Bimetallic Ag–Au nanoparticles as pH dependent dual sensing probe for Mn(II) ion and ciprofloxacin

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Bimetallic Ag-Au nanoparticles as pH dependent dual sensing probe for Mn(II) ion and ciprofloxacin Jaise Mariya George , Ragam N. Priyanka , Beena Mathew PII: DOI: Reference:

S0026-265X(19)33682-3 https://doi.org/10.1016/j.microc.2020.104686 MICROC 104686

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Microchemical Journal

Received date: Revised date: Accepted date:

27 December 2019 24 January 2020 2 February 2020

Please cite this article as: Jaise Mariya George , Ragam N. Priyanka , Beena Mathew , Bimetallic Ag-Au nanoparticles as pH dependent dual sensing probe for Mn(II) ion and ciprofloxacin, Microchemical Journal (2020), doi: https://doi.org/10.1016/j.microc.2020.104686

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Highlights 

Eco-friendly synthesis of mixed silver and gold nanoparticles using ((Ag-Au)mixNP) using β-cyclodextrin.



(Ag-Au)mixNP are effective in the UV-vis. spectroscopic and electrochemical sensing of Mn(II) ions and ciprofloxacin.



The detection limits of Mn (II) ion by optical and electrochemical methods were 18.40 and 8.42 nM, respectively.



The limit of detection of CIP were found to be 10.26 and 7.24 nM for optical and electrochemical methods, respectively.



The real sample analysis by these methods are also applicable.

Bimetallic Ag-Au nanoparticles as pH dependent dual sensing probe for Mn(II) ion and ciprofloxacin Jaise Mariya George, Ragam N. Priyanka and Beena Mathew* School of Chemical Sciences, Mahatma Gandhi University, Kottayam-686560, Kerala, India Email: [email protected] Abstract A facile and eco-friendly method for the synthesis of bimetallic nanoparticles of two coinage metals such as silver and gold ((Ag-Au)mixNP) are detailed in this paper. β-cyclodextrin mediated microwave method was used for the synthesis of bimetallic nanoparticles in aqueous medium. Under the optimal conditions, the addition of Mn(II) ion and ciprofloxacin (CIP) changed the colour and surface plasmon resonance of the (Ag-Au)mixNP. The pH dependent changes associated with the introduction of CIP and Mn(II) ion in (Ag-Au)mixNP were studied using various characterization techniques such as UV-vis., FT-IR, XRD, zeta potential, dynamic light scattering, transmission electron microscopy, EDAX and electrochemical techniques. The host-guest interaction and the corresponding morphological changes of bimetallic nanoparticles induced the aggregation of nanoparticles resulting in a visual colour change of the brick red colour of (Ag-Au)mixNP. The electrochemical behaviour of the (Ag-Au)mixNP/AuE electrode in presence of Mn(II) ion and CIP is a highly sensitive detection method. The detection limits of Mn (II) ion by optical and electrochemical methods were 18.40 and 8.42 nM, respectively. In the case of CIP, these limits were found to be 10.26 and 7.24 nM, respectively. The successful monitoring of Mn(II) ion and CIP were possible in real samples with optical and electrochemical methods.

1. Introduction Metal nanoparticles (NP) are widely studied due to its diverse applications in various fields. Among metal nanoparticles, silver and gold nanoparticles are of great attention due to their catalytic activities, optical properties, bio-compatibility, and ease of synthesis [1-3]. The surface plasmon resonance of these nanoparticles make them available for cancer therapy [4], bio-imaging [5] and surface-enhanced Raman scattering [6]. Due to the blending of two metals, bimetallic nanoparticles (BNP) have improved properties [7]. The improved catalytic, optical and electrical properties of BNP strongly depend on its size, shape and composition [8-10], which is used in catalysis, photonics, optoelectronics and pharmaceutical applications [11-13]. Numerous techniques have been accounted for the synthesis of Ag-Au BNP. Water (single phase) [9] and toluene-water (bi-phasic) medium was [14] used for the synthesis of Ag-Au BNP. Reduction by NaBH4 [9], sodium citrate [15] and hydrazine [16] with support of metal salts were also used for the synthesis of Ag-Au bimetallic NP. In addition, methods including laser irradiation [17], sputter deposition [18], heating [19], sonochemical [20], polymer stabilized [21], biosynthesis [22, 23] and microwave [24] techniques were also used for the Ag-Au BNP. Ag-Au bimetallic NP based electrochemical sensor was developed for the detection of anthracene [25], H2O2 [26], pyrene [7] due to the high surface to volume ratio of BNP [27]. The high stability of Au nanoparticles and plasmonic property of it could be integrated to act as a colorimetric probe [28] for the detection of Hg(II) [29, 30], Pb(II) [30],

Co(II) [31] and cyanide ions [32]. The slight change in the SPR band of BNP highly dependent on the dimensional shell-to-core ratio [32] of Ag-Au that developed obvious colour or spectral change to use them as a colorimetric probe. Thus, BNP based sensing probes provide good stability, low detection background and good sensitivity assays. The excellent in vitro activity against wide varieties of both gram positive and gram negative bacteria, flouroqinolones have wide acceptance in hospitalized and community patients. Ciprofloxacin (1-cyclopropyl-6-fluoro-1, 4 dihydro- 4-oxo-7-(1-piperazinyl)-3 quinoline carboxylic acid) is a commonly used second generation flouroquinolone for the treatments of gastrointestinal, respiratory, urinary, ocular, and skin infections [33]. CIP has easily got absorbed and distributed through body fluids and tissues. The undeniable application of CIP is effective to control and prevent diseases in agricultural systems. However, CIP possesses low biodegradability [34] and has been found in polluted river water [35], water-bodies near to pharmaceutical industries and hospitals [36, 37] and also in soil [38]. Even the low concentration of the accumulation and the existence of this drug cause not only environmental contamination, but also may induce the antibiotic resistance in bacterial communities. Thus, the detection of CIP is widely studied due to its wide pharmaceutical applications and health issues generated from environmental impact. Several methods have been reported for the detection CIP including HPLC [39], micellar liquid chromatography [40], turbidimetry [41], spectrofluorometry [42] and electrochemical analysis [43-45]. Electrochemical strategy of detection is a widely adequate method owing to the high sensitivity in short analysis time. But, the selectivity of this method is low due to the interference of different compounds, which can be eliminated using suitable electroactive catalysts [46].

Manganese is an ubiquitous transition metal on the earth's shell [47]. Manganese is a fundamental element for enzymatic metabolism, however it’s higher concentration cause adverse impact accompanying with the development of Parkinson’s disease and disrupted neurological function in children [48, 49]. As per the ATSDR (Agency for Toxic Substances and Disease Registry), the permissible amount of manganese is 50 ppb (0.91 μM) in drinking water [50]. Anthropogenic sources of manganese in water-bodies are from mining, steel production and refining of manganese alloys [51-53]. Manganese evolutions are also from fertilizers and use of fungicides such as mancozeb and maneb [52]. Many analytical methods, including atomic absorption spectrometry (AAS) [54], coprecipitation [55], colorimetry [56], coupled plasma mass spectrometry (ICP-MS) [57], and electrochemistry [47, 58] have been

applied for the sensing of manganese. Electrochemical method of analysis is suitable for the detection of Mn(II) ion due to the high sensitivity and short analysis time. The microwave-assisted method is rapid, easy and reliable for the synthesis of metal nanoparticle synthesis [1-3]. This method is also used for the synthesis of bimetallic nanoparticle in a biosynthetic way [26]. β-Cyclodextrin (β-CD) was used for the synthesis of silver, gold and Ag-Au core shell nanoparticles. β-CD is non-toxic and water soluble cyclic oligosaccharide with hydrophilic exterior and less hydrophilic inner cavity, and abilities to form guest-host inclusion complexes [59]. Cyclodextrin associated metal nanoparticles are used for colorimetric sensing of metal ions [60], melamine [61] and cyanide [62]. Cyclodextrin based composite is also a suitable platform for electrochemical sensing due to fast electron transfer [44, 45]. This paper mainly describes the pH dependent sensing of both Mn(II) ion and CIP by optical and electrochemical approaches with the support of microwave assisted synthesis of (Ag-Au)mixNP using β-CD in aqueous medium. 2. Materials and methods 2.1 Materials Silver nitrate and metal salts (Pb(NO3)2, HgCl2, CdCl2, CuCl2.2H2O, CrCl3.6H2O, MnCl2.4H2O, ZnCl2, NiCl2.6H2O) were obtained from Merck (India). HAuCl4.3H2O, βcyclodextrin and ciprofloxacin hydrochloride were procured from Sigma-Aldrich. All chemicals used were of analytical grade and used without any further purification. Millipore water was used during the course of experiments. 2.2 Apparatus All optical studies were recorded by UV-vis. spectrophotometer (UV-2450 Shimadzu, Japan) in the range of 200-800 nm at regular intervals of time. The FT-IR spectra were recorded using Perkin-Elmer spectrophotometer in the range of 4000-400 cm-1. The crystallographic studies of (Ag-Au)mixNP and its complex with Mn(II) ion and CIP were carried out by PANalytical XPERT-PRO. The morphological studies were carried out by HRTEM JEOL JEM-2100 model tunnelling electron microscope attached with an energy dispersive X-ray spectrometer. Particle size and zeta potential analyses were carried out using Horiba SZ-100 scientific nanoparticle analyzer. Electrochemical studies were done by using SP-200 Biologic electrochemical workstation. All electrochemical measurements were carried out using a conventional three-electrode system. A modified gold electrode (AuE), a

platinum wire, and a saturated calomel electrode were employed as the working, auxiliary and reference electrodes, respectively. 2.3 Synthesis of (Ag-Au)mix nanoparticles((Ag-Au)mixNP) The procedure for the synthesis of (Ag-Au)mix nanoparticles Water (12 mL) was mixed with 4 mL of 0.01 M β-CD solution and 300 μL of 1M NaOH solution. To this, 2mL of 1 mM AgNO3 solution was added and placed in a domestic microwave oven with a frequency of 2450 MHz (800 W). This solution was subjected to microwave irradiation for 1 minute. The colourless solution changed into dark yellow with the formation of silver nanoparticles. To this, 7 mL of 1 mM HAuCl4 solution was quickly added and again microwave irradiated for 1 minute. The colour of the solution then changed into a brick red colour. The UV-vis. absorption spectra was used to monitor each experiment in order to investigate the formation of Ag-Au mix nanoparticles ((Ag-Au)mixNP). The colloidal solution of (Ag-Au)mixNP solution was kept at 4°C for further studies. 2.4 Optical sensing of manganese and ciprofloxacin For the optical sensing of Mn(II) ion, 2 mL of the (Ag-Au)mixNP solution was mixed with 100 μL of 1 mM MnCl2. 6H2O solution and the pH was maintained at 8.9. This solution was shaken for 10 minutes at room temperature. As a result, the colour of this solution was changed from brick red to rosy brown colour due to the interaction of nanoparticles with Mn(II) ion. In a similar way 100 μL of 1 mM ciprofloxacin drug was mixed with 2 mL (AgAu)mixNP solution and shaken for 8 minutes at a pH of 8.2 at room temperature. A visual colour change from brick red to violet occurred on complexation of CIP. The observed changes in the surface plasmon resonance were monitored with UV-vis. spectrophotometer. 2.5 Fabrication of (Ag-Au)mixNP/AuE for the sensing of Mn(II) ionand CIP The cleaning of the bare AuE was carried out by carefully polishing the electrode with 0.5 μM alumina slurry on chamois leather and ultrasonicated in ethanol-water mixture to remove unwanted substances adhered on the surface of the electrode. Electrode was again washed thoroughly with ultrapure water. A small aliquot of the (Ag-Au)mixNP solution was casted on the dried AuE electrode surface and dried under an IR lamp for few minutes to obtain Ag-AumixNP/AuE. After this, the modified electrode was readily used for electrochemical studies that include cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. A stock solution of 0.05 μM Mn(II) ion and CIP was made

by dissolving the required amount in ultrapure water. The stock solution was added to the electrochemical cell, which contain 0.01 M PBS solution. Cyclic voltammetric runs were carried out by applying sweeping potential from 200 to 1300 mV at a scan rate of 100 mV/s in 0.01 M PBS (pH 7.9) solution at room temperature for Mn(II) ion sensing. For the sensing of CIP, potential from 700 to 1300 mV was applied at a scan rate of 100mV/s in 0.01 M PBS (pH 6.2) solution. The modified electrodes were optimized under different conditions with respect to a reference electrode (Ag/AgCl) for the sensing of Mn(II) ion and ciprofloxacin. 3. Results and discussions Surface plasmon resonance depends on several factors such as size and shape of the metallic nanoparticles and its surrounding environments. The changes in the colloidal system of nanoparticles could be ascertained by UV-vis. spectroscopy. In this green approach of synthesis of (Ag-Au)mixNP, β-CD acted as both capping and reducing agent [63]. The high degree of the absorption profile of nanoparticles indicates the reproducibility of the β-CD assisted system. In the initial stage, the appearance of a high intense sharp peak at 402 nm indicates the formation of uniformly shaped and homogenously well dispersed silver nanoparticles with relatively small size [63]. During the formation of (Ag-Au)mixNP, different amount of 1 mM HAuCl4 were added and the changes were recorded (Fig.1). For 1-9 mL of the HAuCl4 solution, the peaks were shifted to longer wavelength from 402 nm. This red shift is attributed to the formation of (Ag-Au)mixNP.

Fig. 1.UV-vis. spectra of (a) formation of (Ag-Au)mix NP and (b) photographic image of (AgAu)mixNP with different concentration of gold salt UV-vis. spectrum of pure AuNP obtained using the same method exhibited a sharp peak at 521 nm, which is the characteristic peak of gold nanoparticles with small size and uniform shape [60]. In the presence of 7 mL HAuCl4 (1 mM) solution, an intense broad peak obtained at 471 nm, which is midway between the absorption maxima for pure AgNP and AuNP. In addition, the change of the colour of the solution from yellow to deep brick red colour also account for the formation of (Ag-Au)mixNP, and the pure AuNP showed a pink colour in the colloidal system. Both Ag(I) ions and Au(III) ions were reduced into Ag(0) and Au(0) nanoparticles, respectively by the primary hydroxyl groups present in the smaller rim of β-CD and oxidised into carboxylic acid. This carboxylic acid groups stabilize (AgAu)mixNP through their strong interaction with both Ag and Au nanoparticles [61]. 3.1 Characterization FT-IR analysis The FT-IR spectra of various samples are given in Fig.2.

The (Ag-Au)mixNP

exhibited two characteristic peaks at 3297 and 1635 cm-1 due to the O‒H stretching vibrations of β-CD [61]. The appearance of bands at 2935 and 935 cm-1 indicated the C-H stretching

and skeletal modes of vibrations of α-1→4 linkage of β-CD in (Ag-Au)mixNP. The bands observed at 751, 697 and 577 cm-1 are allocated to the pyranose ring vibrations [64]. The peak at 1428 cm-1 indicated the O‒H bending in carboxylic acid, suggesting the oxidation of O‒H groups in the -CD for the formation of (Ag-Au)mixNP. In presence of Mn(II) ion and CIP, the relative intensities corresponding to C–H skeletal and pyranose ring stretching vibrations were reduced or shifted from (Ag-Au)mixNP. The O‒H stretching vibrations were merely shifted in the presence of Mn(II) ion. The peak around 1420 cm-1 from (Ag-Au)mixNP is drastically shifted in the presence Mn(II) ion suggesting the binding of carboxyl group with Mn(II) ion. This carboxyl group is merely shifted in the presence of CIP. The FT-IR band at 3310 cm-1 corresponding to the O‒H stretching vibrations of (Ag-Au)mixNP/CIP is shifted from 3297 cm-1 of Ag-AumixNP, suggesting the interaction between the nanoparticles and CIP. In addition, the observed difference in the peak intensities at 1642 cm-1 of (Ag-Au)mixNP in presence of CIP is attributed to the involvement of hydrogen bonding in sensing.

Fig. 2. FT-IR spectra of (Ag-Au)mixNP, (Ag-Au)mixNP/Mn(II) and (Ag-Au)mixNP/CIP.

XRD analysis The crystallographic studies of the (Ag-Au)mixNP were observed by XRD measurements (Fig.3). Four peaks were obtained at 2 angles of 38.11°, 44.66°, 64.87° and 77.73°. These peaks correspond to (111), (200), (220) and (311) crystal planes of face centred cubic Ag or Au (JCPDS #04-0784 file or JCPDS #04-0783 file) [1]. Obviously, the chemical

instability of Ag element was overcome by the incorporation of Au element. Thus the superiority of the (Ag-Au)mixNP contrast with monometallic AgNP is confirmed [65].

Fig. 3. XRD patterns of (Ag-Au)mixNP, (Ag-Au)mixNP/Mn(II) and (Ag-Au)mixNP/CIP In the presence of Mn(II) ion, the peak position and intensities were decreased and shifted in the XRD pattern. This suggests the effective interaction of (Ag-Au)mixNP with Mn(II) ion. Similarly interaction of CIP with (Ag-Au)mixNP was also observed through XRD studies in which, the sharp intensities of peaks were decreased. Morphological analysis Morphology and particle size of (Ag-Au)mixNP were followed using HR-TEM analysis (Fig.4a1, 4a2, and 4a3). Most of the nanoparticles appeared as in fused state and some of the nanoparticles are having core-shell structures. From the particle size histogram of (Ag-Au)mixNP (Fig.4b), it is clear that most of the nanoparticles are quasi spherical with a mean diameter of 25.24 nm. SAED pattern (Fig.4c) exhibited characteristic ring patterns, suggesting the crystallinity of the (Ag-Au)mixNP with face centred cubic (fcc) lattice. The well distinct inter-particle separation without any direct physical contact in SAED pattern indicate the covering of cyclodextrin around (Ag-Au)mixNP. The (Ag-Au)mix nanoparticles exhibit a multiple twinned structure representing fused nanosized particles in fcc lattice structure [66].

Fig.4.TEM images of (a1, a2 and a3) (Ag-Au)mixNP with different magnifications, (b) SAED pattern of (Ag-Au)mixNP and (c) particle size histogram of (Ag-Au)mixNP The TEM images of (Ag-Au)mix/Mn(II) (5a1, 5a2 and 5a3) exhibited lumps of nanoparticle aggregation with fused arrangement. This kind of interaction is probably due to the affinity between the core of the (Ag-Au)mixNP with Mn(II) ions. Nori The aggregation was induced by non-covalent interactions between the β-CD modified nanoparticles and CIP drug molecules [67].

Fig.5. TEM images of (a1, a2 and a3) (Ag-Au)mixNP/Mn(II) and (b1, b2 and b3) (AgAu)mixNP/CIP under different magnifications.

DLS and zeta potential measurements The dynamic light scattering (DLS) technique for hydrodynamic diameter and zeta potential analysis for surface charge measurements were carried out for (Ag-Au)mixNP, (AgAu)mix/Mn(II) and (Ag-Au)mix/CIP. The particle size of the (Ag-Au)mixNP is found to be 61.35 nm from DLS measurements (Fig.S1a). The higher value of particle size in DLS measurements is due to the hydrodynamic radius, whereas the results gained from TEM image gave information about the diameter of the core of the nanoparticle [68]. DLS and zeta potential values of (Ag-Au)mixNP, (Ag-Au)mixNP/Mn(II) and (Ag-Au)mixNP/CIP are gathered in Table1. The hydrodynamic radius by dynamic light scattering of (Ag-Au)mixNP, (AgAu)mixNP/CIP and (Ag-Au)mixNP/Mn(II) are displayed in Fig. S1 (a, b and c). The increase of the size of (Ag-Au)mixNP on the addition of Mn(II) or CIP is due to the aggregation of nanoparticles. The extent of interaction is higher for CIP than Mn(II) ion due to the difference in the effective of interaction between the Mn(II) and CIP with (Ag-Au)mixNP. The zeta potential value for (Ag-Au)mixNP, (Ag-Au)mixNP/Mn(II) and (Ag-Au)mixNP/CIP are -12.50, 24.28 and -15.24 mV respectively, denoting the negative surface charges. Relative variation of zeta potential on the addition of Mn(II) ion and CIP are due to the aggregation induced change in surface charges.

Table 1. DLS and zeta potential values of (Ag-Au)mixNP, (Ag-Au)mixNP/Mn(II) and (AgAu)mixNP/CIP

Sample

DLS values (nm)

Zeta potential (mV)

(Ag-Au)mixNP

61.35

-12.50

(Ag-Au)mixNP/Mn(II)

386.46

-24.28

(Ag-Au)mixNP/CIP

1631.97

-15.24

EDAX analysis The elemental composition of (Ag-Au)mixNP and the effect of binding with Mn(II) ion and CIP were studied using energy dispersive X-ray analysis (EDAX). The EDAX spectrum of (Ag-Au)mixNP exhibited characteristic signals at 2.34, 8.51, 9.71 and 11.48 keV for gold and 2-4 keV for silver Fig. S2a [1]. Besides, the higher peak intensity of Au element compared to that of Ag element is predictable with the volume ratio (2:7) utilized in the synthesis of (Ag-Au)mixNP. In the EDAX spectrum for (Ag-Au)mixNP/Mn(II) (Fig. S2b), the peaks around 0.67 and 5.91-6.82 keV verified the complexation of manganese. The peak of copper is from the copper grid used in EDAX analysis.

3.2 Optical sensing of Mn(II) ion using (Ag-Au)mixNP The addition of Mn(II) ion induces colour change of (Ag-Au)mixNP solution and the SPR peak at 471 nm decreased and shifted to higher wavelength. (Ag-Au)mixNP were stable at room temperature and their induced complexation occurred on the addition of Mn(II) ion. Cyclodextrin based silver and gold nanoparticles were used for the sensing of various metal ions [60, 78]. In basic medium, the deprotonation of the secondary hydroxyl group of β-CD occurred and it results in the complexation of Mn(II) ion. The formation of (Ag-Au)mixNP by β-CD also occurred in the pH range (10.5-11) and hence the deprotonated secondary ‒OH groups of β-CD are available for complexation with metal ions [60]. Thus, the addition of metal ions into the system resulted in a red shift in the surface plasmon resonance. The shift in the absorption band and visual colour change of the nanoparticle solution ascribed aggregation of nanoparticles in the presence of metal cations [69].

Effect of concentration The extent of the shift in the surface plasmon resonance peak depends on the concentration of metal ions in the (Ag-Au)mixNP solution [70]. Under the optimal conditions, the synthesized colorimetric assay was utilized for quantitative sensing of Mn(II) ions. The colour of the colloidal nanoparticle solution was changed from brick red to rosy brown with the increase in the concentration of Mn(II) ion from 0.02 to 0.20 μM. The UV-vis. absorption spectra of (Ag-Au)mixNP with different concentration of Mn(II) ion is depicted in Fig. 6. The absorbance at 471 nm decreased and shifted to higher wavelength with increasing concentration of Mn(II) ions. So, the complexation of metal ions with the secondary hydroxyl groups present on the surface of the NP could bring the (Ag-Au)mixNP close together [60]. This resulted in the complex formation of Mn(II) ion with (Ag-Au)mixNP resulting in the aggregation of nanoparticles. The absorbance at 471 nm (A471) was chosen for the quantitative determination of Mn(II) ions. The limit of detection (LOD) by (Ag-Au)mixNP for Mn(II) ions was obtained from the linear plot of the calibration curve and found to be 18.40 nM (S/N=3)(Inset. Fig. 6).

Fig. 6.Variation of the UV-vis. absorption spectrum of (Ag-Au)mixNP on the addition of different concentrations of Mn(II) ion. Inset: linear plot of concentration vs. absorbance at 471 nm. Effect of pH The pH of the solution can influence the nature of analyte, its aggregation, and surface charge of NP and subsequently the analytical signal. The effect of pH was studied in the range 6.5 - 11.7 by the addition of dilute acid or alkali on the interaction of (Ag-Au)mixNP with Mn(II) ion (Fig.7). β-CD based silver or gold nanoparticles are unstable in acidic pH [65, 66]. With the increase in pH, the absorbance ratio at 471 to 505 nm increased and

reached a maximum at 8.90 and further decreased. At higher pH, Mn(II) ions precipitate as manganese hydroxide [47].

Fig. 7. Effect of pH on the complexation of Mn(II) ion with (Ag-Au)mixNP

Selectivity studies The selectivity is another significant factor for the sensing of Mn(II) ions. So as to achieve the selectivity of this assay, the optical response of environmentally significant metal ions such as Cd(II), Co(II), Cr(III), Pb(II), Ni(II),Cu(II), Zn(II) and Hg(II) ions with double the concentration of Mn(II) ion (0.1 M) were measured under the same condition with (AgAu)mix NP (Fig.8a). The photographic image (Fig.8b) demonstrates the colour change of (Ag-Au)mixNP upon the addition of different metal ions. The addition of environmentally relevant metal ions to Ag-AumixNP did not produce any significant colour change, while in the presence of Mn(II) ions a rosy brown colour was developed for the nanoparticle solution. According to Fig.8a, the addition of various metal ions did not produce obvious absorbance changes of the (Ag-Au)mixNP solution with an exception of Mn(II) ions. This is due to the complexation of metal ions with the secondary hydroxyl groups present on the surface of the NP could bring the (Ag-Au)mixNP close together [60]. This resulted in the complex formation of Mn(II) ion with (Ag-Au)mixNP resulting in the aggregation of nanoparticles. Thus, the suggested optical method exhibited good selectivity for the sensing of Mn(II) ions.

Fig. 8. UV-vis. absorption spectra of (a) (Ag-Au)mixNP on the addition of various metal ions. Photographic image of (b) (Ag-Au) mixNP in the presence of different metal ions

3.3 Optical sensing of CIP using (Ag-Au)mixNP The colorimetric changes occurred with the addition of CIP into the (Ag-Au)mixNP and the SPR peak at 471 nm decreased with a shift to higher wavelength. -CD is a water soluble cyclic oligosaccharide with hydrophilic exterior and less hydrophilic inner cavities. The less hydrophilic inner cavity of β-CD forms inclusion complex via guest/host binding with CIP mainly through hydrophobic, dipole - dipole and Van der Waals forces [67]. This additive effect may facilitate the recognition of CIP through the host-guest interaction of less hydrophilic cavities in β-CD and CIP that induced the aggregation of nanoparticles. Thus, the addition of CIP in to the system resulted in bathochromic shift of the surface plasmon resonance.

Effect of concentration Effect of concentration of CIP with (Ag-Au)mixNP was attained by changing the concentration of CIP from 0.02 - 0.2 μMin aqueous solution of (Ag-Au)mixNP solution. The extent of SPR peak shifted with increase in concentration of CIP. As concentration of the CIP increased, a visual change in colour of the solution from brick red to violet was observed. As the concentration increased, the absorption peak at 471 nm decreased with blue shift (Fig. 9). In the guest-host interaction of β-CD with CIP, nanoparticles induces the aggregation

through non-covalent interactions. The absorbance at 471 nm (A471) was chosen for the quantitative determination of CIP. The limit of detection (LOD) for CIP by (Ag-Au)mixNP was obtained from the linear plot of the calibration curve (Inset: Fig. 9) and is found to be 10.26 nM (R2=0.990).

Fig. 9. UV-vis. absorption spectra of (Ag-Au)mixNP on the addition of different concentration of CIP, Inset: linear plot of concentration versus absorbance at 471 nm

Effect of pH The influence of pH on the sensing of CIP by (Ag-Au)mixNP is shown in Fig. 10. The ratio of A471/A583 at 0.1 μM CIP increased with increase in pH (6.3 - 11.5) and reached a maximum at 7.8. Further increase in pH caused a decrease in sensing. The variation in sensing with pH ascribed to the pH dependent interaction of CIP with (Ag-Au)mixNP. Ciprofloxacin exist as a zwitter ionic compound. The cationic form found at pH < 6.1 and anionic form found at pH > 8.7 [76]. When the pH value was very low, β-CD based silver and gold nanoparticles are unstable [61, 66]. As the pH increased, the solubility of CIP also decreased [72] and the zwitter ionic form exists in pH between 6.1 and 8.7, which promote the sensing of CIP. The optimum pH was found to be 8.1 for the sensing of CIP.

Fig. 10. Effect of pH on the sensing of CIP by (Ag-Au)mixNP

Selectivity studies In order to investigate the specificity of the proposed analytical system, the optical response of the solution mixture was studied with different structural analogous, organic compounds and inorganic salts (Fig. 11a). Solutions of double the concentration of CIP (0.1 M) such as (A) levofloxacin, (B) quinine, (C) hydroxy chloroquine, (D) 4-acetamidophenol, (E) glucose, (F) glycine, (G) NaCl, (H) CaCl2, and (I) KCl were added and examined under the optimized conditions at room temperature. It could be observed that the (Ag-Au)mixNP solutions remained brick red with the addition of other interfering compounds except CIP (Fig.11b). The absorption spectra of (Ag-Au)mixNP solution in presence of other compounds remained the same and only in the case of CIP shifted to higher wavelength. This is due to the recognition of CIP through the host-guest interaction of hydrophobic cavities in β-CD and CIP that induced the aggregation of nanoparticles [67]. These results confirmed that (AgAu)mixNP based colorimetric sensing exhibited good specificity towards CIP.

Fig. 11. (a) UV-vis. absorption spectra of (Ag-Au)mixNP on the addition of various interfering and structurally similar substances. (b) Photographic image of (Ag-Au)mixNP in presence of various interfering and structurally similar substances. (A) levofloxacin, (B) quinine sulphate, (C) hydroxychloroquine sulphate, (D) 4-Acetamidophenol, (E) glucose, (F) glycine, (G) NaCl, (H) CaCl2, and (I) KCl 3.4 Electrochemical sensing of Mn(II) ionby (Ag-Au)mixNP/AuE Cyclic voltammetric (CV) studies using three electrode system were carried out in the potential range from 200 to 1400 mV at a scan rate of 100 mV/s in PBS with pH 7.9 for characterizing the electrochemical behaviour of Mn(II) ion using (Ag-Au)mixNP/AuE. The drop casting method was chosen for the modification of gold electrode with (Ag-Au)mixNP. The electrochemical behaviour of the modified and unmodified AuE in the presence of Mn(II) ion is depicted in Fig.12. The redox peak in the bare AuE was due to the slow electron transfer. Both the oxidation and reduction currents increased after modification with (AgAu)mixNP. This is attributed to the electrical conductivities of both silver and gold nanoparticles at the surface of the electrode. With the addition of Mn(II) ion, the redox peak increased with a negative shift in the reduction peak current. This is attributed to the binding of Mn(II) ion to (Ag-Au)mixNP in the gold electrode and resulting complexation enhanced the redox current on the surface of the electrode.

Fig. 12. Cyclic voltammograms of bare and modified gold electrode in the absence and presence of Mn(II) ion in 0.1M PBS solution

Effect of scan rate The

effect

of

scan

rate

on

the

electrochemical

behaviour

of

(Ag-

Au)mixNP/AuE/Mn(II) was studied by varying the scan rate from 20 to 200 mV/s in the potential range from 200 to 1400 mV (Fig. 13). As the scan rate increased, the cathodic and anodic peak currents shifted to slight lower and higher potential, respectively. The linear plot of scan rate versus peak current indicated that the redox process is a surface confined process [75] (Inset: Fig.13). The change in the peak position with an increase in scan rate suggests that the redox reaction is quasi-reversible [76]. The proportion of cathodic to anodic peak current is approximately unity as expected for surface confined sites that trigger the fast electrode process [77].

Fig. 13.Cyclic voltammogram of (Ag-Au)mixNP/AuE/Mn(II) at different scan rates. Inset: linear plot of scan rate versus peak current

Effect of pH and accumulation time

Fig. 14 Effect of (a) pH on the peak current of (Ag-Au)mixNP/AuE in 0.1M PBS, and (b) accumulation time of (Ag-Au)mixNP/AuE in 0.05 μM Mn(II) ion The influence of pH on the sensing of Mn(II) ion using Ag-AumixNP/AuE was examined using phosphate buffer solution by varying the pH from 5.7 to 10.5. The optimum pH for the electrochemical sensing of Mn(II) ion using the modified electrode was found to be 7.9 (Fig.14a). At more basic pH, Mn(II) ion precipitated as insoluble manganese hydroxide [47]. At low pH, the peak current decreased because of the excess hydrogen ion in solution [47]. In addition, cyclodextrin modified nanoparticles are unstable at lower pH. Therefore, PBS with pH 7.9 was selected as optimum medium for electrochemical investigations. In order to determine the accumulation time for Mn(II) ion sensing, the

voltammetric response of the (Ag-Au)mixNP/AuE in 0.1 M PBS buffer was examined at regular time intervals (Fig.14b). The peak current increased with increase in time and reached maximum at 4 minutes. After four minutes, the current response decreased and remained constant. Concentration To evaluate the sensitivity of the sensor, various concentrations of Mn(II) ion (0.010.05 μM) solutions were used and the differential pulse voltammetric measurements were conducted with pulse width 200 ms and pulse amplitude 28 mV in PBS solution of pH 7.9. As the concentration of Mn(II) ion increased, the peak current signals also increased (Fig.15). In the inset of Fig.15, a linear correlation between peak current and Mn(II) ion concentrations was obtained in the range from 0.01-0.05 μM with a detection limit of 8.42 nM. The result was mainly due to the enhancement of electrical conductivity of the (Ag-Au)mixNP modified working electrode.

Fig. 15 DPVs of (Ag-Au)mixNP/AuE at different concentrations of Mn(II) ion ranging from 0.01 to 0.05 μM. Inset: linear plot of concentration versus peak current

Selectivity studies The specificity of the fabricated sensor towards Mn(II) ion was achieved by selecting different metal cations such as Cd(II), Co(II), Cr(III), Pb(II), Ni(II),Cu(II), Zn(II) and Hg(II) with double the concentration Mn(II) ion and monitored their electrochemical signals using DPV under same conditions. The bar diagram (Fig.16) suggests that the (Ag-Au)mixNP/AuE selectively detect Mn(II) ion among various metal ions even at high concentration. The

interaction of the secondary hydroxyl groups present on the surface of the NP with Mn(II) ion could bring the (Ag-Au)mixNP close together [60]. This resulted in the complex formation of Mn(II) ion with (Ag-Au)mixNP resulting in the aggregation of nanoparticles. Hence, the response obtained for these metal ions were less compared with that of 0.1 μM Mn(II) ion.

Fig.16. Peak currents from DPV measurements of (Ag-Au)mixNP/AuE in presence of various metal ions

3.5 Electrochemical sensing of CIP using (Ag-Au)mixNP/AuE The electrochemical behaviour of AuE modified with (Ag-Au)mixNP in presence of CIP was studied using cyclic voltammetric technique under the potential range from 700 to 1400 mV with a scan rate of 100 mV/s in 0.1 M phosphate buffer solution (pH 6.5). Drop casting method was adopted for the fabrication of (Ag-Au)mixNP/AuE. Fig.17 is the cyclic voltammogram obtained for bare, (Ag-Au)mixNP/AuE and (Ag-Au)mixNP/AuE/CIP in 0.1 M PBS. The bare AuE exhibited a small current due to slow mass transfer.

Fig. 17.Cyclic voltammograms of bare and (Ag-Au)mixNP modified AuE in the absence and presence of CIP in 0.1 M PBS solution After the modification of gold electrode with (Ag-Au)mixNP, the peak current increased. This is attributed to the high electrical conductivity of the silver and gold nanoparticles. After the addition of 0.05 μM CIP, the oxidation peak current increased at a potential of 0.89 V. The electrochemical oxidation of CIP indicated irreversible electrode process. The structure of CIP has secondary amine group which is a strong electron acceptor and the irreversible oxidation of CIP involves two electron and two proton transfer process [78, 39]. The high electrical conductivity of nanoparticles and the guest-host interaction of βCD with CIP attributed to the effective sensing of CIP by (Ag-Au)mixNP/AuE.

Effect of scan rate

Fig.18. (a) Cyclic voltammogram of (Ag-Au)mixNP/AuE/CIP at different scan rates and (b) the linear plot of scan rate versus peak current Impact of scan rate on the oxidation peak current and potential gave information about the kinetics of electrode reaction. CV experiments conducted at different scan rates (40-200 mV/s) were used to examine the electron transfer process of CIP on the (AgAu)mixNP/AuE in 0.1 M PBS at pH 6.2. In the recorded CV run, the oxidation peak current increased with increase in scan rate with a slight positive shift in potential (Fig.18a). The linear plot of peak current versus scan rate revealed that the electrode process of CIP was adsorption controlled (Fig.18b).

Effect of pH and incubation time To estimate the optimal pH for the sensing of CIP, the pH of the PBS with 0.05 μM CIP varied in the range 4.2 - 9.2. As seen in Fig.19a, the oxidation peak current of CIP increased gradually with increase in pH and reached a maximum at 6.2. The proton

concentration supported the electro-active oxidation of CIP [77]. Further increase of pH from 6.2 to 9.3 resulted in a decrease of anodic peak current. Thus, PBS of pH 6.2 was chosen as the supportive electrolyte for further experiments. The dependence of accumulation time was studied on the electrochemical response of 0.05 μM of CIP in 0.1 M PBS (6.2) by (AgAu)mixNP/AuE and found to be 6 minutes (Fig.19b). This is because of the development of host-guest interaction between (Ag-Au)mixNP and CIP molecules.

Fig. 19.Effect of (a) pH on the peak current of (Ag-Au)mixNP/AuE in 0.1 M PBS and (b) accumulation time of (Ag-Au)mixNP/AuE in 0.05 μM CIP

Effect of concentration To evaluate the analytical utility of the fabricated sensor for the detection of CIP, DPV method was adopted with pulse width 200 ms and amplitude as 30 mV, respectively in PBS with different concentrations of CIP (0.01 - 0.05 μM). Quantitative assessment depends on the linear relationship between peak current and concentration. From the Fig.20, it is obvious that the peak current increased with an increase in concentration of CIP. The inset of Fig.20 is the linear fit of peak current with concentration and the detection limit obtained is 7.24 nM (R2 = 0.99).

Fig. 20. DPVs of (Ag-Au)mixNP/AuE at different concentrations of CIP ranging from 0.01 to 0.05 μM. Inset: linear plot of concentration versus peak current

Selectivity studies

Fig. 21. Peak current from DPV measurements of (Ag-Au)mixNP/AuE towards various interfering and structurally similar compounds. (A) levofloxacin, (B) quinine, (C) hydroxy chloroquine, (D) 4-acetamidophenol, (E) glucose, (F) glycine, (G) NaCl, (H) CaCl2 and (I) KCl. In order to analyse the performance of the selectivity of (Ag-Au)mixNP/AuE for CIP, DPV measurements were carried out in presence of other interfering compounds and salts under identical conditions. The bar diagram (Fig.21) showed that the fabricated sensor exhibited high sensitivity towards CIP even at low concentration. The weak interactions generated among CIP and hydrophobic cavities of β-CD present in the nanoparticles system facilitate the host-guest interaction that responsible for the induced aggregation of nanoparticles [67]. This effective binding accountable for the selective sensing of CIP at a defenite pH with other interfering compounds and salts under identical conditions.

3.6 Real sample analysis To demonstrate the efficiency of the proposed sensor for the analysis of Mn(II) ion in real samples, water samples from the Meenachil river and well water from flood affected areas in Kottayam district, Kerala (India) were collected and analysed using atomic absorption spectroscopy to quantify the manganese ion content in them. The same samples when subjected to optical and electrochemical sensing approaches, the results obtained are given in Table S1. The results demonstrated the capability of the developed sensor for the accurate determination of Mn(II) ion in real water samples. The electrochemical detection by (Ag-Au)mixNP/AuE for Mn(II) ions showed better performance than the other reported methods [58, 47]. The validity of the proposed sensor was affirmed for pharmaceutical formulations utilizing optical and electrochemical techniques for the detection of CIP in its pharmaceutical samples. CIPRO XR (Ciprofloxacin hydrochloride -500 mg) was weighed and powdered. This powder was disintegrated in double refined water and separated. From this solution different concentrations (0.01-0.03 μM) were taken and the standard addition method was used for the detection of CIP. The results of real sample analysis are tabulated in Table S2. This sensor exhibits a better performance and is less expensive compared with other electrochemical techniques for the detection of ciprofloxacin (Table S3).

4. Conclusion Bimetallic nanoparticles of silver and gold were successfully synthesized by βcyclodextrin as the capping agent by microwave treatment in aqueous medium. βcyclodextrin provides a rational support for the suitable interaction of CIP and Mn(II) ion with (Ag-Au)mixNP under optimal conditions and the induced aggregation makes it as a suitable optical and electrochemical sensor for Mn(II) ion and CIP. In presence of other competing metal ions, Mn(II) ion exhibited high sensing performance with limit of detection of 8.42 and 18.40 nM by optical and electrochemical methods, respectively. This sensor offers a competitive platform for the optical and electrochemical determination of CIP with limit of detection 10.26 and 7.24 nM, respectively with good selectivity. The assay also displayed effective applications in real water and pharmaceutical samples. Acknowledgement

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