different formulations such as powder-injection (22), tablet (23–28), injection (29,30) and capsule (31,32). Combined with pretreatment technology, several FI–CL methods had been developed to detect drugs in biological samples (33–36). In addition, Fe2+ (37), azoxystrobin (38) and nitrite (39) have been rapidly detected using the FI–CL method. Based on the luminol– CoFe2O4NP–sulfite CL system, a sensitive and rapid method has been established for the detection of the trace amounts of sulfite in white wine samples (40). Lin and coworkers (41) developed a CL system for the determination of 7,10-BaPQ in airborne particulates. Although the application of FI–CL has been widely explored, its application with β2 adrenergic agonists is scarce. In this work, we found that β2 adrenergic agonists, such as isoproterenol, salbutamol, terbutaline and ractopamine, whose chemical structures were similar, could obviously enhance the
* Correspondence to: Prof. Qiang Fu, Xi’an Jiaotong University, 76 Yanta Westroad, Xi’an, 710061 Shaanxi, People’s Republic of China. Tel: +8602982655382; Fax: +86-02982655382. E-mail: [email protected] a
School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061 Shaanxi, People’s Republic of China
b
Institute of Analytical Science, Xi’an Jiaotong University, Xi’an, 710061 Shaanxi, People’s Republic of China
Copyright © 2014 John Wiley & Sons, Ltd.
Chemiluminescence method to detect β2 adrenergic agonist CL intensity of a potassium ferricyanide–luminol system. A sensitive and rapid method was developed for the detection of β2 adrenergic agonist and three β2 adrenergic agonist preparations. The CL mechanism of the potassium ferricyanide–luminol–β2 adrenergic agonist system was studied using UV/vis spectra.
Experimental Apparatus The manifold used to deliver all solutions is shown in Fig. 1; this equipment was an IFFM-E mode FI–CL analysis system, manufactured by Xi’an Remax Electronic Science-Tech Co. Ltd (China). The analysis system consisted of two peristaltic pumps, a six-way injection valve with an injection loop, and a IFFS-A mode CL detection system. All flow lines were made from PTFE tubing (0.8 mm i.d.). The UV spectrum was obtained by using a UV spectrophotometer (UV-1800, SHIMADZU). The reference method for the determination of β2 adrenergic agonist was carried out using HPLC with a UV detector (LC-20A, SHIMADZU). The CL signal was recorded on a computer, which was installed with an IFFM-E mode FI–CL analysis workstation. Reagents Standard β2 adrenergic agonists, including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine, were purchased from the National Institute for Food and Drug Control (Beijing, China). All β2 adrenergic agonist preparations were purchased from the domestic drugs market – isoprenaline hydrochloride injection (1 mg/branch), terbutaline sulfate tablets (2.5 mg/tablet) and salbutamol sulfate tablets (2.4 mg/tablet), were made by Shanghai Harvest Pharmaceutical (Group) Co., Ltd (Shanghai, China), AstraZeneca Pharmaceutical Co., Ltd (Jiangsu, China) and Shijiazhuang Kangli Pharmaceutical Co., Ltd (Shijiazhuang, China), respectively. 3-Aminophthalhydrazide (luminol) was purchased from ABCR GmbH & Co. KG (Germany), potassium ferricyanide (K3Fe(CN)6), sodium hydroxide (NaOH), sodium chloride, potassium chloride, calcium chloride, copper chloride, cuprous chloride, manganese chloride, chromium chloride, magnesium sulfate, lead nitrate, ferric nitrate, ferrous
sulfate, starch, acetone, hydrochloric acid, disodium edetate, saccharin, glucose, sucrose, lactose, mannitol, ethanol, sodium carboxymethyl cellulose, sodium metabisulfite and formaldehyde were obtained from Xi’an Chemical Reagent Factory (Xi’an, China). All solutions were prepared from analytical reagent (AR) grade chemicals combined with double-distilled water. A stock solution of potassium ferricyanide (0.01 mol/L) was prepared by dissolving 0.3293 g of K3Fe(CN)6 in 100 mL of water. A solution of luminol (0.01 mol/L) was prepared by diluting 1.7720 g of luminol with 0.01 M NaOH to 100 mL. β2 adrenergic agonist standard stock solution – isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine solution, 0.01 g/mL, were prepared daily by dissolving 1 g of each compound in 100 mL of water. The stock solutions were stored in a refrigerator and in the dark. Working solutions were prepared by the appropriate dilution of stock solutions with water. Pretreatment of β2 adrenergic agonist preparations The proposed method was applied to the analysis of three commercial pharmaceutical preparations, namely, terbutaline sulfate tablets, isoprenaline hydrochloride injection and salbutamol sulfate tablets. Each sample stock solution was prepared by dissolving a quantity of the sample equivalent to each tablet or branch, from 20 tablets or 6 branches, by sonication with appropriate volume of water. The dissolved tablet samples were filtered through a microporous membrane (0.45 μm) and diluted with water to 100 mL. The sample stock solution was prepared daily and kept at 4 ºC. More dilute solutions were prepared by serial dilution. CL detection method The FI–CL configuration (Fig. 1) consisted of a three-channel manifold in which either the standard or sample solution was introduced as the carrier stream. Potassium ferricyanide solution (A) was introduced into the pipeline via a peristaltic pump (P1). The mixed solution of luminol (C) and NaOH (D) was injected into the carrier stream via a six-way injection valve (V) and a sample loop, which allowed mixing with the sample or blank solution (B). Finally, all solutions were mixed by a three-way ‘Y’
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Figure 1. Schematic diagram of FI–CL analysis. A, potassium ferricyanide; B, sample or blank solution; C, luminol solution; D, sodium hydroxide solution; P1, P2, peristaltic pump; Y1, Y2, three-way ‘Y’ connector; W, waste; PMT, photomultiplier tube; R, signal converter.
G. Zhang et al. connector (Y2), then the CL emission signal, in the flat spiral flow cell, was detected with photomultiplier tube (PMT) in the detection system. The CL emission intensity of the K3Fe(CN)6–luminol– H2O was recorded as the background blank signal (baseline). Determination of the β2 receptor agonist was based on the increase in the CL intensity, calculated as ΔI = I – I0, herein, I was the net CL signal of the system in the presence of β2 adrenergic agonist and I0 was the CL intensity corresponding to the baseline. The uniform design experiment Optimization of the method was carried out by application of a uniform design (Ud) to search for factors affecting the CL response. Terbutaline sulfate, 15 ng/mL, was used as a model to optimize the method. In this study, the effect of influencing factors, including the concentrations of potassium ferricyanide (X1), luminol (X2) and NaOH (X3), pump speed (X4), and the distance from ‘Y2’ to the flow cell (X5) were investigated, and 10 levels were taken for each factor (Table S1). The uniform design and data analysis were performed using DPS v. 6.55 software.
Results and discussion Optimization of the CL conditions An efficient experimental design is crucial in the study of CL conditions. Uniform design, as proposed by Chinese mathematicians Kaitai Fang and Yuan Wang, is one of the most widely used approaches for exploring experimental conditions. It possesses a space-filling property in which the design points are spaced evenly across the experimental region. The advantage of uniform design is that it reduces the number of tests. In this study, a uniform design of U10 (105) including 10 levels in five factors was used to optimize the influence of factors. The results are listed in Table 1, and the quadratic polynomial regression was as follows:
mmol/L, X4 = 2.6 mL/min, X5 = 1.1678 cm and ΔI = 649.0293. The optimal conditions were validated and the average relative CL intensity by experiment was 596, which is in agreement with the predictive condition.
Validation of the method Appropriate validation of new methods for analyzing pharmaceuticals is required by the regulatory authorities, and the current method was validated in compliance with guidelines Q2 (R1) issued by the International Conference on Harmonisation (ICH; http://www. ich.org/products/guidelines/quality/article/quality-guidelines.html). Linearity and range. Under optimal conditions, calibration curves for the determination of isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine were established by triplicate injection of various concentrations of their standard solutions. The results are illustrated in Fig. 2, the linear ranges of isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate, and ractopamine were 10–100, 20–100, 8–200 and 20–100 ng/mL, respectively. The regression equations and correlation coefficients (R2) were ΔI = 11.57C – 2.7288 (R2 = 0.9992) for isoprenaline hydrochloride, ΔI = 16.269C – 317.37 (R2 = 0.9969) for salbutamol sulfate, ΔI = 78.055C – 654.36 (R2 = 0.9994) for terbutaline sulfate and ΔI = 10.029C – 149.11 (R2 = 0.9991) for ractopamine. Accuracy and precision. The accuracy of the method was tested using low, medium and high concentrations of each β2 adrenergic agonist standard substance. The intermediate precision of the method was studied by analyzing three identical samples. Intra-day precision was obtained by injecting five times for each sample within one day, and inter-day precision was determined by injecting three times for each sample on three consecutive days. The results are listed in Table 2. The accuracy was in the range 97.9–100.6%, the intra-RSD values were 10,000 100 100 80 50 50 20 20 20 1
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Analytical application
CL mechanism
The proposed FI–CL method was successfully applied to the analysis of commercial pharmaceutical formulations of three β2 adrenergic agonists, terbutaline sulfate tablets, isoprenaline hydrochloride injection and salbutamol sulfate tablets. Recoveries were conducted by adding known quantities of each β2 adrenergic agonist to their preparations, and the results are shown in Table 4. To further validate this method, HPLC, a standard detection method recorded in the Chinese Pharmacopoeia, was carried out to determine the content of each β2 adrenergic agonist preparation. Table 4 shows that the results obtained using the current method were in good agreement with the HPLC results.
The β2 adrenergic agonists isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine obviously enhanced the CL intensity of the potassium ferricyanide–luminol system. The chemical structure of most β2 adrenergic agonists contains phenolic hydroxy, which is easily oxidized by potassium ferricyanide to quinone. In order to study the CL mechanism, the UV spectra of potassium ferricyanide, luminol, the reactant of ferricyanide and luminol, terbutaline sulfate and the reactant of ferricyanide and terbutaline sulfate were investigated. Figure 4 shows the UV spectra for terbutaline sulfate solution (a), luminol solution (b), the reaction solution of K3Fe(CN)6, luminol and terbutaline sulfate (c), the reaction solution of K3Fe(CN)6 and
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Chemiluminescence method to detect β2 adrenergic agonist Table 4. Comparison of the HPLC and FI–CL methods Drugs
Number
Nominal content (mg per tablet or branch)
HPLC method (mg per tablet or branch)
Proposed method (mg per tablet or branch)
added
Found (mg)
Average recovery (%)
Isoprenaline hydrochloride injection Salbutamol sulfate tablets
5
1
0.95 ± 0.02
0.96 ± 0.02
2.4
2.32 ± 0.04
2.35 ± 0.08
Terbutaline sulfate tablets
5
2.5
2.42 ± 0.03
2.40 ± 0.06
1.79 1.97 2.17 4.31 4.73 5.23 4.48 4.97 5.44
97.7
5
0.8 1.0 1.2 2.0 2.4 2.9 2.0 2.5 3.0
Figure 4. UV spectra for terbutaline sulfate solution (a), luminol solution (b), the reaction solution of K3Fe(CN)6, luminol and terbutaline sulfate (c), the reaction solution of K3Fe(CN)6 and terbutaline sulfate (d), the reaction solution of K3Fe(CN)6 and luminol (e), and K3Fe(CN)6 solution (f).
96.8
98.5
to λ282, which could be attributed to structural changes in the oxidation products of terbutaline sulfate. There was no new absorption peak in the reaction solution of K3Fe(CN)6 and luminol (e), but the absorption peak λ347 of luminol in NaOH solution disappeared. Moreover, the absorption intensities of λ302 and λ420 for K3Fe(CN)6 were obviously decreased. It could be demonstrated that the light emitter of the CL system was the excited state of 3-aminophthalhydrazide, which was in agreement with reports that the luminant of potassium ferricyanide with luminol was considered to be the excited state of 3-aminophthalhydrazide (43–46); the light emission emanating from relaxation of the excited state of 3-aminophthalhydrazide then returned to ground state. Terbutaline sulfate could be oxidized by K3Fe(CN)6, and during this process produced active oxygen-containing reactant intermediates, such as superoxide radical (·O2). The produced superoxide radical could oxidize luminol to give a stronger CL in alkaline solution. It can be concluded that the enhancement effect on CL by the β2 adrenergic agonist was attributed to the formation of · O2 in the potassium ferricyanide–luminol–β2 adrenergic agonist system. In light of above research, the possible CL mechanism is given in Fig. 5.
Conclusions
Figure 5. Possible mechanism of the potassium ferricyanide–luminol–β2 adrenergic agonist chemiluminescence system.
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terbutaline sulfate (d), the reaction solution of K3Fe(CN)6 and luminol (e), and K3Fe(CN)6 solution (f). As can be seen Fig. 4, the absorption peak λ276 of terbutaline sulfate was red-shifted
The proposed FI–CL method to determine β2 adrenergic agonist has been shown to be sensitive and rapid. It was successfully applied to the analysis of three pharmaceutical preparations, and the results obtained were in reasonable agreement with the amount of each β2 adrenergic agonist drug. The influence of K3Fe(CN)6–luminol–β2 adrenergic agonist chemiluminescence was optimized using uniform design experimentation, and it was shown that uniform design could be applied to optimize the influence of factors in the FI-CL analysis method. The proposed method was then validated by linearity, range, accuracy, precision, LOD, robustness and interference experiments. The possible CL mechanism was discussed. It was suggested that the luminant was the excited state of 3-aminophthalhydrazide. β2 adrenergic agonist could enhance the CL intensity via the produced superoxide radical. Coupled with other techniques like HPLC, capillary electrophoresis and molecular imprinting, the proposed method can be applied to detect β2 adrenergic agonists in biological samples.
G. Zhang et al. Acknowledgment This work was financially supported by National Natural Science Foundations of China (No. 30873193, 81173024, and 81227802).
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Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web site.
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Revised: 27 March 2014,
Accepted: 3 April 2014
Published online in Wiley Online Library: 16 May 2014
(wileyonlinelibrary.com) DOI 10.1002/bio.2698
Flow-injection chemiluminescence method to detect a β2 adrenergic agonist Guangbin Zhang,a,b Yuhai Tang,b Jian Shang,b Zhongcheng Wang,a Hua Yu,a Wei Dua and Qiang Fua* ABSTRACT: A new method for the detection of β2 adrenergic agonists was developed based on the chemiluminescence (CL) reaction of β2 adrenergic agonist with potassium ferricyanide–luminol CL. The effect of β2 adrenergic agonists including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine on the CL intensity of potassium ferricyanide– luminol was discovered. Detection of the β2 adrenergic agonist was carried out in a flow system. Using uniform design experimentation, the influence factors of CL were optimized. The optimal experimental conditions were 1 mmol/L of potassium ferricyanide, 10 μmol/L of luminol, 1.2 mmol/L of sodium hydroxide, a flow speed of 2.6 mL/min and a distance of 1.2 cm from ‘Y2’ to the flow cell. The linear ranges and limit of detection were 10–100 and 5 ng/mL for isoprenaline hydrochloride, 20–100 and 5 ng/mL for salbutamol sulfate, 8–200 and 1 ng/mL for terbutaline sulfate, 20–100 and 4 ng/mL for ractopamine, respectively. The proposed method allowed 200 injections/h with excellent repeatability and precision. It was successfully applied to the determination of three β2 adrenergic agonists in commercial pharmaceutical formulations with recoveries in the range of 96.8–98.5%. The possible CL reaction mechanism of potassium ferricyanide–luminol–β2 adrenergic agonist was discussed from the UV/vis spectra. Copyright © 2014 John Wiley & Sons, Ltd. Additional supporting information may be found in the online version of this article at the publisher’s web site. Keywords: flow injection (FI); chemiluminescence (CL); β2 adrenergic agonist
Introduction
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β2 adrenergic agonists, such as isoproterenol, salbutamol, terbutaline and ractopamine, can bind to receptors on cell membranes to produce physiological effects such as increasing heart rate and relaxation of muscle tissues in the bronchi, uterus or intestinal wall. β2 adrenergic agonists were originally developed to treat pulmonary diseases. However, they have also been used illegally as a growth promoter in cattle, rabbits, poultry, pigs and other livestock. In addition, many incidences of poisoning (1,2) involving these drugs have happened recently. Therefore, the detection of a β2 adrenergic agonist is critical to food safety and public health. Many methods have been developed to detect β2 adrenergic agonists successfully, such as spectrophotometry (3), microemulsion high-performance liquid chromatography (MELC) (4), liquid chromatography–tandem mass spectrometry (LC-MS/MS) (5,6), high-performance liquid chromatography with fluorescence detection (7), electrochemical analysis (8–11), immunoassays (12–16), electrochemiluminescence (17,18), Raman spectroscopy (19) and chemiluminescence (20,21). However, low sensitivity and a narrow linear range were obtained using spectrophotometric methods. Detection of β2 adrenergic agonist by fluorospectrophotometry requires sample derivatization, which is time-consuming and error-prone. The electrochemical method has the advantage of a low limit of detection (LOD), but it is limited by electrode life. Immunoassays with high specificity are commonly used to detect biological samples, however, this method limited by the reaction of antibody and antigen. A MS detector has high sensitivity and specificity, but requires expensive equipment. So a new method is needed that is rapid, sensitive and of low cost for the detection of β2 adrenergic agonists.
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Recently, extremely sensitive chemiluminescence (CL)-based detection techniques have been developed and have attracted considerable attention. Coupled with flow injection (FI) techniques, FI–CL analysis has the advantage of being rapid, sensitive and economical, with a wide linear range, and has been applied in various fields, especially in pharmaceutical analysis. Recently, several reports have described the application of FI–CL analysis to different formulations such as powder-injection (22), tablet (23–28), injection (29,30) and capsule (31,32). Combined with pretreatment technology, several FI–CL methods had been developed to detect drugs in biological samples (33–36). In addition, Fe2+ (37), azoxystrobin (38) and nitrite (39) have been rapidly detected using the FI–CL method. Based on the luminol– CoFe2O4NP–sulfite CL system, a sensitive and rapid method has been established for the detection of the trace amounts of sulfite in white wine samples (40). Lin and coworkers (41) developed a CL system for the determination of 7,10-BaPQ in airborne particulates. Although the application of FI–CL has been widely explored, its application with β2 adrenergic agonists is scarce. In this work, we found that β2 adrenergic agonists, such as isoproterenol, salbutamol, terbutaline and ractopamine, whose chemical structures were similar, could obviously enhance the
* Correspondence to: Prof. Qiang Fu, Xi’an Jiaotong University, 76 Yanta Westroad, Xi’an, 710061 Shaanxi, People’s Republic of China. Tel: +8602982655382; Fax: +86-02982655382. E-mail: [email protected] a
School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, 710061 Shaanxi, People’s Republic of China
b
Institute of Analytical Science, Xi’an Jiaotong University, Xi’an, 710061 Shaanxi, People’s Republic of China
Copyright © 2014 John Wiley & Sons, Ltd.
Chemiluminescence method to detect β2 adrenergic agonist CL intensity of a potassium ferricyanide–luminol system. A sensitive and rapid method was developed for the detection of β2 adrenergic agonist and three β2 adrenergic agonist preparations. The CL mechanism of the potassium ferricyanide–luminol–β2 adrenergic agonist system was studied using UV/vis spectra.
Experimental Apparatus The manifold used to deliver all solutions is shown in Fig. 1; this equipment was an IFFM-E mode FI–CL analysis system, manufactured by Xi’an Remax Electronic Science-Tech Co. Ltd (China). The analysis system consisted of two peristaltic pumps, a six-way injection valve with an injection loop, and a IFFS-A mode CL detection system. All flow lines were made from PTFE tubing (0.8 mm i.d.). The UV spectrum was obtained by using a UV spectrophotometer (UV-1800, SHIMADZU). The reference method for the determination of β2 adrenergic agonist was carried out using HPLC with a UV detector (LC-20A, SHIMADZU). The CL signal was recorded on a computer, which was installed with an IFFM-E mode FI–CL analysis workstation. Reagents Standard β2 adrenergic agonists, including isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine, were purchased from the National Institute for Food and Drug Control (Beijing, China). All β2 adrenergic agonist preparations were purchased from the domestic drugs market – isoprenaline hydrochloride injection (1 mg/branch), terbutaline sulfate tablets (2.5 mg/tablet) and salbutamol sulfate tablets (2.4 mg/tablet), were made by Shanghai Harvest Pharmaceutical (Group) Co., Ltd (Shanghai, China), AstraZeneca Pharmaceutical Co., Ltd (Jiangsu, China) and Shijiazhuang Kangli Pharmaceutical Co., Ltd (Shijiazhuang, China), respectively. 3-Aminophthalhydrazide (luminol) was purchased from ABCR GmbH & Co. KG (Germany), potassium ferricyanide (K3Fe(CN)6), sodium hydroxide (NaOH), sodium chloride, potassium chloride, calcium chloride, copper chloride, cuprous chloride, manganese chloride, chromium chloride, magnesium sulfate, lead nitrate, ferric nitrate, ferrous
sulfate, starch, acetone, hydrochloric acid, disodium edetate, saccharin, glucose, sucrose, lactose, mannitol, ethanol, sodium carboxymethyl cellulose, sodium metabisulfite and formaldehyde were obtained from Xi’an Chemical Reagent Factory (Xi’an, China). All solutions were prepared from analytical reagent (AR) grade chemicals combined with double-distilled water. A stock solution of potassium ferricyanide (0.01 mol/L) was prepared by dissolving 0.3293 g of K3Fe(CN)6 in 100 mL of water. A solution of luminol (0.01 mol/L) was prepared by diluting 1.7720 g of luminol with 0.01 M NaOH to 100 mL. β2 adrenergic agonist standard stock solution – isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine solution, 0.01 g/mL, were prepared daily by dissolving 1 g of each compound in 100 mL of water. The stock solutions were stored in a refrigerator and in the dark. Working solutions were prepared by the appropriate dilution of stock solutions with water. Pretreatment of β2 adrenergic agonist preparations The proposed method was applied to the analysis of three commercial pharmaceutical preparations, namely, terbutaline sulfate tablets, isoprenaline hydrochloride injection and salbutamol sulfate tablets. Each sample stock solution was prepared by dissolving a quantity of the sample equivalent to each tablet or branch, from 20 tablets or 6 branches, by sonication with appropriate volume of water. The dissolved tablet samples were filtered through a microporous membrane (0.45 μm) and diluted with water to 100 mL. The sample stock solution was prepared daily and kept at 4 ºC. More dilute solutions were prepared by serial dilution. CL detection method The FI–CL configuration (Fig. 1) consisted of a three-channel manifold in which either the standard or sample solution was introduced as the carrier stream. Potassium ferricyanide solution (A) was introduced into the pipeline via a peristaltic pump (P1). The mixed solution of luminol (C) and NaOH (D) was injected into the carrier stream via a six-way injection valve (V) and a sample loop, which allowed mixing with the sample or blank solution (B). Finally, all solutions were mixed by a three-way ‘Y’
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Figure 1. Schematic diagram of FI–CL analysis. A, potassium ferricyanide; B, sample or blank solution; C, luminol solution; D, sodium hydroxide solution; P1, P2, peristaltic pump; Y1, Y2, three-way ‘Y’ connector; W, waste; PMT, photomultiplier tube; R, signal converter.
G. Zhang et al. connector (Y2), then the CL emission signal, in the flat spiral flow cell, was detected with photomultiplier tube (PMT) in the detection system. The CL emission intensity of the K3Fe(CN)6–luminol– H2O was recorded as the background blank signal (baseline). Determination of the β2 receptor agonist was based on the increase in the CL intensity, calculated as ΔI = I – I0, herein, I was the net CL signal of the system in the presence of β2 adrenergic agonist and I0 was the CL intensity corresponding to the baseline. The uniform design experiment Optimization of the method was carried out by application of a uniform design (Ud) to search for factors affecting the CL response. Terbutaline sulfate, 15 ng/mL, was used as a model to optimize the method. In this study, the effect of influencing factors, including the concentrations of potassium ferricyanide (X1), luminol (X2) and NaOH (X3), pump speed (X4), and the distance from ‘Y2’ to the flow cell (X5) were investigated, and 10 levels were taken for each factor (Table S1). The uniform design and data analysis were performed using DPS v. 6.55 software.
Results and discussion Optimization of the CL conditions An efficient experimental design is crucial in the study of CL conditions. Uniform design, as proposed by Chinese mathematicians Kaitai Fang and Yuan Wang, is one of the most widely used approaches for exploring experimental conditions. It possesses a space-filling property in which the design points are spaced evenly across the experimental region. The advantage of uniform design is that it reduces the number of tests. In this study, a uniform design of U10 (105) including 10 levels in five factors was used to optimize the influence of factors. The results are listed in Table 1, and the quadratic polynomial regression was as follows:
mmol/L, X4 = 2.6 mL/min, X5 = 1.1678 cm and ΔI = 649.0293. The optimal conditions were validated and the average relative CL intensity by experiment was 596, which is in agreement with the predictive condition.
Validation of the method Appropriate validation of new methods for analyzing pharmaceuticals is required by the regulatory authorities, and the current method was validated in compliance with guidelines Q2 (R1) issued by the International Conference on Harmonisation (ICH; http://www. ich.org/products/guidelines/quality/article/quality-guidelines.html). Linearity and range. Under optimal conditions, calibration curves for the determination of isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine were established by triplicate injection of various concentrations of their standard solutions. The results are illustrated in Fig. 2, the linear ranges of isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate, and ractopamine were 10–100, 20–100, 8–200 and 20–100 ng/mL, respectively. The regression equations and correlation coefficients (R2) were ΔI = 11.57C – 2.7288 (R2 = 0.9992) for isoprenaline hydrochloride, ΔI = 16.269C – 317.37 (R2 = 0.9969) for salbutamol sulfate, ΔI = 78.055C – 654.36 (R2 = 0.9994) for terbutaline sulfate and ΔI = 10.029C – 149.11 (R2 = 0.9991) for ractopamine. Accuracy and precision. The accuracy of the method was tested using low, medium and high concentrations of each β2 adrenergic agonist standard substance. The intermediate precision of the method was studied by analyzing three identical samples. Intra-day precision was obtained by injecting five times for each sample within one day, and inter-day precision was determined by injecting three times for each sample on three consecutive days. The results are listed in Table 2. The accuracy was in the range 97.9–100.6%, the intra-RSD values were 10,000 100 100 80 50 50 20 20 20 1
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Analytical application
CL mechanism
The proposed FI–CL method was successfully applied to the analysis of commercial pharmaceutical formulations of three β2 adrenergic agonists, terbutaline sulfate tablets, isoprenaline hydrochloride injection and salbutamol sulfate tablets. Recoveries were conducted by adding known quantities of each β2 adrenergic agonist to their preparations, and the results are shown in Table 4. To further validate this method, HPLC, a standard detection method recorded in the Chinese Pharmacopoeia, was carried out to determine the content of each β2 adrenergic agonist preparation. Table 4 shows that the results obtained using the current method were in good agreement with the HPLC results.
The β2 adrenergic agonists isoprenaline hydrochloride, salbutamol sulfate, terbutaline sulfate and ractopamine obviously enhanced the CL intensity of the potassium ferricyanide–luminol system. The chemical structure of most β2 adrenergic agonists contains phenolic hydroxy, which is easily oxidized by potassium ferricyanide to quinone. In order to study the CL mechanism, the UV spectra of potassium ferricyanide, luminol, the reactant of ferricyanide and luminol, terbutaline sulfate and the reactant of ferricyanide and terbutaline sulfate were investigated. Figure 4 shows the UV spectra for terbutaline sulfate solution (a), luminol solution (b), the reaction solution of K3Fe(CN)6, luminol and terbutaline sulfate (c), the reaction solution of K3Fe(CN)6 and
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Chemiluminescence method to detect β2 adrenergic agonist Table 4. Comparison of the HPLC and FI–CL methods Drugs
Number
Nominal content (mg per tablet or branch)
HPLC method (mg per tablet or branch)
Proposed method (mg per tablet or branch)
added
Found (mg)
Average recovery (%)
Isoprenaline hydrochloride injection Salbutamol sulfate tablets
5
1
0.95 ± 0.02
0.96 ± 0.02
2.4
2.32 ± 0.04
2.35 ± 0.08
Terbutaline sulfate tablets
5
2.5
2.42 ± 0.03
2.40 ± 0.06
1.79 1.97 2.17 4.31 4.73 5.23 4.48 4.97 5.44
97.7
5
0.8 1.0 1.2 2.0 2.4 2.9 2.0 2.5 3.0
Figure 4. UV spectra for terbutaline sulfate solution (a), luminol solution (b), the reaction solution of K3Fe(CN)6, luminol and terbutaline sulfate (c), the reaction solution of K3Fe(CN)6 and terbutaline sulfate (d), the reaction solution of K3Fe(CN)6 and luminol (e), and K3Fe(CN)6 solution (f).
96.8
98.5
to λ282, which could be attributed to structural changes in the oxidation products of terbutaline sulfate. There was no new absorption peak in the reaction solution of K3Fe(CN)6 and luminol (e), but the absorption peak λ347 of luminol in NaOH solution disappeared. Moreover, the absorption intensities of λ302 and λ420 for K3Fe(CN)6 were obviously decreased. It could be demonstrated that the light emitter of the CL system was the excited state of 3-aminophthalhydrazide, which was in agreement with reports that the luminant of potassium ferricyanide with luminol was considered to be the excited state of 3-aminophthalhydrazide (43–46); the light emission emanating from relaxation of the excited state of 3-aminophthalhydrazide then returned to ground state. Terbutaline sulfate could be oxidized by K3Fe(CN)6, and during this process produced active oxygen-containing reactant intermediates, such as superoxide radical (·O2). The produced superoxide radical could oxidize luminol to give a stronger CL in alkaline solution. It can be concluded that the enhancement effect on CL by the β2 adrenergic agonist was attributed to the formation of · O2 in the potassium ferricyanide–luminol–β2 adrenergic agonist system. In light of above research, the possible CL mechanism is given in Fig. 5.
Conclusions
Figure 5. Possible mechanism of the potassium ferricyanide–luminol–β2 adrenergic agonist chemiluminescence system.
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terbutaline sulfate (d), the reaction solution of K3Fe(CN)6 and luminol (e), and K3Fe(CN)6 solution (f). As can be seen Fig. 4, the absorption peak λ276 of terbutaline sulfate was red-shifted
The proposed FI–CL method to determine β2 adrenergic agonist has been shown to be sensitive and rapid. It was successfully applied to the analysis of three pharmaceutical preparations, and the results obtained were in reasonable agreement with the amount of each β2 adrenergic agonist drug. The influence of K3Fe(CN)6–luminol–β2 adrenergic agonist chemiluminescence was optimized using uniform design experimentation, and it was shown that uniform design could be applied to optimize the influence of factors in the FI-CL analysis method. The proposed method was then validated by linearity, range, accuracy, precision, LOD, robustness and interference experiments. The possible CL mechanism was discussed. It was suggested that the luminant was the excited state of 3-aminophthalhydrazide. β2 adrenergic agonist could enhance the CL intensity via the produced superoxide radical. Coupled with other techniques like HPLC, capillary electrophoresis and molecular imprinting, the proposed method can be applied to detect β2 adrenergic agonists in biological samples.
G. Zhang et al. Acknowledgment This work was financially supported by National Natural Science Foundations of China (No. 30873193, 81173024, and 81227802).
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Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web site.
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