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Spherical silver nanoparticles as substrates in surface-enhanced Raman spectroscopy for enhanced characterization of ketoconazole
Materials Science and Engineering C 76 (2017) 356–364
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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Spherical silver nanoparticles as substrates in surface-enhanced Raman spectroscopy for enhanced characterization of ketoconazole Mutasem M. Al-Shalalfeh, Abdulmujeeb T. Onawole, Tawfik A. Saleh ⁎, Abdulaziz A. Al-Saadi Department of Chemistry, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 24 November 2016 Received in revised form 15 January 2017 Accepted 10 March 2017 Available online 12 March 2017 Keywords: Silver Ketoconazole SERS Computational
a b s t r a c t A new method was developed for the characterization and detection of ketoconazole using surface enhanced Raman spectroscopy (SERS) by designing substrates and performing the bands' assignments. Thus, spherical silver nanoparticles (Ag-NPs) were synthesized by a reduction method and designed as substrates for SERS application. The Ag-NPs were characterized using a scanning electron microscope, Fourier transformed infrared spectroscopy and a high-resolution transmission electron microscope. TEM results indicated that the average size of the Ag-NPs was 15 nm. The UV spectrum showed a maximum absorbance of Ag-NPs at about 400 nm. When Ag-NPs were used as substrates in SERS, the Raman spectra of KCZ showed a significant enhancement of the Raman bands. An important finding is a linear relationship between the logarithmical scale of KCZ concentration and the intensity of the SERS bands, for example at 1050 cm−1 of KCZ, which is due to the C\\N vibration. This was optimized and utilized to develop a calibration curve, which was then used for the detection of the KCZ in real pharmaceutical samples. The method has the advantages of a wide dynamic range with a high coefficient of determination and detection limit calculated based on the signal-to-noise ratio of 3, was 2.6 × 10−10 M and the limit of quantification was 7.8 × 10−10 M. The potential applications that take advantage of the high SERS sensitivity of this method are discussed for practical KCZ analysis where were quantified with this method. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Ketoconazole (cis-1-acetyl-4-{4-[[2-(2,4-dichloro-phenyl)-2-(1Himidazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl} piperazine,), is a broad-spectrum antifungal agent used as an agent against dermatophytes and yeast. The assaying of ketoconazole in pharmaceutical compounds and formulations is vital. Ketoconazole (KCZ) has been determined in pharmaceutical preparations by spectroscopic, chromatographic and electrochemical methods [1–5]. These methods have the disadvantage of being time and labor intensive and often involves the extraction of solvents, some of which are potentially toxic to humans and the environment. For these reasons, in recent years, the need of alternative methods is a challenge that has been discussed by several researchers [6]. Surface Enhanced Raman Spectroscopy (SERS) is an important technique for the identification and detection of solid, liquid, and gas samples in various applications. SERS is a highly sensitive and selective method when compared with Raman spectroscopy [6,7]. Recently, it has been used in many important research areas such as medical applications, analytical chemistry [8,9]. SERS has been studied both theoretically and experimentally. The first study, by ⁎ Corresponding author. E-mail addresses: tawfi[email protected], tawfi[email protected] (T.A. Saleh). URL: http://faculty.kfupm.edu.sa/CHEM/tawfik/ (T.A. Saleh).
http://dx.doi.org/10.1016/j.msec.2017.03.081 0928-4931/© 2017 Elsevier B.V. All rights reserved.
Fleischmann, was performed using pyridine absorbed at the surface of a silver electrode [10]. SERS is a method used to study bounding of the analyte to the substrate, and it is characterized by its high sensitivity and low detection limits [11]. SERS commonly refers to the phenomenon whereby Raman-signals from adsorbates on suitable surfaces are enhanced several times due to the excitation Surface Plasmon Resonance (SPR) on the surface of metals such as silver, gold, and copper [12,13]. The enhancement can be explained by two mechanisms: chemical mechanism and electromagnetic enhancement. The latter is considered the dominant effect due to the SPR [14–16]. This mechanism is sometimes called the Raman reflectance mechanism and it can also arise from modulated overlap between the molecule and surface orbitals. Metal nanoparticles have been widely used in SERS due to their unique properties, such as their size and shape [17–20]. Silver colloids are the most common type of SERS substrate; they exhibit large enhancement, a strong surface Plasmon polarization mode in the visible light range, and are relatively stable [21,22,23]. There are several methods to synthesize metal nanoparticles, including chemical methods such as chemical reduction and thermal decomposition [24], and physical methods, such as vapor deposition and microwave irradiation [25]. The reduction methods are the most commonly used for the synthesis of nanoparticles. The reduction method requires three main components: (i) a precursor like metal salt, (ii) a reducing agent
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like trisodium citrate, ethylene glycol, and sodium borohydride, and (iii) a stabilizing agent like vinyl pyrrolidone, dodecanoic acid, and oleylamine [26–28]. Silver nanoparticles (Ag-NPs) have been known to be used in the pharmaceutical industry based on their optical, electrical and thermal properties [29,30]. Ag-NPs have been used for treating various human diseases, due to the high surface area resulting from the ability of Ag-NPs to coordinate with legends [31,32]. The computational method is useful to investigate the design of new drugs and materials that are difficult to find or very expensive; further, it is useful to study the properties of molecules and the assignment of IR and Raman bands [33]. This method is based on mathematical algorithms, statistics, and databases to integrate chemical theory [34]. Ab initio, semiempirical and molecular mechanics numerical techniques were used to determine the geometry optimizations, potential energy surface calculations, and frequency calculation, as seen in the calculations [35–37]. The main goal of this study was to develop an efficient SERS method to determine the KCZ in pharmaceutical formulations. Thus, Ag-NPs were prepared, characterized and designed as substrates for SERS measurements. The method was optimized and applied for the detection of KCZ in commercial samples. The DFT calculations were carried out to obtain a detailed interpretation of the SERS spectra and to collect the vibrational assignment.
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pellet was prepared by mixing the sample and KBr with a ratio (1:100) [38]. FT-IR measurement was scanned at a range of wavelength from (400 to 4000) cm− 1 . He-Ne laser source operating at 0.5 W was utilized for sample excitation. 2.4. Surface-enhanced Raman spectroscopy (SERS) The SERS spectra of KCZ were obtained by a using Raman spectroscopy system, namely a Lab Ram HP Evolution Raman spectrometer equipped with an internal He-Ne 17 mW laser at a 633 nm excitation wavelength. SERS samples were prepared by using a 3:1 volume ratio of the KCZ solutions to the colloid in a cuvette. The parameters of the
2. Experimental 2.1. Chemicals and materials Ketoconazole (KCZ) named as ((±)-cis-1-Acetyl-4-(4-[(2-[2, 4dichlorophenyl]-2-[1H-imidazol-1-ylmethyl]-1,3-dioxolan-4-yl)methoxy] phenyl) piperazine) ≥98% purity was purchased from SigmaAldrich. Silver nitrate (AgNO3), CAS No 7761-88-8, was purchased from BDH ACS. Sodium borohydride (NaBH4) 90% purity and Potassium Bromide (KBr) ≥99% purity were purchased from Sigma-Aldrich. All solutions were prepared with ultrapure water obtained from a water purification system (Ultra Clear™ Lab Water Systems, Siemens Water Technologies USA). 2.2. Synthesis of Ag-NPs Ag-NPs were prepared by the chemical reduction method. First, 50 ml of aqueous 0.001 M of AgNO3 solution was prepared as a precursor of Ag-NPs. Then, 150 ml aqueous solution 0.0020 M NaBH4 was prepared as a stabilizing and reducing agent (the NaBH4 solution was prepared fresh), by dissolving 11.34 mg in distilled water. The sodium borohydride was placed on ice for 20 min to cool; then the AgNO3 solution was added to the NaBH4 solution at a rate of 1 drop/s under continuous stirring. When the silver nitrate was added the color of the mixture turned to dark yellow; this color indicates the formation of the neutral Ag-NPs. The chemical equation of Ag-NPs formation is: AgNO3 þNaBH4 →Agþ1=2H2 þ1=2B2 H6 þNaNO3
2.3. Characterization The Ag-NPs were characterized by using Ultraviolet–visible spectroscopy to determine the surface Plasmon band λ max of the Ag-NPs, the UV spectrum was recorded in 200–800 nm range. Two milliliters of Ag-NPs were placed into a quartz cuvette and placed in the sample holder of Beckman DU640 UV/Vis spectrophotometer. The smaller Ag-NPs showed a surface Plasmon band λmax of 400 nm. TEM and SEM techniques were used for the determination of the morphology, particle size, and particle distributions of Ag-NPs. FT-IR spectra of KCZ was obtained by Perkin-Elmer FT-IR spectrophotometer using potassium bromide (KBr) pellets. The
Fig. 1. (a) UV–Vis absorption spectra and (b) TEM image of Ag-NPs; (c) particle size distribution histogram; where a.u. stands for an arbitrary unit.
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instrument were optimized for all measurements as laser wavelength at 633 nm, acquisition time larger than 200 s, and objective ×10 vi's. The SERS spectra were obtained. For the determination of ketoconazole in the real sample, three different brands of commercial cream samples were obtained. In order to access the matrix effect, the relative recovery of the method was obtained. The SERS experiments were collected by mixing determined amounts of each sample with the NPs in a cuvette placed at a distance of 50 mm from the target and held at room temperature. The SERS was performed under the optimum conditions used for creating the calibration curve. 2.5. Computational methodology In our study, the DFT calculation with B3LYP/6-311 ++G (d, p) triple basis set was selected to calculate the vibrational frequencies of KCZ using the Gaussian 09 program. It was used to calculate the optimized geometry and vibrational frequencies of KCZ molecule and partial charges. A Gaussian09 program was utilized to detect and assign all peaks in the experimental Raman spectrum of KCZ, with and without Ag-NPs. 3. Result and discussion
Table 1 Mulliken atomic charges of KCZ using B3LYP/6-311++G (d, p) basis sets. Atoms
Charge
Atoms
Charge
Atoms
Charge
Cl Cl C H H N N O O C H O C C H C C H C H C H H
0.475547 0.505318 −0.465472 0.210114 0.183287 0.275365 0.101361 0.003152 0.12129 −0.732817 0.207985 0.148667 −0.675932 0.184236 0.192287 −0.573548 0.383441 0.173352 −0.047783 0.237131 −1.000297 0.215746 0.15137
C H C C H H C H N C C N C H H C H H C H C C H
−0.000423 0.171044 0.169414 −0.838386 0.225644 0.183222 0.21838 0.155433 0.344832 −0.171096 −0.111502 −0.102154 −0.477893 0.156505 0.14859 −1.037709 0.162693 0.169305 −0.17431 0.21031 0.161183 −0.430243 0.166662
H C H C H O C H C H C C H H C H H H
0.169469 −0.490145 0.149555 0.452659 0.243471 −0.333115 0.048669 0.151941 −0.366591 0.171341 −0.323615 0.199371 0.175661 0.151529 −0.491926 0.160004 0.204973 0.153449
3.1. Characterization of Ag-NPs Several techniques were used to characterize Ag-NPs including ultraviolet-visible spectroscopy (UV–vis) absorbance, SEM, and TEM [39]. Fig. 1a shows the absorption spectra of the yellow silver colloids prepared by sodium borohydride reduction. The absorption characteristic maximum of Ag-NPs was found at 400 nm, which corresponds upon the surface plasmon resonance of Ag-NPs indicating the presence of spherical Ag-NPs, and TEM image confirmed this. Fig. 1c depicts the average size particles distribution of the synthesized spherical Ag-NPs which is about 15 nm. 3.2. Density functional theory (DFT) 3.2.1. Molecular geometry of KCZ Density Functional Theory (DFT) works using Becke's threeparameter hybrid exchange functional with the Lee-Yang-Parr correlation functional, of the density functional theory. The 6-311 ++G (d, p) basis set was employed to optimize the structure and to calculate the electronic properties of the drug molecule [40]. The optimized geometry of KCZ structure, shown in Fig. 2, was achieved by minimizing potential energy, using DFT calculation with B3LYP/6-311 ++G (d, p) method. The important parameters of the optimized geometry such
Fig. 2. The optimized KCZ structure.
Table 2 Experimental and calculated B3LYP/6-311 ++G (d, p) level vibrational frequencies (cm−1) FT-IR and Raman of KCZ. Calculation IR & Ramana
Exp. IRb
Exp. Ramanc
3142 3119 3074 3049 3009 2964 2945 2885 2869 1679 1630 1588 1564 1516 1468 1450 1396 1379 1366 1339 1298 1213 1142 1116 1050 1007 914 843 806 748 711 670 588 567
3139 3118 3073 3043 2997 2963 2940 2885 2856 1644
vw m w w w m w s w vs
1584 1555 1509 1461 1442
v w vs w w
SERS
3136 m 3116 m 3076 vs 3000 2965 2938 2883
s w w s
1639 1617 1583 1552 1503 1462 1443 1394
m vs vs w v m w w
1661 m 1600 w 1577 w 1512 m
1399 vw
1373 m 1333 vw 1290 w 1201 s 1142 w 1106 s 1050 w 1004 w 906 s 837 m 795 m 736 m 703 m 667 s 589 s 566 m
1361 vw 1332 vw 1291 m 1199 m 1140 m 1107 vs 1048 m 1003 vw 904 m 834 m 799 m 741 w 704 m 666 s 585 m 562 w
1363 m 1327 w 1188 w 1163 m 1102 vw 1041 s
828 s 730 w 663 vw 577 w
Assignments C_C\ \H str. N_C\ \H str. C\ \H ring asym. str. C\ \H ring asym. str. CH2 cyclic sym. str. CH2 sym. str. O\ \C\ \H sym. str. N\ \CH2 sym. str. C\ \CH2 cyclic sym. str. C_O str. C_C ring str. C_C ring str. C_C ring str. N\ \C_C ring str. CH2 scissor N\ \CH2 scissor, C\ \N str. C\ \N str. C\ \C ring str, CH bend C\ \N str. CH3 scissor CH2 wag, CNC bend in-p C\ \N str, CH2 rock, CH bend C\ \N bend, C\ \O bend, CH2 twist C\ \N str, ring bend C\ \N str, N\ \CH bend C\ \O str, C\ \N str CCC in-p bend, CCH in-p bend CCN bend out-ph, CCH bend C\ \N str C\ \Cl str, ring bend COC in-p bend, CCC in-p bend CCN in-p bend, OCO in-p bend CNC out-p bend NCO out-p bend Ring bend def, CCCl out-p bend
Values are in cm−1. a IR intensities and Raman activities are calculated in (km/mol), (Ǎ4/amu) respectively. b vs = very strong; s = strong; m = medium; w = weak; vw = very weak, sh = shoulder. c ν, stretching, vibration; δ, bending in the plane; γ, bending out of the plane.
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Fig. 3. FT-IR spectra of KCZ, theoretical (a) and experimental (b); Raman spectra of KCZ, theoretical (c) and experimental (d); where a.u. stands for an arbitrary unit.
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as bond length, and bond angles, are presented in Table S1, and Table S2, respectively.
3.2.2. Mulliken analysis An important application of quantum mechanics, a Mulliken analysis is used to estimate the partial atomic charge from calculations derived by the methods of computational chemistry [41]. The calculation charge method is based on Linear Combination of Atomic Orbitals (LCAO) basis sets [42]. The results of the atomic charges are summarized in Table 1. The magnitude atomic charge of carbon and oxygen atoms were found to be either positive or negative charge. All the hydrogen atoms have a positive charge, the two chloride atoms have a positive charge, the three nitrogen atoms have a positive charge, and one of the oxygen atoms has a negative charge.
3.3. Vibrational assignments of KCZ 3.3.1. Vibrational assignments theoretically, by DFT In order to understand the interaction between the KCZ molecules and the surface of the Ag-NPs, it is important to assign the Raman bands with the vibrational modes. The vibrational frequency modes of KCZ calculated by the DFT with B3LYP 6-311 ++G (d, p) triple basis sets, and the experimental FT-IR and Raman vibrational frequencies, are given in Table 2. The calculated FT-IR and Raman wavenumbers showed good correlation between the intensities of experimental vibration modes. The calculated FT-IR vibration spectrum is shown in Fig. 3a, and Raman spectrum is in Fig. 3c. The calculated wavenumber was scaled using the scaling factor 0.961 for frequency region ≥ 2000 cm−1, and scaling factor 0.985 for frequency region N2000 cm−1 [43]. The Raman activities (Si) were calculated with the Gaussian 09 program by converting to Theoretical Raman intensities, using the following
Fig. 4. (a) Raman spectrum of aqueous KCZ solution at different Concentrations. (b) SRES spectrum of 1 × 10−5 M of KCZ with and without Ag-NPs. Laser ʎ = 633 nm, acquisition time; 200 s, and objective; 10×.
Table 3 SERS enhancement factor of KCZ on silver colloid. Substrate
Normal Raman spectra (cm−1)
SERS spectra (cm−1)
EFs
Silver colloid
1489 1358 1151 1050 798
1512 1363 1157 1041 820
2.1 3.3 1.7 7.9 3.4
× × × × ×
102 102 103 103 103
relationship derived from the intensity theory of Raman scattering [44,45]. Ii ¼
f ðvo −vi Þ4Si ; −hcvi vi exp kT
where v0 is the exciting wave number in cm−1, vi the vibrational wavenumber of i –th normal mode, h, c and k universal constants and f are a suitably chosen common normalization factor for all peak intensities. 3.3.2. Vibrational assignments experimentally 3.3.2.1. FT-IR analysis. Fig. 3b shows the IR spectra of the pure drug solid sample. The stretching, vibration C_C\\H is observed at 3139 cm−1
Fig. 5. (a) SERS spectra of KCZ at different concentrations; (b) Calibration curve of the band at 1041 cm−1). Laser ʎ = 633 nm, acquisition time; 200 s, and objective; 10×.
M.M. Al-Shalalfeh et al. / Materials Science and Engineering C 76 (2017) 356–364 Table 4 Analytical parameters (features) of proposed method for KCZ determination. Parameters
Value
Dynamic Linear Range (Linearity interval) (DLR); a linear relationship between the SERS signal intensity and the logarithmical scale of KCZ concentration Coefficient of determination (R2) Standard deviation (SD) % Detection limit (LOD): calculated as three-time of the baseline noise Limit of Quantification (LOQ): calculated as 3 × LOD Repeatability (%)a Reproducibility (%)b
1.0 × 10−9 M–1.0 × 10−5 M 0.9956 0.63 2.6 × 10−10 M 7.8 × 10−10 M 2 (n = 5) 4 (n = 5)
a Repeatability is the variation in measurements taken by the reported SERS method on the KCZ, under the same conditions, and in the same day. b Reproducibility is the variation in measurements taken by the reported SERS method independently on the KCZ, in different days.
with medium intensity, and peaks at 3073, 3043 cm−1 are for aromatic symmetry C\\H stretch (medium intensity), and stretching vibration for cyclic (epoxy) C\\O at 1050 cm− 1 (weak intensity) [46]. The stretching vibration of C_O is observed at 1644 cm− 1 [47]. The stretching vibration, C\\N peak can be observed at 1442, 1290, 1106, and 1050 cm− 1, The peaks at 1584, 1555 and 1509 cm−1 represent the C_C aromatic group, and CCC bending in the plane can be seen at 1004, and 736 cm−1 [48]. The CNC and CCN peaks could be observed at 1333 and 703 cm−1 respectively [49,50]. The CCCl bending out of a plane peak occurs at 556 cm−1 while the C\\Cl stretching vibration appears at 795 cm −1 [51]. 3.3.2.2. Raman analysis. The Fig. 3d shows the experimental spectra of KCZ with pure solid. The peaks at 3136 cm−1 and 3000 cm−1 are for C=_C\\H stretch and the cyclic CH respectively. The C\\O bend and stretch peaks appeared at 1199 and 1048 cm−1 respectively. The peak at 1617, 1583, and 1552 cm−1 were detected for aromatic C_C with sharp intensity. The peak at 1639 cm−1 with medium intensity represents C_O while the peak of C\\Cl was detected at 799 cm−1. 3.4. SERS results of KCZ on Ag-NPs The Raman signal can be enhanced several times by using some of the nanomaterials to adsorb the analyte at the surface of the metal surface, due to the interactions [52,53]. The Ag-NPs were used as substrates of SERS. The KCZ solution serves as a target to study the SERS sensitivity [54]. 1 ml of KCZ solution was placed in a glass cell. Fig. 4a shows the Raman spectra for KCZ at different concentrations. Multiple sharp peaks can be assigned to the KCZ molecule. The peaks observed were 798 cm−1 for the C\\N stretching vibration, 1050 cm−1 for the C\\O vibration, 1389 cm−1 for C\\N stretching vibration, 1610 cm−1 for the C_C aromatic stretching vibration and the 1635 cm−1 for C_O. It was observed that the intensity of the C\\O peak increased with an increase in the concentration of KCZ solution.
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Table 6 Determination of KCZ in cream samples (n = 3). Sample
Commercial dosage mg/g
Expected mg/g
Found mg/g
Recovery (%)
Bias (%)
Cream 1 Cream 2 Cream 3
20 20 20
20 20 20
18.23 18.57 19.15
91.2 92.9 95.8
−8.8 −7.1 −4.2
The SERS measurements were conducted by mixing the KCZ solution sample with varying ml of Ag-NPs using a ratio 3:1. The Raman spectra of KCZ indicated that the wavelength of the band in the compound was changed. Fig. 4b represents the Raman spectra of 1 × 10−5 KCZ with and without Ag-NPs. It can be seen that a number of bands were enhanced due to the interaction between the KCZ and Ag-NPs. The peak intensity of KCZ at 1050 cm−1 is in the normal Raman spectrum for C\\O stretching; the vibration mode with Ag-NPs is highly enhanced and is stronger than without Ag-NPs. As shown in Fig. 4b, it shifted to 1041 cm−1 in the SERS spectra. In addition, there is a significant enhancement of the C\\N peak at 798 cm−1 in the normal Raman spectra, which shifted to 820 cm− 1 in the SERS spectra. The band at 1151 cm− 1 in the normal Raman spectrum shifted to 1157 cm−1 in the SERS spectrum. This band shows a medium enhancement factor, which is attributed to the C\\N stretching. The weak modes at 1489 and 1358 cm− 1 in the normal Raman spectrum are shifted to 1512 and 1363 cm−1 respectively in the SERS spectrum. These bands are enhanced to higher intensities in the SERS spectrum than in the normal Raman spectrum, which is attributed to N\\C_C ring stretching, and C\\N stretching respectively. The SERS enhancement factors for the vibrations of KCZ (1 × 10−5 M) on silver colloid to the corresponding band obtained from KCZ saturated solution were calculated using the following equation. EFs ¼ ðδSERS Cnormal Þ=ðδnormal CSERS Þ where δ and C are the Raman mode intensity and sample concentration, respectively. The Enhancement Factors (EFs) for the SERS peaks of KCZ on silver colloid are given in Table 3. The EFs is not the same for the different KCZ concentrations. It was calculated considering log scale as in Fig. 5b. 3.5. Calibration curve and method validation The concentration-dependent SERS spectra of KCZ obtained by using Ag-NPs are given in Fig. 5a. We can see that the SERS intensity was affected by changing the concentration of KCZ. Fig. 5b shows the calibration curve considering the band at 1041 cm− 1. The SERS intensity increased proportionally with increased concentrations of KCZ solutions. The calibration curve was plotted, under most favorable conditions, as intensity vs log [KCZ]. To evaluate the analytical performance of the proposed method, parameters like linearity, repeatability, limits of detection and limits of quantification were investigated under
Table 5 Comparison of linear concentration ranges and detection limits with other methods for the determination of KCZ. Method
Calibration range (μM)
Detection limits (μM)
R2
Ref.
Surface-enhanced Raman spectroscopy (SERS) Solid phase extraction-high performance liquid chromatography (SPC-HPLC) Square-wave voltammetric (SWV) Differential pulse voltammetry (DPV) Square-wave voltammetric (SWV) Differential pulse voltammetry (DPV) High performance liquid chromatography (HPLC)
0.001–10 0.2–2.0 0.287–12.0 10–80 0.0317–0.32 1.0–30 6.0–40.0
0.00091 0.02 0.083 0.1054 0.00747 0.44 1.0
0.9956 0.9949 0.9989 0.9996 0.9989 0.9962 0.9992
Present work [55] [56] [57] [58] [59] [35]
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Fig. 6. Mapping showing the KCZ distribution of a selected band at 1041 cm−1.
optimum experimental conditions. Good linearity was observed over a concentration range of 1 × 10−5 to 1 × 10−9 mol·L−1 with a coefficient of determination, R2, equal to 0.9956. The SERS detection limit in this report reached 2.6 × 10−10 mol·L−1, and the limit of quantification (LOQ) was 7.8 × 10−10 M. The analytical parameters (features) of the proposed method for KCZ determination are listed in Table 4. The results obtained by the reported SERS method were compared with other methods reported in the literature in term of calibration range, detection limits, and determination coefficient (R2). The comparison with other methods for the determination of KCZ is summarized in Table 5. It is clear that the method is comparable with other methods. 3.6. KCZ in real samples The determination of KCZ in cream samples was examined to demonstrate the ability of the SERS method for the determination of KCZ in real samples. The proposed method was applied for the determination
of KCZ in real pharmaceutical samples. For this purpose, three different brands of cream samples were obtained. In order to access the matrix effect, the relative recovery of the method was calculated. The results given in Table 6 indicate that the SERS method retained its efficiency for the determination of KCZ in real samples. The Raman modes of KCZ in the presence of cream can be seen clearly with almost no interference because the additives in the cream sample are not Raman active within the considered working range between 650 and 1300 cm−1, as shown in Fig. S1b. The distribution of the KCZ in the cream samples was also investigated by using a mapping function incorporated with the Lab Ram HP Evolution Raman spectrometer. The mapping is a good method to investigate the distribution of the drug with the additives of the cream. Chemical mapping of KCZ in the cream sample was created from the Raman band at 1041 cm−1. Mappings were obtained as an average of 20 Raman spectra of cream samples; one example is shown in Fig. 6. The mapping images indicated a uniform distribution of the KCZ within the other additives in the cream.
Fig. 7. (A) Docked conformation of ketoconazole in the active site of the androgen receptor (PDB: 2AX6). (B) The molecular interactions between ketoconazole and the androgen receptor.
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3.6.1.1. Molecular docking for ketoconazole. The docking analysis of KCZ with the crystal structure of an androgen receptor, PDB ID: 2AX6 [60] was done using CLC drug discovery workbench 3.0 [61]. KCZ is the first non-steroidal compound to compete in binding to androgen with sex hormone binding globulin. Amongst other antifungal imidazole derivatives such as clotrimazole and fluconazole, KCZ (ketoconazole) is the only one which interacts with the androgen receptor [62]. It acts as an antagonist thereby making it useful in the treatment of androgen-dependent prostate cancer [60]. However, the mode of action of KCZ has not really been understood. Molecular docking is an in-silico method that is used in understanding the interactions between ligand in this case, KCZ and a target protein in this case, the androgen receptor. The validity of the target protein using Ramachandran plot gave an outlier of 0.9%, which falls within the recommended range of 0–5% for a good quality protein [63]. The water molecules were removed before binding the ligand to the receptor and the initial ligand in the crystal structure of the target protein was used as the reference binding site within a radius of 13 Å. The number of iterations was set to 100 to get the best binding mode. After docking KCZ to the androgen receptor, the ligand was optimized to give a docking score of −57.55 which implied a strong binding between the ligand and the receptor since the higher the negative value of a docking score the stronger the binding. The interactions between the ligand and the receptor showed many favorable interactions such as pi-alkyl, pi-cation, hydrogen and halogen bonds with the amino acids found in the binding site and only two unfavourable interactions with MET 745 and GLN 711. The binding mode and molecular interactions between KCZ, and the androgen receptor may help understand the former's role in treating prostate cancer (Fig. 7). 4. Conclusions The procedure herein reported thus provides a simple way of achieving ultrasensitive SERS spectroscopy for ketoconazole detection by using the prepared Ag-NPs substrates. The optimized conformation of KCZ on the silver surface was discussed by SERS and DFT calculation with B3LYP/6-311++G (d, p) basis set. The intensities and the wavenumber of vibration frequency bands in the theoretical spectrum are close to experimental spectra. The bands assigned to the C\\O and to C\\N stretching vibration modes are clearly enhanced. These results indicate that KCZ molecules are mostly chemisorbed on the silver substrates, and are significantly enhanced through the O and N atoms. The SERS determination on KCZ was studied at different concentrations; the detection limit of 2.6 × 10−10 M was obtained. The ability to resolve the identity of molecular species in low concentration renders optical SERS analysis an excellent tool for ultrasensitive detection. The docking analysis showed the possible molecular interactions between KCZ and the androgen receptor which would be useful in understanding the treatment of prostate cancer. Acknowledgements The authors would like to acknowledge the support provided by King Abdulaziz City for Science and Technology (KACST) through project No. A.T.34-8. The authors would like also to acknowledge the support by King Fahd University of Petroleum and Minerals (KFUPM). References [1] S.S. Ranea, P. Padmaja, Spectrophotometric method for the determination of ketoconazole based on amplification reactions, J. Pharm. Anal. 2 (1) (2012) 43–47. [2] E.R. Kedor-Hackmann, M.I. Santoro, A.K. Singh, A.C. Peraro, First-derivative ultraviolet spectrophotometric and high performance liquid chromatographic determination of ketoconazole in pharmaceutical emulsions, Rev. Bras. Cienc. Farm. 42 (2006) 91–98. [3] F.M. Abou-Attia, Y.M. Issa, F.M. Abdel-Gawad, S.M. AbdelHamid, Quantitative determination of some pharmaceutical piperazine derivatives through complexation with iron(III) chloride, Farmaco 58 (2003) 573–579.
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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Spherical silver nanoparticles as substrates in surface-enhanced Raman spectroscopy for enhanced characterization of ketoconazole Mutasem M. Al-Shalalfeh, Abdulmujeeb T. Onawole, Tawfik A. Saleh ⁎, Abdulaziz A. Al-Saadi Department of Chemistry, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 24 November 2016 Received in revised form 15 January 2017 Accepted 10 March 2017 Available online 12 March 2017 Keywords: Silver Ketoconazole SERS Computational
a b s t r a c t A new method was developed for the characterization and detection of ketoconazole using surface enhanced Raman spectroscopy (SERS) by designing substrates and performing the bands' assignments. Thus, spherical silver nanoparticles (Ag-NPs) were synthesized by a reduction method and designed as substrates for SERS application. The Ag-NPs were characterized using a scanning electron microscope, Fourier transformed infrared spectroscopy and a high-resolution transmission electron microscope. TEM results indicated that the average size of the Ag-NPs was 15 nm. The UV spectrum showed a maximum absorbance of Ag-NPs at about 400 nm. When Ag-NPs were used as substrates in SERS, the Raman spectra of KCZ showed a significant enhancement of the Raman bands. An important finding is a linear relationship between the logarithmical scale of KCZ concentration and the intensity of the SERS bands, for example at 1050 cm−1 of KCZ, which is due to the C\\N vibration. This was optimized and utilized to develop a calibration curve, which was then used for the detection of the KCZ in real pharmaceutical samples. The method has the advantages of a wide dynamic range with a high coefficient of determination and detection limit calculated based on the signal-to-noise ratio of 3, was 2.6 × 10−10 M and the limit of quantification was 7.8 × 10−10 M. The potential applications that take advantage of the high SERS sensitivity of this method are discussed for practical KCZ analysis where were quantified with this method. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Ketoconazole (cis-1-acetyl-4-{4-[[2-(2,4-dichloro-phenyl)-2-(1Himidazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl} piperazine,), is a broad-spectrum antifungal agent used as an agent against dermatophytes and yeast. The assaying of ketoconazole in pharmaceutical compounds and formulations is vital. Ketoconazole (KCZ) has been determined in pharmaceutical preparations by spectroscopic, chromatographic and electrochemical methods [1–5]. These methods have the disadvantage of being time and labor intensive and often involves the extraction of solvents, some of which are potentially toxic to humans and the environment. For these reasons, in recent years, the need of alternative methods is a challenge that has been discussed by several researchers [6]. Surface Enhanced Raman Spectroscopy (SERS) is an important technique for the identification and detection of solid, liquid, and gas samples in various applications. SERS is a highly sensitive and selective method when compared with Raman spectroscopy [6,7]. Recently, it has been used in many important research areas such as medical applications, analytical chemistry [8,9]. SERS has been studied both theoretically and experimentally. The first study, by ⁎ Corresponding author. E-mail addresses: tawfi[email protected], tawfi[email protected] (T.A. Saleh). URL: http://faculty.kfupm.edu.sa/CHEM/tawfik/ (T.A. Saleh).
http://dx.doi.org/10.1016/j.msec.2017.03.081 0928-4931/© 2017 Elsevier B.V. All rights reserved.
Fleischmann, was performed using pyridine absorbed at the surface of a silver electrode [10]. SERS is a method used to study bounding of the analyte to the substrate, and it is characterized by its high sensitivity and low detection limits [11]. SERS commonly refers to the phenomenon whereby Raman-signals from adsorbates on suitable surfaces are enhanced several times due to the excitation Surface Plasmon Resonance (SPR) on the surface of metals such as silver, gold, and copper [12,13]. The enhancement can be explained by two mechanisms: chemical mechanism and electromagnetic enhancement. The latter is considered the dominant effect due to the SPR [14–16]. This mechanism is sometimes called the Raman reflectance mechanism and it can also arise from modulated overlap between the molecule and surface orbitals. Metal nanoparticles have been widely used in SERS due to their unique properties, such as their size and shape [17–20]. Silver colloids are the most common type of SERS substrate; they exhibit large enhancement, a strong surface Plasmon polarization mode in the visible light range, and are relatively stable [21,22,23]. There are several methods to synthesize metal nanoparticles, including chemical methods such as chemical reduction and thermal decomposition [24], and physical methods, such as vapor deposition and microwave irradiation [25]. The reduction methods are the most commonly used for the synthesis of nanoparticles. The reduction method requires three main components: (i) a precursor like metal salt, (ii) a reducing agent
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like trisodium citrate, ethylene glycol, and sodium borohydride, and (iii) a stabilizing agent like vinyl pyrrolidone, dodecanoic acid, and oleylamine [26–28]. Silver nanoparticles (Ag-NPs) have been known to be used in the pharmaceutical industry based on their optical, electrical and thermal properties [29,30]. Ag-NPs have been used for treating various human diseases, due to the high surface area resulting from the ability of Ag-NPs to coordinate with legends [31,32]. The computational method is useful to investigate the design of new drugs and materials that are difficult to find or very expensive; further, it is useful to study the properties of molecules and the assignment of IR and Raman bands [33]. This method is based on mathematical algorithms, statistics, and databases to integrate chemical theory [34]. Ab initio, semiempirical and molecular mechanics numerical techniques were used to determine the geometry optimizations, potential energy surface calculations, and frequency calculation, as seen in the calculations [35–37]. The main goal of this study was to develop an efficient SERS method to determine the KCZ in pharmaceutical formulations. Thus, Ag-NPs were prepared, characterized and designed as substrates for SERS measurements. The method was optimized and applied for the detection of KCZ in commercial samples. The DFT calculations were carried out to obtain a detailed interpretation of the SERS spectra and to collect the vibrational assignment.
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pellet was prepared by mixing the sample and KBr with a ratio (1:100) [38]. FT-IR measurement was scanned at a range of wavelength from (400 to 4000) cm− 1 . He-Ne laser source operating at 0.5 W was utilized for sample excitation. 2.4. Surface-enhanced Raman spectroscopy (SERS) The SERS spectra of KCZ were obtained by a using Raman spectroscopy system, namely a Lab Ram HP Evolution Raman spectrometer equipped with an internal He-Ne 17 mW laser at a 633 nm excitation wavelength. SERS samples were prepared by using a 3:1 volume ratio of the KCZ solutions to the colloid in a cuvette. The parameters of the
2. Experimental 2.1. Chemicals and materials Ketoconazole (KCZ) named as ((±)-cis-1-Acetyl-4-(4-[(2-[2, 4dichlorophenyl]-2-[1H-imidazol-1-ylmethyl]-1,3-dioxolan-4-yl)methoxy] phenyl) piperazine) ≥98% purity was purchased from SigmaAldrich. Silver nitrate (AgNO3), CAS No 7761-88-8, was purchased from BDH ACS. Sodium borohydride (NaBH4) 90% purity and Potassium Bromide (KBr) ≥99% purity were purchased from Sigma-Aldrich. All solutions were prepared with ultrapure water obtained from a water purification system (Ultra Clear™ Lab Water Systems, Siemens Water Technologies USA). 2.2. Synthesis of Ag-NPs Ag-NPs were prepared by the chemical reduction method. First, 50 ml of aqueous 0.001 M of AgNO3 solution was prepared as a precursor of Ag-NPs. Then, 150 ml aqueous solution 0.0020 M NaBH4 was prepared as a stabilizing and reducing agent (the NaBH4 solution was prepared fresh), by dissolving 11.34 mg in distilled water. The sodium borohydride was placed on ice for 20 min to cool; then the AgNO3 solution was added to the NaBH4 solution at a rate of 1 drop/s under continuous stirring. When the silver nitrate was added the color of the mixture turned to dark yellow; this color indicates the formation of the neutral Ag-NPs. The chemical equation of Ag-NPs formation is: AgNO3 þNaBH4 →Agþ1=2H2 þ1=2B2 H6 þNaNO3
2.3. Characterization The Ag-NPs were characterized by using Ultraviolet–visible spectroscopy to determine the surface Plasmon band λ max of the Ag-NPs, the UV spectrum was recorded in 200–800 nm range. Two milliliters of Ag-NPs were placed into a quartz cuvette and placed in the sample holder of Beckman DU640 UV/Vis spectrophotometer. The smaller Ag-NPs showed a surface Plasmon band λmax of 400 nm. TEM and SEM techniques were used for the determination of the morphology, particle size, and particle distributions of Ag-NPs. FT-IR spectra of KCZ was obtained by Perkin-Elmer FT-IR spectrophotometer using potassium bromide (KBr) pellets. The
Fig. 1. (a) UV–Vis absorption spectra and (b) TEM image of Ag-NPs; (c) particle size distribution histogram; where a.u. stands for an arbitrary unit.
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instrument were optimized for all measurements as laser wavelength at 633 nm, acquisition time larger than 200 s, and objective ×10 vi's. The SERS spectra were obtained. For the determination of ketoconazole in the real sample, three different brands of commercial cream samples were obtained. In order to access the matrix effect, the relative recovery of the method was obtained. The SERS experiments were collected by mixing determined amounts of each sample with the NPs in a cuvette placed at a distance of 50 mm from the target and held at room temperature. The SERS was performed under the optimum conditions used for creating the calibration curve. 2.5. Computational methodology In our study, the DFT calculation with B3LYP/6-311 ++G (d, p) triple basis set was selected to calculate the vibrational frequencies of KCZ using the Gaussian 09 program. It was used to calculate the optimized geometry and vibrational frequencies of KCZ molecule and partial charges. A Gaussian09 program was utilized to detect and assign all peaks in the experimental Raman spectrum of KCZ, with and without Ag-NPs. 3. Result and discussion
Table 1 Mulliken atomic charges of KCZ using B3LYP/6-311++G (d, p) basis sets. Atoms
Charge
Atoms
Charge
Atoms
Charge
Cl Cl C H H N N O O C H O C C H C C H C H C H H
0.475547 0.505318 −0.465472 0.210114 0.183287 0.275365 0.101361 0.003152 0.12129 −0.732817 0.207985 0.148667 −0.675932 0.184236 0.192287 −0.573548 0.383441 0.173352 −0.047783 0.237131 −1.000297 0.215746 0.15137
C H C C H H C H N C C N C H H C H H C H C C H
−0.000423 0.171044 0.169414 −0.838386 0.225644 0.183222 0.21838 0.155433 0.344832 −0.171096 −0.111502 −0.102154 −0.477893 0.156505 0.14859 −1.037709 0.162693 0.169305 −0.17431 0.21031 0.161183 −0.430243 0.166662
H C H C H O C H C H C C H H C H H H
0.169469 −0.490145 0.149555 0.452659 0.243471 −0.333115 0.048669 0.151941 −0.366591 0.171341 −0.323615 0.199371 0.175661 0.151529 −0.491926 0.160004 0.204973 0.153449
3.1. Characterization of Ag-NPs Several techniques were used to characterize Ag-NPs including ultraviolet-visible spectroscopy (UV–vis) absorbance, SEM, and TEM [39]. Fig. 1a shows the absorption spectra of the yellow silver colloids prepared by sodium borohydride reduction. The absorption characteristic maximum of Ag-NPs was found at 400 nm, which corresponds upon the surface plasmon resonance of Ag-NPs indicating the presence of spherical Ag-NPs, and TEM image confirmed this. Fig. 1c depicts the average size particles distribution of the synthesized spherical Ag-NPs which is about 15 nm. 3.2. Density functional theory (DFT) 3.2.1. Molecular geometry of KCZ Density Functional Theory (DFT) works using Becke's threeparameter hybrid exchange functional with the Lee-Yang-Parr correlation functional, of the density functional theory. The 6-311 ++G (d, p) basis set was employed to optimize the structure and to calculate the electronic properties of the drug molecule [40]. The optimized geometry of KCZ structure, shown in Fig. 2, was achieved by minimizing potential energy, using DFT calculation with B3LYP/6-311 ++G (d, p) method. The important parameters of the optimized geometry such
Fig. 2. The optimized KCZ structure.
Table 2 Experimental and calculated B3LYP/6-311 ++G (d, p) level vibrational frequencies (cm−1) FT-IR and Raman of KCZ. Calculation IR & Ramana
Exp. IRb
Exp. Ramanc
3142 3119 3074 3049 3009 2964 2945 2885 2869 1679 1630 1588 1564 1516 1468 1450 1396 1379 1366 1339 1298 1213 1142 1116 1050 1007 914 843 806 748 711 670 588 567
3139 3118 3073 3043 2997 2963 2940 2885 2856 1644
vw m w w w m w s w vs
1584 1555 1509 1461 1442
v w vs w w
SERS
3136 m 3116 m 3076 vs 3000 2965 2938 2883
s w w s
1639 1617 1583 1552 1503 1462 1443 1394
m vs vs w v m w w
1661 m 1600 w 1577 w 1512 m
1399 vw
1373 m 1333 vw 1290 w 1201 s 1142 w 1106 s 1050 w 1004 w 906 s 837 m 795 m 736 m 703 m 667 s 589 s 566 m
1361 vw 1332 vw 1291 m 1199 m 1140 m 1107 vs 1048 m 1003 vw 904 m 834 m 799 m 741 w 704 m 666 s 585 m 562 w
1363 m 1327 w 1188 w 1163 m 1102 vw 1041 s
828 s 730 w 663 vw 577 w
Assignments C_C\ \H str. N_C\ \H str. C\ \H ring asym. str. C\ \H ring asym. str. CH2 cyclic sym. str. CH2 sym. str. O\ \C\ \H sym. str. N\ \CH2 sym. str. C\ \CH2 cyclic sym. str. C_O str. C_C ring str. C_C ring str. C_C ring str. N\ \C_C ring str. CH2 scissor N\ \CH2 scissor, C\ \N str. C\ \N str. C\ \C ring str, CH bend C\ \N str. CH3 scissor CH2 wag, CNC bend in-p C\ \N str, CH2 rock, CH bend C\ \N bend, C\ \O bend, CH2 twist C\ \N str, ring bend C\ \N str, N\ \CH bend C\ \O str, C\ \N str CCC in-p bend, CCH in-p bend CCN bend out-ph, CCH bend C\ \N str C\ \Cl str, ring bend COC in-p bend, CCC in-p bend CCN in-p bend, OCO in-p bend CNC out-p bend NCO out-p bend Ring bend def, CCCl out-p bend
Values are in cm−1. a IR intensities and Raman activities are calculated in (km/mol), (Ǎ4/amu) respectively. b vs = very strong; s = strong; m = medium; w = weak; vw = very weak, sh = shoulder. c ν, stretching, vibration; δ, bending in the plane; γ, bending out of the plane.
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Fig. 3. FT-IR spectra of KCZ, theoretical (a) and experimental (b); Raman spectra of KCZ, theoretical (c) and experimental (d); where a.u. stands for an arbitrary unit.
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as bond length, and bond angles, are presented in Table S1, and Table S2, respectively.
3.2.2. Mulliken analysis An important application of quantum mechanics, a Mulliken analysis is used to estimate the partial atomic charge from calculations derived by the methods of computational chemistry [41]. The calculation charge method is based on Linear Combination of Atomic Orbitals (LCAO) basis sets [42]. The results of the atomic charges are summarized in Table 1. The magnitude atomic charge of carbon and oxygen atoms were found to be either positive or negative charge. All the hydrogen atoms have a positive charge, the two chloride atoms have a positive charge, the three nitrogen atoms have a positive charge, and one of the oxygen atoms has a negative charge.
3.3. Vibrational assignments of KCZ 3.3.1. Vibrational assignments theoretically, by DFT In order to understand the interaction between the KCZ molecules and the surface of the Ag-NPs, it is important to assign the Raman bands with the vibrational modes. The vibrational frequency modes of KCZ calculated by the DFT with B3LYP 6-311 ++G (d, p) triple basis sets, and the experimental FT-IR and Raman vibrational frequencies, are given in Table 2. The calculated FT-IR and Raman wavenumbers showed good correlation between the intensities of experimental vibration modes. The calculated FT-IR vibration spectrum is shown in Fig. 3a, and Raman spectrum is in Fig. 3c. The calculated wavenumber was scaled using the scaling factor 0.961 for frequency region ≥ 2000 cm−1, and scaling factor 0.985 for frequency region N2000 cm−1 [43]. The Raman activities (Si) were calculated with the Gaussian 09 program by converting to Theoretical Raman intensities, using the following
Fig. 4. (a) Raman spectrum of aqueous KCZ solution at different Concentrations. (b) SRES spectrum of 1 × 10−5 M of KCZ with and without Ag-NPs. Laser ʎ = 633 nm, acquisition time; 200 s, and objective; 10×.
Table 3 SERS enhancement factor of KCZ on silver colloid. Substrate
Normal Raman spectra (cm−1)
SERS spectra (cm−1)
EFs
Silver colloid
1489 1358 1151 1050 798
1512 1363 1157 1041 820
2.1 3.3 1.7 7.9 3.4
× × × × ×
102 102 103 103 103
relationship derived from the intensity theory of Raman scattering [44,45]. Ii ¼
f ðvo −vi Þ4Si ; −hcvi vi exp kT
where v0 is the exciting wave number in cm−1, vi the vibrational wavenumber of i –th normal mode, h, c and k universal constants and f are a suitably chosen common normalization factor for all peak intensities. 3.3.2. Vibrational assignments experimentally 3.3.2.1. FT-IR analysis. Fig. 3b shows the IR spectra of the pure drug solid sample. The stretching, vibration C_C\\H is observed at 3139 cm−1
Fig. 5. (a) SERS spectra of KCZ at different concentrations; (b) Calibration curve of the band at 1041 cm−1). Laser ʎ = 633 nm, acquisition time; 200 s, and objective; 10×.
M.M. Al-Shalalfeh et al. / Materials Science and Engineering C 76 (2017) 356–364 Table 4 Analytical parameters (features) of proposed method for KCZ determination. Parameters
Value
Dynamic Linear Range (Linearity interval) (DLR); a linear relationship between the SERS signal intensity and the logarithmical scale of KCZ concentration Coefficient of determination (R2) Standard deviation (SD) % Detection limit (LOD): calculated as three-time of the baseline noise Limit of Quantification (LOQ): calculated as 3 × LOD Repeatability (%)a Reproducibility (%)b
1.0 × 10−9 M–1.0 × 10−5 M 0.9956 0.63 2.6 × 10−10 M 7.8 × 10−10 M 2 (n = 5) 4 (n = 5)
a Repeatability is the variation in measurements taken by the reported SERS method on the KCZ, under the same conditions, and in the same day. b Reproducibility is the variation in measurements taken by the reported SERS method independently on the KCZ, in different days.
with medium intensity, and peaks at 3073, 3043 cm−1 are for aromatic symmetry C\\H stretch (medium intensity), and stretching vibration for cyclic (epoxy) C\\O at 1050 cm− 1 (weak intensity) [46]. The stretching vibration of C_O is observed at 1644 cm− 1 [47]. The stretching vibration, C\\N peak can be observed at 1442, 1290, 1106, and 1050 cm− 1, The peaks at 1584, 1555 and 1509 cm−1 represent the C_C aromatic group, and CCC bending in the plane can be seen at 1004, and 736 cm−1 [48]. The CNC and CCN peaks could be observed at 1333 and 703 cm−1 respectively [49,50]. The CCCl bending out of a plane peak occurs at 556 cm−1 while the C\\Cl stretching vibration appears at 795 cm −1 [51]. 3.3.2.2. Raman analysis. The Fig. 3d shows the experimental spectra of KCZ with pure solid. The peaks at 3136 cm−1 and 3000 cm−1 are for C=_C\\H stretch and the cyclic CH respectively. The C\\O bend and stretch peaks appeared at 1199 and 1048 cm−1 respectively. The peak at 1617, 1583, and 1552 cm−1 were detected for aromatic C_C with sharp intensity. The peak at 1639 cm−1 with medium intensity represents C_O while the peak of C\\Cl was detected at 799 cm−1. 3.4. SERS results of KCZ on Ag-NPs The Raman signal can be enhanced several times by using some of the nanomaterials to adsorb the analyte at the surface of the metal surface, due to the interactions [52,53]. The Ag-NPs were used as substrates of SERS. The KCZ solution serves as a target to study the SERS sensitivity [54]. 1 ml of KCZ solution was placed in a glass cell. Fig. 4a shows the Raman spectra for KCZ at different concentrations. Multiple sharp peaks can be assigned to the KCZ molecule. The peaks observed were 798 cm−1 for the C\\N stretching vibration, 1050 cm−1 for the C\\O vibration, 1389 cm−1 for C\\N stretching vibration, 1610 cm−1 for the C_C aromatic stretching vibration and the 1635 cm−1 for C_O. It was observed that the intensity of the C\\O peak increased with an increase in the concentration of KCZ solution.
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Table 6 Determination of KCZ in cream samples (n = 3). Sample
Commercial dosage mg/g
Expected mg/g
Found mg/g
Recovery (%)
Bias (%)
Cream 1 Cream 2 Cream 3
20 20 20
20 20 20
18.23 18.57 19.15
91.2 92.9 95.8
−8.8 −7.1 −4.2
The SERS measurements were conducted by mixing the KCZ solution sample with varying ml of Ag-NPs using a ratio 3:1. The Raman spectra of KCZ indicated that the wavelength of the band in the compound was changed. Fig. 4b represents the Raman spectra of 1 × 10−5 KCZ with and without Ag-NPs. It can be seen that a number of bands were enhanced due to the interaction between the KCZ and Ag-NPs. The peak intensity of KCZ at 1050 cm−1 is in the normal Raman spectrum for C\\O stretching; the vibration mode with Ag-NPs is highly enhanced and is stronger than without Ag-NPs. As shown in Fig. 4b, it shifted to 1041 cm−1 in the SERS spectra. In addition, there is a significant enhancement of the C\\N peak at 798 cm−1 in the normal Raman spectra, which shifted to 820 cm− 1 in the SERS spectra. The band at 1151 cm− 1 in the normal Raman spectrum shifted to 1157 cm−1 in the SERS spectrum. This band shows a medium enhancement factor, which is attributed to the C\\N stretching. The weak modes at 1489 and 1358 cm− 1 in the normal Raman spectrum are shifted to 1512 and 1363 cm−1 respectively in the SERS spectrum. These bands are enhanced to higher intensities in the SERS spectrum than in the normal Raman spectrum, which is attributed to N\\C_C ring stretching, and C\\N stretching respectively. The SERS enhancement factors for the vibrations of KCZ (1 × 10−5 M) on silver colloid to the corresponding band obtained from KCZ saturated solution were calculated using the following equation. EFs ¼ ðδSERS Cnormal Þ=ðδnormal CSERS Þ where δ and C are the Raman mode intensity and sample concentration, respectively. The Enhancement Factors (EFs) for the SERS peaks of KCZ on silver colloid are given in Table 3. The EFs is not the same for the different KCZ concentrations. It was calculated considering log scale as in Fig. 5b. 3.5. Calibration curve and method validation The concentration-dependent SERS spectra of KCZ obtained by using Ag-NPs are given in Fig. 5a. We can see that the SERS intensity was affected by changing the concentration of KCZ. Fig. 5b shows the calibration curve considering the band at 1041 cm− 1. The SERS intensity increased proportionally with increased concentrations of KCZ solutions. The calibration curve was plotted, under most favorable conditions, as intensity vs log [KCZ]. To evaluate the analytical performance of the proposed method, parameters like linearity, repeatability, limits of detection and limits of quantification were investigated under
Table 5 Comparison of linear concentration ranges and detection limits with other methods for the determination of KCZ. Method
Calibration range (μM)
Detection limits (μM)
R2
Ref.
Surface-enhanced Raman spectroscopy (SERS) Solid phase extraction-high performance liquid chromatography (SPC-HPLC) Square-wave voltammetric (SWV) Differential pulse voltammetry (DPV) Square-wave voltammetric (SWV) Differential pulse voltammetry (DPV) High performance liquid chromatography (HPLC)
0.001–10 0.2–2.0 0.287–12.0 10–80 0.0317–0.32 1.0–30 6.0–40.0
0.00091 0.02 0.083 0.1054 0.00747 0.44 1.0
0.9956 0.9949 0.9989 0.9996 0.9989 0.9962 0.9992
Present work [55] [56] [57] [58] [59] [35]
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Fig. 6. Mapping showing the KCZ distribution of a selected band at 1041 cm−1.
optimum experimental conditions. Good linearity was observed over a concentration range of 1 × 10−5 to 1 × 10−9 mol·L−1 with a coefficient of determination, R2, equal to 0.9956. The SERS detection limit in this report reached 2.6 × 10−10 mol·L−1, and the limit of quantification (LOQ) was 7.8 × 10−10 M. The analytical parameters (features) of the proposed method for KCZ determination are listed in Table 4. The results obtained by the reported SERS method were compared with other methods reported in the literature in term of calibration range, detection limits, and determination coefficient (R2). The comparison with other methods for the determination of KCZ is summarized in Table 5. It is clear that the method is comparable with other methods. 3.6. KCZ in real samples The determination of KCZ in cream samples was examined to demonstrate the ability of the SERS method for the determination of KCZ in real samples. The proposed method was applied for the determination
of KCZ in real pharmaceutical samples. For this purpose, three different brands of cream samples were obtained. In order to access the matrix effect, the relative recovery of the method was calculated. The results given in Table 6 indicate that the SERS method retained its efficiency for the determination of KCZ in real samples. The Raman modes of KCZ in the presence of cream can be seen clearly with almost no interference because the additives in the cream sample are not Raman active within the considered working range between 650 and 1300 cm−1, as shown in Fig. S1b. The distribution of the KCZ in the cream samples was also investigated by using a mapping function incorporated with the Lab Ram HP Evolution Raman spectrometer. The mapping is a good method to investigate the distribution of the drug with the additives of the cream. Chemical mapping of KCZ in the cream sample was created from the Raman band at 1041 cm−1. Mappings were obtained as an average of 20 Raman spectra of cream samples; one example is shown in Fig. 6. The mapping images indicated a uniform distribution of the KCZ within the other additives in the cream.
Fig. 7. (A) Docked conformation of ketoconazole in the active site of the androgen receptor (PDB: 2AX6). (B) The molecular interactions between ketoconazole and the androgen receptor.
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3.6.1.1. Molecular docking for ketoconazole. The docking analysis of KCZ with the crystal structure of an androgen receptor, PDB ID: 2AX6 [60] was done using CLC drug discovery workbench 3.0 [61]. KCZ is the first non-steroidal compound to compete in binding to androgen with sex hormone binding globulin. Amongst other antifungal imidazole derivatives such as clotrimazole and fluconazole, KCZ (ketoconazole) is the only one which interacts with the androgen receptor [62]. It acts as an antagonist thereby making it useful in the treatment of androgen-dependent prostate cancer [60]. However, the mode of action of KCZ has not really been understood. Molecular docking is an in-silico method that is used in understanding the interactions between ligand in this case, KCZ and a target protein in this case, the androgen receptor. The validity of the target protein using Ramachandran plot gave an outlier of 0.9%, which falls within the recommended range of 0–5% for a good quality protein [63]. The water molecules were removed before binding the ligand to the receptor and the initial ligand in the crystal structure of the target protein was used as the reference binding site within a radius of 13 Å. The number of iterations was set to 100 to get the best binding mode. After docking KCZ to the androgen receptor, the ligand was optimized to give a docking score of −57.55 which implied a strong binding between the ligand and the receptor since the higher the negative value of a docking score the stronger the binding. The interactions between the ligand and the receptor showed many favorable interactions such as pi-alkyl, pi-cation, hydrogen and halogen bonds with the amino acids found in the binding site and only two unfavourable interactions with MET 745 and GLN 711. The binding mode and molecular interactions between KCZ, and the androgen receptor may help understand the former's role in treating prostate cancer (Fig. 7). 4. Conclusions The procedure herein reported thus provides a simple way of achieving ultrasensitive SERS spectroscopy for ketoconazole detection by using the prepared Ag-NPs substrates. The optimized conformation of KCZ on the silver surface was discussed by SERS and DFT calculation with B3LYP/6-311++G (d, p) basis set. The intensities and the wavenumber of vibration frequency bands in the theoretical spectrum are close to experimental spectra. The bands assigned to the C\\O and to C\\N stretching vibration modes are clearly enhanced. These results indicate that KCZ molecules are mostly chemisorbed on the silver substrates, and are significantly enhanced through the O and N atoms. The SERS determination on KCZ was studied at different concentrations; the detection limit of 2.6 × 10−10 M was obtained. The ability to resolve the identity of molecular species in low concentration renders optical SERS analysis an excellent tool for ultrasensitive detection. The docking analysis showed the possible molecular interactions between KCZ and the androgen receptor which would be useful in understanding the treatment of prostate cancer. Acknowledgements The authors would like to acknowledge the support provided by King Abdulaziz City for Science and Technology (KACST) through project No. A.T.34-8. The authors would like also to acknowledge the support by King Fahd University of Petroleum and Minerals (KFUPM). References [1] S.S. Ranea, P. Padmaja, Spectrophotometric method for the determination of ketoconazole based on amplification reactions, J. Pharm. Anal. 2 (1) (2012) 43–47. [2] E.R. Kedor-Hackmann, M.I. Santoro, A.K. Singh, A.C. Peraro, First-derivative ultraviolet spectrophotometric and high performance liquid chromatographic determination of ketoconazole in pharmaceutical emulsions, Rev. Bras. Cienc. Farm. 42 (2006) 91–98. [3] F.M. Abou-Attia, Y.M. Issa, F.M. Abdel-Gawad, S.M. AbdelHamid, Quantitative determination of some pharmaceutical piperazine derivatives through complexation with iron(III) chloride, Farmaco 58 (2003) 573–579.
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