Voltammetric determination of salicylic acid in pharmaceuticals formulations of acetylsalicylic acid

Talanta 62 (2004) 247–254

Voltammetric determination of salicylic acid in pharmaceuticals formulations of acetylsalicylic acid Angel A.J. Torriero a , Juan M. Luco a , Leonides Sereno b , Julio Raba a,∗ a

b

Departamento de Qu´ımica, Facultad de Qu´ımica, Bioqu´ımica y Farmacia, Universidad Nacional de San Luis, Chacabuco y Pedernera 5700, San Luis, Argentina Departamento de Qu´ımica, Universidad Nacional de R´ıo Cuarto Agencia Postal No. 3, 5800 R´ıo Cuarto, Córdoba, Argentina Received 13 May 2003; received in revised form 14 July 2003; accepted 14 July 2003

Abstract The electrochemical oxidation of salicylic acid (SA) has been studied on a glassy carbon electrode using cyclic voltammetry and differential pulse voltammetric (DPV) method. SA gives a single irreversible oxidation wave over the wide pH range studied. The irreversibility of the electrode process was verified by different criteria. The mechanism of oxidation is discussed. Using differential pulse voltammetry, SA yielded a well-defined voltammetric response in Britton–Robinson buffer solution, pH 2.37 at 1.088 V (versus Ag/AgCl). The method was linear over the SA concentration range: 1–60 ␮g ml−1 . The method was successfully applied for the analysis of SA as a hydrolysis product, in solid pharmaceutical formulations containing acetylsalicylic acid (ASA). © 2003 Elsevier B.V. All rights reserved. Keywords: Electroanalysis; Cyclic voltammetry; Differential pulse voltammetry; Salicylic acid; Acetylsalicylic acid

1. Introduction The systemic use of salicylic acid (SA) may cause severe irritations and only can be utilized in external form. Thus, several derivatives have been synthesized. Two types are considered: (a) the esters of SA obtained by reaction of the carboxylic group with alcohols, and (b) esters of the phenolic group of SA with organic acids. In general, the salicylates action is achieved by the SA contents, although some of the characteristic properties of the acetylsalicylic acid (ASA) is their ability for protein acetylation. The esters in the carboxylic or phenolic groups change the power in the salicylates toxicity [1]. The techniques described for the determination of ASA in pharmaceuticals formulations are many and varied. These include the conventional back-titration method [2], high performance liquid chromatography (HPLC) [3], UV-Vis spectrophotometry [4–7], spectrofluorimetry [8–10], semiautomated-UV detection method [11], and flow injection analysis (FIA) with spectrophotometric detection ∗ Corresponding author. Tel.: +54-2652-42-5385; fax: +54-2652-43-0224. E-mail address: [email protected] (J. Raba).

0039-9140/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.talanta.2003.07.005

[12,13]. In spite of this there are only a few reports for quantitative determination of SA in ASA pharmaceutical preparations. In fact, the amount of SA, depending on the specific ASA formulation, is limited to 0.1–3%, as specified by the various Pharmacopoeias [2,3]. This determination includes chromatographic methods, such as HPLC [14–20]. Chromatographic methods require separation of the pharmaceutical from additives (excipients and antiacids) [21], which are time consuming and complex. The iron(III)–salicylate reaction has been used for quantitative determination of SA in ASA samples and the appropriate conditions for the reaction were established. The maximum color intensity was obtained at pH 2.5–3.5 [22]. In the literature, there are only a few reports for the assay of SA such as amperometric detection [23–26], ion-selective electrodes [27–29], and enzyme electrode [30]. In this work, we show other aspect of electro-oxidation mechanism of the SA, in order to improve and extend the application of the differential pulse voltammetric (DPV) method proposed by Fung and Luk [31] in order to determine SA as impurity in solid ASA pharmaceuticals preparations. The method cited is not applicable to our samples due to the fact that ASA gives hydrolysis product under the experimental conditions for their approach. Moreover,

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a simple dissolution and filtration step replaces the two extraction steps, introducing smaller error in the measure. According to the literature data [26], the rate of decomposition of ASA is pH dependent. At pH 2–3 [32] the maximum stability is attained; in neutral and acidic solutions (pH 4–8), the hydrolysis rate is slow, and at pH 11–12, ASA is immediately hydrolyzed. This experiment was repeated by us and similar results were found. The validation parameters of the method were evaluated. The developed method was applied to the analysis of six different commercial pharmaceutical tablet formulations. The results were compared with those obtained by HPLC. Finally, the aim of this work was to develop a new method for SA determination in pharmaceutical preparations avoiding ASA hydrolysis.

in the pH range between 2 and 12 and the sweep rate (υ) varied from υ = 0.100 to 2.400 V s−1 . All the solutions were free of oxygen by bubbling pure nitrogen, and during the experiment nitrogen being directed above the solution. The HPLC experiments were performed with a Beckman model 332 liquid chromatograph equipped with a variable wavelength detector model 164 operated at λ = 254 nm. The retention times as well as peak area measurements were obtained with a Varian 4290 integrator. The operating temperature was ambient and a Phenosphere 5 ␮m ODS-2 C18 column (250 mm × 4.6 mm) was used in all experiments at a flow rate of 1.5 ml min−1 . The mobile phase consisted of water–methanol–glacial acetic acid (54:45:1, v/v/v). Quantitative data were calculated from the linear regression of external standards of ASA and SA, relating peak area and concentration.

2. Experimental 2.3. Sample preparation for HPLC assay 2.1. Reagents and solvents A stock solution of 0.2 M SA (May & Baker) was prepared in acetonitrile, and stored under refrigeration. The dilute solutions were prepared daily with Britton–Robinson buffer (0.1 M, pH 2.0–12.0) just before use. This buffer was also used as supporting electrolyte in the electrochemical experiments. The purity of SA was tested by capillary electrophoresis and no impurities were found. All the solvents used were HPLC grade and all other reagents employed were of analytical grade and were used without further purifications. All solutions were prepared with ultra-high-quality water obtained from a Barnstead Easy pure RF compact ultra-pure-water system. 2.2. Apparatus Electrochemical experiments were performed in unstirred solutions using a BAS 100B electrochemical analyzer Bioanalytical System, West Lafayette, IN, using positive feedback routine to compensate the ohmic resistance. The three-electrode system consisted of a glassy carbon (GC) working electrode model BAS MF-2012, 3.0 mm diameter, 0.071 cm2 geometrical area, a 3 M NaCl Ag/AgCl reference electrode BAS MF-2052 and a Pt wire counter electrode. Before each voltammogram, the working electrode was carefully polished PK-4 polishing kits, BAS MF-2060, and rinsed following the general guideline for polishing electrodes recommended for BAS Electrode Polishing and Care, BAS A-1302. The pH values of the solutions were recorded with an ORION 920 pH-meter with a combined glass electrode and Ag/AgCl reference electrode. This pH-meter was calibrated with two buffers: biphthalate buffers, prepared by dissolving 2.53 g of potassium biphthalate in 250.0 ml in deionized water for pH 4.0 and tetraborate buffer, prepared by dissolving 0.95 g of sodium tetraborate in 250.0 ml in deionized water for pH 9.0. Voltammograms were recorded changing the concentration of SA (7 × 10−5 to 8 × 10−4 M)

For each pharmaceutical product, a known number of tablets were grounded to a fine power and an accurate mass corresponding to about 500.0 mg of tablet were transferred to a 10 ml calibrated flask and extracted for 15 min with 5.0 ml of cold methanol. Undissolved solids were filtered though a 0.45 ␮m PTFE Whatman filter; and the volume of the filtrate was made up to 10 ml with methanol. 2.4. Sample preparation for voltammetric assay A known number of tablets were grounded to a fine power and an accurate mass of power corresponding to about 500.0 mg of tablet were transferred to a 25 ml calibrated flasks and extracted for 5 min with 10.0 ml of cold methanol. Undissolved solids were filtered and the volume of the filtrate was made up to 25 ml with Britton–Robinson buffer, pH 2.37. This volume was transferred into a voltammetric cell. 2.5. Preparation of synthetic tablet samples Synthetic tablet samples were prepared into a 25 ml calibrated flasks by spiking a placebo (mixture of tablet excipients and ASA) with accurate amount of SA at a concentration similar to contaminant concentration (11.07–30.69 ␮g ml−1 ). Then, it was extracted for 5 min with 10.0 ml of cold methanol. Undissolved solids were filtered and the volume of the filtrate was made up to 25 ml with Britton–Robinson buffer, pH 2.37. This volume was transferred into a voltammetric cell. 2.6. DPV parameters In order to establish the optimum conditions for the determination of SA by means of DPV technique, various instrumental variables were studied and the optimum conditions were: pulse amplitude: 50 mV; scan rate, 40 mV s−1 ;

A.A.J. Torriero et al. / Talanta 62 (2004) 247–254

sample width, 20 ms; pulse width, 50 ms; pulse period, 200 ms; sensitivity, 1 × 10−5 A V−1 .

249

30

1

25 20

3.1. Electrochemical behaviour of SA

15 10 5

IIa

0

IIc

-5

0.0

0.2

0.4

0.6 0.8

1.0

1.2

1.4

E/V Fig. 1. Cyclic voltammogram at GC electrode of SA 6.5 mM, pH = 2.37, υ = 0.2 V s−1 . The numbers indicate first and second scan, respectively.

responding to a peak Ia . Benzoic acid shows an irreversible oxidation peak at more positive potential ∼1.750 V, this fact can be taken as an indirect proof that peak Ia is due to the phenolic moiety. More detailed studies of peak Ia give new insight to the oxidation SA. The plots of peak current (IpIa ) versus υ1/2 give a light downward curvature as shown in Fig. 2 depending on SA concentration. This behavior is typical for diffusion-kinetic control for the overall electrode process, when a chemical reaction is coupled between the two-charge transfers [43–45]. On the other hand, the experimental current function defined as ψ = IpIa /(A υ1/2 c), where A is

80

60

IpIa / µA

SA is a diprotic acid in aqueous media with pKa values 2.97 and 13.40 corresponding to dissociation of carboxylic acid and phenolic groups, respectively [33]. On the other hand, from the electrochemical point of view, this molecule can be considered as a phenol substituted in ortho-position. The electrochemical oxidation of phenol and substituted phenol in aqueous solution at different pH has been the subject of many studies and several features of the mechanism have been elucidated [34–41]. In order to determine some aspects of electrochemical behaviour of SA, cyclic voltammetry studies were carried out in Britton–Robinson buffer 0.1 M at different pH. The information is used in the development of a selective method for quantitative assay of this compound. Quantitative electrochemical studies of phenolic compounds in aqueous solution can be quite difficult due to the formation of polymer films on the electrode surface. Typically, this is observed after a single voltammetric scan mostly when the phenolic compound concentration is higher than mM level [42]. However, if the concentration of is lower than 0.5 mM film formation is negligible and normally voltammetric studies can be carried out [38]. Preliminary voltammetric studies showed that SA is not an exception to this rule, but the limit can be expanded to 0.8 mM, consequently all the studies were made with SA with concentrations in the range from 0.07 to 0.8 mM. A typical cyclic voltammogram of SA in water Britton–Robinson buffer is depicted in Fig. 1. The first anodic scan shows only a peak Ia , whose peak potential appears around 1.140 V depending on the pH and in less extension on the scan rate (υ) and SA concentration. On the reverse scan no complementary reduction peak is observed for Ia in all the range of υ studied (0.1–2.0 V s−1 ). This behavior is typical for a fast irreversible chemical reaction couple to the charge transfer [43–45]. At potential around 0.750 V a new couple (peaks IIc and IIa) are defined, which are assumed to correspond to the reduction–oxidation of a product of the coupled chemical reaction. The nature of this product was not determined, but it might be several of different soluble compounds [41] which can be expected to undergo the reversible redox reaction in this potential zone [38]. These results are in agreement with previous report for SA [25]. In order to determine if the oxidation is due to the benzoic acid moiety, the same voltammetric experiment was carried out with this acid 0.6 mM in Britton–Robinson buffer 0.1 M. In this case no peak is detected in the range of potential cor-

I / µA

3. Results and discussion

Ia

2

40

20

0 υ

1/2

1/2

/ (V/s)

Fig. 2. Dependence of IpIa on sweep rate (υ1/2 ) at different concentrations of SA, pH = 2.37, cSA = (䊉) 0.07, (䊊) 0.20, (䊏) 0.40, (䊐) 0.65, (䉲) 0.80 mM.

A.A.J. Torriero et al. / Talanta 62 (2004) 247–254

1.8

1,6

1.6 -2

Ψ/ [A.(V/s) .M .cm ]

1,8

1,4

1.4

-1/2

-1/2

-1

-1

-2

Ψ / [ A.(V/s) .M .cm ]

250

1,2

1.2

1.0 1,0 0,2

0,4

0,6 υ

1/2

0,8

1,0

1,2

1,4

0.8

1,6

2

4

6

8

1/2

/ (V/s)

Fig. 3. Dependence of ψ on sweep rate (υ1/2 ) at different concentrations of SA, pH = 2.37, cSA = (䊉) 0.07, (䊊) 0.20, (䊏) 0.40, (䊐) 0.65, (䉲) 0.80 mM.

the working electrode area and c the bulk concentration of SA, changes with the concentration of SA (Fig. 3). This fact reinforces the idea of existence of chemical reaction coupled to charge transfer which may have an order higher one [46]. The later is not surprising because in the phenolic moiety only one ortho-position is blocked, and it can be expected a complicate follow-up chemical reaction. It is known that in 2,4,6,-tri-tert-butylphenol the groups in orthoand para-positions limit these type of reactions which can occur upon anodic oxidation, being the coupled kinetic concentration independent [35,37,39]. The “apparent” number of electrons exchanged in the overall process were estimated by using the experimental ψ value (Fig. 3) and compared with model compounds that exchange one and two electrons, measured with the same working electrode in similar experimental conditions. Potassium ferrocyanide was selected as a model for one electron exchange (ψ = 0.71 A V−1/2 s−1/2 cm−2 M−1 ), and 1,4-hidroquinone as a two-electron exchange models [47], (ψ = 1.59 A V−1/2 s−1/2 cm−2 M−1 ). As it can be observed the value of ψ (Fig. 3) indicates that the overall electrode process for SA involves two electrons per molecule. On the other hand, ψ changes very little with the pH (Fig. 4), indicating similar electrode processes for all the pHs studied. These data lead to the conclusion that the oxidation of SA comprised of successive one electron transfers at similar potential, in the range of concentration and pH studied. Thus, being E10 ∼ = E20 [48], only one peak is detected in the first anodic scan. To obtain more insight about the mechanism of electro-oxidation of SA an analysis of the dependence of EpIa versus pH was performed. Usually in water the proton transfers from or toward organic molecule are considered fast [49], meaning that H+ are in equilibrium in solution

10

12

pH Fig. 4. Dependence of ψ on pH, cSA = 0.60 mM, υ = 0.1 V s−1 .

near the electrode. This type of situation should prevail in acidic or not excessively basic media, especially when the site of protonation is an oxygen atom [50]. A plot of EpIa versus pH is shown in Fig. 5. Two linear portions are distinguished, the first one at low pH with a slope of 0.055 V/pH. The break point at about pH ∼ = 3 corresponds to the first pKa for SA. The second portion has a slope of 0.026 V/pH. The higher slope is close to that expected for a monoelectronic/monoprotonic electrode reaction which is 0.0592 V/pH at 25 ◦ C. As it was shown previously the experimental ψ value indicates 2e in all the pH range studied. The only possibility for the pH below 3 is that the number of proton transfer be also two, or 0.0592 (h/n) V/pH where h and n are the number of proton and electron involved in the electrode process (h = n = 2). Taking into account previous results for phenol and related compound [34–40], the electro-oxidation mechanism

1.250

1.200

Ep / V

0,0

1.150

1.100

1.050 1

2

3

4

5

6 pH

7

8

9 10 11

Fig. 5. Dependence of EpIa on pH, cSA = 0.65 mM, υ = 0.2 V s−1 .

A.A.J. Torriero et al. / Talanta 62 (2004) 247–254

6

251

10 9

5

8

4

7

I / µA

6

3 5

2

4 3 2

1

1

b 0 -0.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

E/V Fig. 6. DPV for the electro-oxidation of SA, net current, at different concentrations of SA, cSA = (b) supporting electrolyte, (1) 1.4, (2) 2.8, (3) 4.1, (4) 5.7, (5) 8.3, (6) 11.4, (7) 13.8, (8) 16.6, (9) 19.3, (10) 21.8 ␮g ml−1 . DPV parameter see text, pH = 2.37.

of SA might be complex of the type C1 E1 C2 E2 C3 . At low pH previous to the first electron transfer there is and acid–base equilibrium corresponding to the dissociation carboxylic acid to anion (C1 ), the electron transfer at a potential E1 gives a radical, which in a rapid reaction looses a second proton (C2 ) to give one intermediate which oxidize at E2 followed by an another (C3 ) or several (Cn ) chemical reactions. After the break point (pH ∼ = 3) the carboxylic acid is completely ionized, as a consequence only one proton transfer coupled to the charge transfer is expected. The theoretical slope is now, 0.0296 (V/pH), where (h = 1, n = 2), which agrees with the experimental value. 3.2. DPV technique The DPV method for SA was used over the range of 0.00–1.500 V. After the voltammogram of the supporting electrolyte (blank experiment), SA standard solution was added by micropipette. Nitrogen was passed through the solution for 30 s to mix the solution. The voltammogram was again recorded. This procedure was repeated until the peak height no longer increased. Under this condition, a well-defined DPV peak was observed at about 1.088 V (Fig. 6). Moreover, in solid pharmaceutical formulations containing ASA as majority compound the presence of the hydrolysis product, SA, could be determined in Britton–Robinson buffer, pH 2.37 (pH range between 2 and 3). Under these conditions, the method is selective for SA, avoiding ASA hydrolysis [26].

4. Validation method 4.1. Linearity and range Linearity and range of the method were performed by analyzing 12 different concentrations (n = 6) of the mixed standard solution containing 0.2–80 ␮g ml−1 with Britton–Robinson buffer solution of pH 2.37. The calibration curve was plotted using peak current versus concentration of the standard solutions. Calibration curve was found to be linear over the concentration range 1–60 ␮g ml−1 . The data were analyzed by linear regression least-square fit method. The calibration graph shows negligible intercept and is described by the calibration equation y = a + bx, where y is the peak current, b the slope, a the intercept and x the concentration of the analyte. Linear regression least-square fit data are given in Table 1. The influence of Table 1 The determined parameters for calibration curves of SA obtained from developed method Parameter

DPV (n = 12)

Linear dynamic range (␮g ml−1 ) Regression equation (ya ) Slope (b) Intercept (a) Standar deviation (S.D.) Correlation coefficient (r) LOQ (␮g ml−1 ) LOD (␮g ml−1 )

1–60

a

0.22867 0.04657 0.05335 0.9995 1.04 0.09

y = a + bx, where x is the concentration in ␮g ml−1 .

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Table 2 Accuracy and precision dates for SA obtained by the DPV method Accuracya (percentage relative error)

Added (SA) (␮g ml−1 )

Found (SA) (␮g ml−1 )

Precision (␮g ml−1 )

11.04

11.07

Xb = 11.07 ± 0.015 s = 0.0482 VC = 0.43%

0.27

15.31

15.33

X = 15.33 ± 0.04 s = 0.0481 VC = 0.31%

0.13

X = 23.33 ± 0.02 s = 0.0852 VC = 0.36%

−0.21

X = 30.69 ± 0.04 s = 0.0627 VC = 0.20%

0.26

23.37

30.61

a b

23.33

30.69

Accuracy = [(found − added)/added] × 100. X = mean.

SA concentration on the peak current in Britton–Robinson buffer solution of pH 2.37 using differential pulse voltammetry is shown in Fig. 6.

Table 3 Specificity results of the differential pulse voltammetry (DPV) methoda Sample no.

Pure sample 40.0 (␮g ml−1 )

Synthetic tablet sample (n = 5) X (␮g ml−1 )

1 2 3 4 5 6

40.12 38.57 40.12 39.29 40.21 39.30

40.10 38.50 40.20 39.25 40.20 39.35

X S.D. VC (%)

39.60 ± 0.27 0.66 1.67

39.58 ± 0.28 0.70 1.77

a X (␮g ml−1 ), mean ± S.E., standard error; S.D., standard deviation; VC, variation coefficient.

4.6. Recovery Recovery studies were performed by adding a synthetic mixture prepared according to the manufacturer’s batch formula (talc, and acetylsalicylic acid) to known amount of SA. The recovery was 100.12%. 4.7. Specificity/selectivity

4.2. Quantification limit (QL) QL is generally determined by the samples with known concentrations of analyte and by establishing the minimum level at which the analyte can be quantified with acceptable accuracy and precision [51]. The precision for SA was established by analyzing six different standard solutions containing the lowest concentration on the calibration graph. The variation coefficient (VC) was 18% (it should be <20%). 4.3. Detection limit (DL) DL is the lowest concentration that can be distinguished from the noise level [52]. In this study, the concentration of SA giving a signal-to-noise ratio of 3:1 was 0.09 ␮g ml−1 . 4.4. Precision The precision of a method is defined as the closeness of agreement between independent test results obtained under prescribed conditions. The precision around the mean value should not exceed 15% of the VC [53]. The precision for SA was 0.435% within the range 1–60 ␮g ml−1 (Table 2). 4.5. Accuracy The accuracy of a method is defined as the closeness of agreement between the test result and the accepted reference value. It is determined by calculating the percentage relative error between the measured mean concentrations and the added concentrations [53]. The accuracy for SA was 0.27% (Table 2).

Specificity is the ability of the method to measure the analyte response in the presence of all the potential interference. For the specificity test, voltammograms of standard solution of tablet excipients as starch were recorded at selected conditions. The response of the analyte with excipients and ASA was compared with the response of pure SA. It was found that assay results were not changed. Therefore, impurities, excipients and ASA as majority compound did not interfere with the quantization of SA as such in synthetic as commercial tablet samples. The results are showed in Table 3.

5. Application to pharmaceuticals The developed DPV method for the SA determination was applied to four different commercial preparations. There is no need for any extraction procedure before DPV analysis. No change of the peak potentials in the presence of the excipients was observed. Table 4 gives the results of DPV analysis of commercial preparations. The HPLC method was employed as a comparison to evaluate the validity of the developed method. Table 5 gives the results obtained using the two methods for six separate determinations starting from different groups of tablets of acetylsalicylic acid. The results were compared and there was no significant difference between the methods. The results obtained from this study showed that the proposed methods can be recommended for the determination of salicylic acid in tablets. The developed method could be easily used in quality control laboratory for the analysis of

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253

Table 4 Determination by DPV of amount of SA contained in various ASA tablets Sample no.

Salicylic acid found (mg per 500 mg of tablet) Bayaspirina® (Bayer)

Aspirina Fecofar® (Fecofar)

Geniol® (Smithkline Beecham)

ASAT 500® (E.J. Gezzi)

Aspirina Vent-3® (Vent-3)

AAS® (Sanofi Synthelabo)

1 2 3 4 5 6

0.390 0.407 0.375 0.371 0.386 0.363

0.498 0.495 0.489 0.492 0.501 0.500

0.420 0.415 0.422 0.425 0.418 0.422

0.548 0.521 0.532 0.510 0.545 0.512

0.463 0.461 0.458 0.456 0.463 0.459

0.495 0.486 0.506 0.510 0.491 0.485

X ± S.D.

0.382 ± 0.016

0.496 ± 0.005

0.420 ± 0.004

0.528 ± 0.016

0.460 ± 0.003

0.495 ± 0.01

Table 5 Results for SA-containing commercial tablets analyzed by two techniques for brand A Sample no.

Salicylic acid found (mg per 500 mg of tablet) DPV

HPLC

1 2 3 4 5 6

0.390 0.407 0.375 0.371 0.386 0.363

0.379 0.419 0.362 0.358 0.390 0.343

X ± S.D.

0.382 ± 0.016

0.375 ± 0.027

SA as a hydrolysis product, in solid pharmaceutical formulations containing acetylsalicylic acid.

Acknowledgements The authors wish to thank the financial support from the Universidad Nacional de San Luis and the Consejo Nacional de Investigaciones Cient´ıficas y Técnicas (CONICET). One of the authors (A.A.J. Torriero) acknowledges support in the form of a fellowship from the CONICET.

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