Sensitive and selective detection of 4-aminophenol in the presence of acetaminophen using gold–silver core–shell nanoparticles embedded in silica nanostructures

https://doi.org/10.1016/j.jiec.2019.11.030Get rights and content

Highlights

  • A method was developed for 4-aminophenol detection using SiO2@Au@Ag nanomaterials.

  • SERS intensity achieved the highest value via incubation with 500 μL 4-AP for 8 h.

  • Acetaminophen had a significant influence on the SERS signal of SiO2@Au@Ag@4-AP.

Abstract

Toxic 4-aminophenol (4-AP) can be considered as a primary impurity during the synthesis and/or storage of N-acetyl-para-aminophenol (APAP). In this study, 4-AP was sensitively and selectively detected in the presence of APAP using a gold–silver core–shell nanoparticle-embedded silica nanostructure (SiO2@Au@Ag). First, approximately 200 nm of SiO2@Au@Ag were successfully prepared based on the Au-seed (3 nm) mediated growth of Ag on the surface of SiO2 NP. Upon the incubation of 4-AP with SiO2@Au@Ag nanoparticles (NPs), the surface-enhanced Raman spectroscopy (SERS) intensity of 4-AP at 1591 cm−1 increased proportionally in accordance with an increase in the concentration of 4-AP in the range of 0–800 μM, with a detection limit of 3.5 ppm. In addition, the APAP did not exhibit a significant Raman signal at high concentrations (5 mM) and under the NP incubation condition. In the presence of 1 mM, 3 mM, and 5 mM of APAP, 4-AP was detected using SiO2@Au@Ag NPs within the range of 200–1000 μM, although the slopes decreased from 0.083 cps/μM to 0.059 cps/μM, 0.068 cps/μM, and 0.035 cps/μM, respectively. This study provides a method for the detection of 4-AP in the presence of APAP by using SiO2@Au@Ag for impurity detection in the pharmaceutical field.

Introduction

Acetaminophen (or N-acetyl-para-aminophenol abbreviated as APAP) is an analgesic and antipyretic drug that can be widely used by a variety of patients, including pregnant women, children, and the elderly. However, during the synthesis and/or storage of APAP, it can be partly decomposed to 4-aminophenol (4-AP), which is a primary impurity of APAP in pharmaceutical formulations. The presence of 4-AP in APAP leads to toxicity, which includes the nephrotoxicity and hepatotoxicity of patients [1], [2]. According to the British Pharmacopoeia, the maximum allowable concentration of 4-AP in APAP formulations is 0.1% (w/w) (or 1000 ppm), to ensure drug formulation safety [3], [4], [5].

Several methods such as high-performance liquid chromatography (HPLC) methods, which are based on spectrophotometric [6], [7], [8], [9], [10], [11], electrochemical [12], [13], [14], [15], [16], colorimetric [17], [18], and fluorometric [19] detection, have been employed for the determination of 4-AP in APAP pharmaceutical formulations. Currently, HPLC is the most robust and reliable method for food safety analysis. However, HPLC is time-consuming and expensive; it requires a harsh solvent, high-power source, bulky and sophisticated operations, and a complex multi-step pre-treatment process. Moreover, it must be carried out in laboratories by trained personnel [20], [21]. Hence, a rapid, simple, highly sensitive, and stable method should be developed for the determination of 4-AP in the presence of APAP.

Surface-enhanced Raman scattering (SERS) was developed as a non-destructive, rapid, molecular fingerprinting, ultrasensitive, and photostable detection technique for various applications [22], [23], [24], [25], [26]. Compared with HPLC/mass spectrometry (HPLC–MS), SERS does not require harsh solvents and complicated instrumentation, and it is combined with other detection systems such as fluorescent microscopes [27]. As a result, several studies focused on the use of different types of nanoparticles (NPs) as substrates for the SERS detection of microstructures in the pharmaceutical field [28], such as silver [3], [4] and gold [29], [30], [31], [32] nanostructures. As a result, detection of 4-AP using SERS and aggregated Ag NPs was recently performed by De Bleye et al. [3], [4]. Although the aggregated Ag NPs were based on a 4-AP detection limit of 0.9 ppm, the NP aggregation based technique may be ineffective in quantitative detection, owing to its lack of reproducibility [3], [4].

In this study, Au–Ag alloys were employed for the assembly of silica NPs (SiO2@Au@Ag NPs) based on the Au-seed mediated growth of Ag on the surface of a SiO2 NP template. The presence of Au seeds facilitates and allows for the precise control of the distance and uniform of the Ag shell on SiO2 NPs [33], [34], [35]. The silica template facilitates the control of density, size, shape, and nanogap of NPs on its surface, generating a homogenous SERS substrate [35]. As a result, high-strength and reliable SERS substrates with high reproducibility based on SiO2@Au@Ag can be developed as substrates for the enzyme-linked immunosorbent assay (ELISA) [36], which is an internal SERS [37], [38] pest detection standard [39]. According to our previous report, the enhancement factor of SiO2@Au@Ag nanomaterial is 4.2 × 106 times as compared to without the nanomaterial [33]. However, their use in SERS detection in the pharmaceutical field requires further investigation.

In this study, using the basic structure of SiO2@Au@Ag NPs, a sensitive and selective analytical method was developed for the detection of 4-aminophenol, which is the main acetaminophen impurity, in a pharmaceutical formulation using SERS. This allows for the assessment of a quantification limit below the specification limit of 1000 ppm.

Section snippets

Chemicals and reagents

Tetraethylorthosilicate (TEOS), 3-aminopropyltriethoxysilane (APTS), silver nitrate (AgNO3), chloroauric acid (HAuCl4), tetrakis(hydroxymethyl)phosphonium chloride (THPC), ascorbic acid (AA), polyvinylpyrrolidone (PVP), phosphate buffer saline (PBS), Tween 20, 4-aminophenol (4-AP), and acetaminophen (APAP) were purchased from Sigma–Aldrich (USA). Ethanol (EtOH) and aqueous ammonium hydroxide (NH4OH, 27%) were purchased from Daejung (South Korea); and ultrapure water (18.2  cm) was produced by a

Results and discussion

For the sensitive and selective detection of 4-aminophenol (4-AP) as impurity in the presence of APAP, the following two strategies were employed: 1) SiO2@Au@Ag as a strong SERS substrate, and 2) difference of binding affinity of 4-AP and APAP with respect to the metal surface, for selective detection, as shown in Fig. 1.

While incubating with SiO2@Au@Ag NPs, APAP was not likely to adsorb on the metal surface because it does not have any functional groups with good Ag metal affinity such as

Conclusion

In this study, a method was successfully developed for impurity detection using SiO2@Au@Ag nanomaterials. The presence of Au@Ag alloys on the surface of SiO2 was confirmed by the broad bands in UV–vis spectra between 320–700 nm, with a maximum peak at ∼450 nm; which indicates the generation of bumps on the Ag shell. For detection of 4-AP as an impurity in APAP, the SERS intensity of 4-AP-incubated SiO2@Au@Ag showed the highest value via incubation with 500 μL 4-AP for 8 h. The SERS intensity of

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgment

This work was supported by the KU Research Professor Program of Konkuk University and funded by the Ministry of Science, ICT and Future Planning [NRF-2016M3A9B6918892].

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