INTRODUCTION:

Paracetamol or acetaminophen (N-acetyl-p-aminophenol) which is shown in Figure 1, is a commonly used as over-the-counter analgesic (pain reliever) and antipyretic (fever reducer) ^{1, 2}. It is generally used for the relief of headaches and other minor aches and pains. Paracetamol molecule is also the main component in a great number of cold and flu medicines. But when it is combined with opioid analgesics, paracetamol can also be used to alleviate more cruel pain such as post-surgical pain as well as offer palliative care in advanced cancer patients. If it is taken at recommended doses, there is no problem. But excess use of paracetamol creates toxic effect in the body. Overdose of paracetamol leads to the accumulation of poisonous metabolites in the liver,

which may cause severe or fatal hepatotoxicity and nephrotoxicity, skin rashes, and pancreas inflammation. Thus liver and kidney failure occurs. So, a simple, accurate, sensitive and fast analytical method for determination and estimation of paracetamol in pharmaceutical preparations and human plasma is needed. A variety of techniques have been promoted for paracetamol determination in pharmaceutical formulations, biological samples (biological fluids) and even wastewaters, individually or associated to other active compounds (in combination with other drugs).

Figure 1.

Available Techniques:

The different available methods are titrimetric analysis³, Spectrofluorimetry⁴, Chronoamperometry⁵, Colorimetry⁶, Amperometry⁷, Chemiluminescence^8,9, Spectrophotometry (Uv-spectrophotometry)¹⁰, High Performance Liquid Chromatography^11,12 Quantitative Thin-layer Chromatography (TLC)¹³, Flow Injection Analysis (FIA) (using different methods of detection)¹⁴, Gas Chromatography¹⁵. However, the main drawbacks of these techniques are time-consuming. Spectrophotometric, titrimetric, and chemiluminescence methods engage a tedious extraction process before detection; whereas liquid chromatography is time-consuming that makes them unsuitable.

The tremendous progress in experimental electrochemical methods in the field of analysis of drugs is due to their simplicity, cost effective and relatively short analysis time when compared with the other methods. Actually, electrochemical techniques have proven to be helpful for development of very sensitive, accurate and selective methods for the determination of organic molecules including drugs. From electrochemical study, redox properties of drugs can be described. Redox properties of drug molecules can give insights into their metabolic fate or their in vivo redox processes or pharmaceutical activity. Electro analytical techniques can effortlessly solve many problems of pharmaceutical interest with a high degree of accuracy, precision, sensitivity, and selectivity employing this approach. Some of the most important electro analytical techniques are based on the concept of constantly changing the applied potentials to the electrode-solution interface and the resulting current. Voltammetric methods have been very popular and have made valuable contributions. The importance of cyclic voltammetry applications increased gradually, and this due to the following advantages:

1. High level of sensitivity and accuracy

2. The sensitivity may be increased more by modifying voltammety techniques (using microelectrodes and ultra microelectrodes) that improve significantly sensitivity and selectivity of the method.

3. Voltammetry attached with different instruments such as (HPLC, Flow Injection (FI) and Capillary Electrophoresis (CE)) enhancing the analytical properties for complex mixtures in different compounds.

4. It is easily employed in turbid and colored solutions,

5. Only little volumes of samples are necessary.

6. The short analysis time in these techniques makes it very smart for routine determination of the analytes in different samples.

Different Kinds of Electrodes:

Electrochemical methods including voltammetric techniques have been developed for the determination of paracetamol. In cyclic voltammetry experiments, working electrode (sensor electrode) plays the most important role. The electrochemical determination and estimation of paracetamol using various modified electrodes reported in literature, they are: the use of glassy carbon electrodes (GCEs) modified with carbon-coated nickel magnetic nanoparticles¹⁶, GCEs modified with graphene–chitosan composite¹⁷, C60-modified GCE¹⁸, GCEs modified with Nafion/TiO₂–graphene¹⁹, SPE modified with carbon nano tube(CNT)²⁰ and pencil graphite electrode²¹.The electrochemical determination of paracetamol using various modified electrodes constructed from CNTs has been reported^22-28. The nanomaterial-modified electrodes have been employed for electrochemical studies of paracetamol because of their good characteristics, for example, carbon nanotube-modified basal-plane pyrolytic graphite electrodes²³, nanogold-modified indium tin oxide electrodes¹, a polyaniline multi-walled carbon nanotube composite²⁹, single-wall carbon nanotube-dicetyl phosphate films³⁰, glassy carbon electrodes (GCEs) modified with carbon-coated nickel magnetic nanoparticles¹⁶.

Wang et al.¹⁶ prepared carbon-coated nickel magnetic nanoparticles modified glass carbon electrodes (C–Ni/GCE) and the electrochemical properties of paracetamol (ACOP) were examined on the C–Ni/GCE. Carbon-coated nickel magnetic nanoparticles showed an excellent electro catalytic activity for the oxidation of paracetamol and accelerated electron transfer between the electrode and paracetamol. The anodic peaks of paracetamol, dopamine (DA) and ascorbic acid can be well separated on the C–Ni/GCE. Differential pulse voltammetry (DPV) was used for their simultaneous determination. The linear calibration curve of paracetamol was obtained in the range of 7.8 × 10⁻⁶ to 1.1 × 10⁻⁴ mol L⁻¹.The C–Ni/GCE showed good sensitivity, selectivity and stability, and has been applied to the determination of ACOP in effervescent dosage samples. Sun etal³⁰ dispersed single-wall carbon nanotubes (SWNT) into water in the presence of dicetyl phosphate (DCP), and then a SWNT-DCP film-coated glassy carbon electrode (GCE) was developed. The electrochemical response of paracetamol at bare GCE and SWNT-DCP modified GCE were studied and compared, from the result it is seen that the SWNT-DCP-modified GCE significantly increases the oxidation peak current of acetaminophen. A sensitive and simple electrochemical method with a good linear relationship in the range of 1.0 × 10⁻⁷–2.0 × 10⁻⁵ mol L⁻¹, was constructed for the determination of acetaminophen. The detection limit is 4.0× 10⁻⁸ mol L⁻¹.

Kuskur et al³¹ modified carbon paste electrode by electropolymerisation of 1 mM Glycine in 0.2 M Acetate buffer solution (ABS) at pH-5. The voltammetric response of Paracetamol at Poly (Glycine) Modified carbon paste electrode (MCPE) exhibits good electrocatalytic activity when compared to bare carbon paste electrode at sweep rate of 100 mV s^-1. Scan rate variation study showed that the electrode process was diffusion controlled. The concentration effect of paracetamol was also studied.

Fernandez etal³² demonstrated a sensitive sensor electrode for the electrochemical detection of paracetamol. The electrochemical behaviours of paracetamol on screen printed graphene electrodes were studied by cyclic voltammetry. The results indicate that the screen printed graphene electrodes revealed exceptional electrocatalytic activity to paracetamol. The response showed by this sensor was superior when it was compared to the bare screen printed electrodes. This is due to its unique physical and chemical characteristics, π-π interactions and a strong adsorptive capability. They studied the effect of supporting electrolyte, pH of the solution and scan rate. The peak current due to oxidation was linearly proportional to the concentration of paracetamol in the range from 0.1 to 50μM. The proposed method was successfully applied to paracetamol determination in biological samples. An electroanalytical method was developed for the direct quantitative determination of paracetamol in tablet dosage forms based on its oxidation behavior by Engin etal³³. The electrochemical oxidation bhaviour and determination of paracetamol were simply done on glassy carbon electrode (GCE) using different voltammetric techniques. The electrochemical studies were carried out on GCE in various buffer solutions in the pH range from 0.51 to 12.00 by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques. The dependence of pH on the anodic peak current and peak potential was studied. Acetate buffer (pH 4.51) was chosen for analytical purposes. Scan rate variation study shows the diffusion controlled reaction. A linear calibration curve for DPV analysis was constructed in the paracetamol concentration range from 4x10^-6 mol.L^-1 to 1x10^-4 mol.L^-1. Limit of detection (LOD) and limit of quantification (LOQ) were obtained as 3.69 x 10^-7 mol.L^-1and 1.23x10^-6 mol.L^-1respectively. A single-walled carbon nanotube/nickel (SWCNT/Ni) nanocomposite was prepared and immobilized on a glassy carbon electrode (GCE) surface via mechanical attachment by Ngai et al³⁴. They studied the effect of paracetamol concentration, scan rate, pH, and temperature at a SWCNT/Ni-modified electrode in the determination of paracetamol. The characterization of the SWCNT/Ni/GCE was done by cyclic voltammetry. Variable pressure scanning electron microscopy (VPSEM) and energy dispersive X-ray (EDX) spectrometer had been used to examine the surface morphology and elemental profile of the modified electrode, respectively. Cyclic voltammetry results showed significant enhancement in peak current for the determination of paracetamol at the SWCNT/Ni modified electrode. A linear calibration curve was constructed for the paracetamol concentration between 0.05 and 0.50 mM. The SWCNT/Ni/GCE displayed a detection limit of 1.17 × 10⁻⁷ M in paracetamol detection. Results indicate that electrodes modified with SWCNT and nickel nanoparticles exhibit better electro catalytic activity towards paracetamol.

An electrochemical sensor based on the electrocatalytic activity of functionalized graphene for sensitive detection of paracetamol was presented by Kanga et al ³⁵. The electrochemical behaviors of paracetamol on grapheme modified glassy carbon electrodes (GCEs) were studied by cyclic voltammetry and square-wave voltammetry. The results showed that the graphene-modified electrode exhibits excellent electrocatalytic activity to paracetamol. A quasi-reversible redox process of paracetamol at the modified electrode was obtained, and the over-potential of paracetamol decreased significantly compared with that at the bare GCE. Such electrocatalytic behavior of graphene is attributed to its unique physical and chemical properties, e.g., subtle electronic characteristics, attractive – interaction, and strong adsorptive capability. This electrochemical sensor shows an excellent performance for detecting paracetamol with a detection limit of 3.2 × 10⁻⁸ M. The sensor shows great promise for simple, sensitive, and quantitative detection and screening of paracetamol. The electrochemical behavior of paracetamol was also studied at a graphene - modified carbon paste electrode by cyclic voltammetry in an ammonium buffer solution (pH 8.5) by Bahramipur et al ³⁶. The modified electrode showed excellent electrocatalytic activity towards the oxidation and reduction of paracetamol resulting in a remarkable lowering of the peak potentials and considerable improvement of the peak currents as compared to the bare electrode. Despite the irreversible behavior at the surface of a carbon paste electrode, a quasi-reversible redox process at the graphene modified electrode was observed for paracetamol with a peak separation of 66 mV at a scan rate of 50 mV s^-1. The advantages are related to the unique properties of graphene such as large surface area, and increased electron transfer abilities compared to graphite. Square wave voltammetry was applied to the quantitative determination of paracetamol using the graphene modified carbon paste electrode after an accumulation time of 2 min. The method was used in the determination of paracetamol in pharmaceutical preparations and urine samples successfully. Gete³⁷ et al studied the electrochemical response characteristics of modified carbon paste electrode towards detection and determination of paracetamol. They used cyclic voltammetric technique in 0.1 M acetate buffer solution containing 0.1 M KCl as supporting electrolyte. Nickel Hexacyanoferrate modified carbon paste electrode was developed by immobilizing different ratios of Nickel Hexacyanoferrate. The most excellent ratio for kinetic parameter and paracetamol determination was 20% (w/w) NiHCF; 55% graphite and 25% (w/w) paraffin oil respectively. For the determination of paracetamol concentration, an accurate amount of 500 mg Paramol, Cadimol, Paracetamol and Panamol tablets were given to four different 100 ml volumetric flask and this volume filled with acetate buffer (pH 7.5).The percentage content or concentration of acetaminophen in these 500 mg paracetamol tablet samples were determined. The detection limit of the modified carbon paste electrode was 8.89 x 10^-5 M for paracetamol. The relative standard deviations for the determination of paracetamol was less than 2%. Transfer coefficient (α) and heterogeneous electron transfer rate constant k for catalytic reaction were 0.705 and 2.37 × 10^-2 s ^-1 respectively.

CONCLUSION:

Quantitative determination of paracetamol is important in the quality assurance of pharmaceutical industry and vital for the healthcare industry. Cyclic voltammetry is a powerful and versatile analytical technique that offers high sensitivity, accuracy, and precision. The above reported methods for synthesizing high performance catalysts for paractetamol showed good detection limits and sensitivity.

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Received on 12.04.2017 Modified on 20.04.2017

Res. J. Pharmacology & Pharmacodynamics.2017; 9(2): 88-92.

DOI: 10.5958/2321-5836.2017.00015.5