1 Introduction

The most prevalent complaint of patients examined by the physician is headache [1]. The intracranial and extracranial arteries dilate causing vascular headaches which are categorized as migraine or non-migraine [2]. A reported study regarding the paracetamol/metoclopramide co-formulation showed that this combination was more efficient than using paracetamol only [3]. Metoclopramide (MCP) is a dopamine receptor antagonist, and it is mainly used for its antiemetic effect. Moreover, MCP is used for management of symptomatic gastro-esophageal reflux, vomiting, and nausea induced by chemotherapeutic drugs [4]. Pharmacological effects of metoclopramide is mediated through the cholinergic response of gastrointestinal tract by preventing smooth muscle relaxation resulted from released dopamine [5]. Furthermore, transdermal antiemetic patches with low dose are very effective in relieving chemotherapy patients’ nausea. Therefore, it is crucial to develop a reliable, sensitive, and easy analytical sensors for MCP in vitro/in vivo determination [6].

Paracetamol (PAR) or acetaminophen (AC) is a widely used over-the-counter pain killer and fever reliever [7]. Standard usage of paracetamol is safe on the human body; however, drug over-use may have serious side effects, such as disorders in liver functions, rashes on the skin, and pancreas inflammation [8]. Overdose of PAR is the leading cause of acute liver failure in the UK and the USA. However, currently there is not any rapid and selective point-of-care diagnostic kit available for PAR assessment in the emergency triage [9]. Thus, development of a simple, precise, and selective sensor for determining both PAR and its impurities is very important [10] as PAR impurities are toxic. The PAR impurities that have been studied in this research are the genotoxic and nephrotoxic p-aminophenol (PAP), i.e., acetaminophen impurity E and the hepatotoxic and nephrotoxic p-chloroacetanilide (i.e., acetaminophen related compound J) [11]. PAP is reported to be five times more toxic to the kidney than acetaminophen. PAP is considered as acetaminophen nephrotoxic metabolite as it mediates acetaminophen renal toxicity. Drug safety is affected by the toxicological properties of both the active pharmaceutical ingredient and its impurities. Impurities affect the quality and safety of pharmaceutical products. The impurity profiling of active pharmaceutical ingredients has recently acquired a greater attention [12].

The literature review shows that numerous techniques have been used for the detection of paracetamol, including (HPLC) [13], spectrophotometry [14], chemiluminescence [15], capillary electrophoresis (CE) [35].

The relation between the peak potential and scan rate shows that increasing the scan rate shifts Ep to more positive potentials as represented in Fig. 5D, and the results can be expressed by the following equations:

$$E_p \left( {\text{V}} \right) \, = 0.3375 + 0.0557 \, \log \, \nu \, (Vs^{ - 1} )\left( {R^2 = 0.9993} \right){\text{ for PAR at}}\;{\text{ZrO}}_2 {\text{NP}}/{\text{IL}}/{\text{CPE}}$$
$$E_p \left( {\text{V}} \right) \, = 0.7202 + 0.0539 \, \log \, \nu \, (Vs^{ - 1} )\left( {R^2 = 0.9990} \right){\text{ for MCP at}}\;{\text{ZrO}}_2 {\text{NP}}/{\text{IL}}/{\text{CPE}}$$

Lavern’s theory for irreversible processes [36] was applied in order to calculate the number of electron transferred and to determine other kinetic parameters for PAR and MCP oxidation on the ZrO2NP/IL/CPE.

$$E = E^\circ + 2.303RT/\alpha nF,[\log R\;{\text{at}}\;{\text{K}}^\circ /\alpha nF] + 2.303RT/\alpha nF\,(\log v)$$

where R is the gas constant, T is the temperature, F is the Faraday constant, α is the electron transfer coefficient, and n is the number of the electrons and αn can be calculated from the slope of peak potential against log scan rate. For the system under study, the slopes were 0.0557 and 0.0539 and αn were calculated to be 1.061 and 1.095 for PAR and MCP at ZrO2NP/IL/CPE, respectively. Since for a totally irreversible electron transfer α assumed to be 0.5 [37], therefore “n” value was calculated to be 2.12 and 2.19 for PAR and MCP, respectively, which is consistent with 2 electron transfer processes involved in the oxidation of PAR and MCP at the modified sensor.

3.4.3 Suggested mechanism of PAR and MCP electrochemical oxidation

Based on the results of the experiments, the number of electrons transported (n) for both medicines were determined to be two electrons. As a result, the likely electro-oxidation pathways for both medicines are provided in Scheme 1.

Scheme 1
scheme 1

Proposed mechanisms for oxidation of (i) AMP and (ii) MCP

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3.5 Method validation

The figures of merit were established in compliance with the International Conference on Harmonization (ICH) Guidelines [38].

3.5.1 Linearity

We investigated the electro-analytical response to PAR in the presence of MCP to determine the specificity of the proposed ZrO2NP/IL/CPE sensor. This was accomplished by varying the concentrations of the PAR and MCP at the same time while recording the SWVs with the ZrO2NP/IL/CPE and comparing the results to bare CPE. The voltammetric response of ZrO2NP/IL/CPE sensor toward PAR in the presence of MCP is shown in Fig. 6A. Peak current values and the calibration curves were plotted using the average of three replicate measurements as illustrated in Fig. 6B, C. Linear regression equations of the low concentration range for both the drugs arising from calibration plots are represented as follows:

$$I_{\text{p}} \, = \, 0.{451}C + \, 0.0{531},\quad r^2 = \, 0.{\text{9988 for PAR}}$$
$$I_{\text{p}} \, = \, 0.{9332}C + { 2}.0{248},\quad r^2 = \, 0.{\text{9988 for MCP}}$$
Fig. 6
figure 6

A Square wave voltammogram for different concentrations of PAR and MCP shows well-defined anodic peaks at potentials of +0.421 and +0.792 V (vs. Ag/AgCl), corresponding to the oxidation of PAR and MCP, respectively. B Calibration curve for the low range of concentrations of PAR and MCP. C Calibration curve for the wider range of concentrations of PAR and MCP

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The findings show well-defined anodic peaks corresponding to the oxidation of PAR at potential (+0.421 V) and MCP at potential (+0.792 V) (vs. Ag/AgCl). The calibration parameters are shown in Table 1.

Table 1 Validation parameters of the proposed voltammetric method for determination of PAR and MCP in Britton–Robinson buffer (pH 7.0) at ZrO2NP/IL/CPE
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The formula LOD = 3 s/m is used to measure the limit of detection (LOD), while the formula LOQ = 10 s/m is used to measure the limit of quantification (LOQ), where s is the standard deviation of background current and m is the slope of calibration curve [39]. The LODs for PAR and MCP were determined to be 28 and 29 pM, respectively, while the LOQs were determined to be 93.3 and 96.6 pM, respectively. The calibration characteristics acquired for MCP and PAR are listed in Table 1 since it is vital to calculate validation parameters for any analytical procedure. These results indicate that the proposed method is both accurate and precise.

3.5.2 Specificity (separation peak potential (ΔE p))

Table 2 shows the peak potentials of PAR, MCP, and the toxic metabolites PAP and p-chloroacetanilide. Therefore, we find that the separation peak potential (ΔEp) between PAP and PAR = 0.323 V, PAR and MCP = 0.371 V, and MCP and p-chloroacetanilide = 0.438 V indicating excellent and complete separation of peaks. The suggested method’s specificity was demonstrated by its ability to assess PAR and MCP in pharmaceutical product without interference from frequently used excipients.

Table 2 Peak potentials of PAR, MCP, and PAR Impurities
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Paracetamol is hydrolyzed to p-aminophenol and acetic acid. p-chloroacetanilide could be one of the most related substances to paracetamol [40]. These interfering molecules were chosen from a list of components that are often encountered in pharmaceutical formulations or biological fluids. The concentration of PAR and MCP in a mixed solution containing PAP and p-chloroacetanilide was determined and represented in Fig. 7 showing no interference and good recovery.

Fig. 7
figure 7

SWV voltammogram of PAP (50 nM), p-chloroacetanilide (50 nM), PAR (90 nM), and MCP (90 nM) in a mixture

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3.5.3 Effect of interfering materials

Interfering materials such as starch, glucose, cellulose, sucrose, and K+, Mg2+, and Na+ ions can affect the electro-catalytic determination of PAR and MCP. The response signal of PAR and MCP has been recorded after the incorporation of these compounds into sample solution showing that the applied sensors have high selectivity, and no interference affects the electro-analytical assessment of PAR and MCP, as illustrated in Table 3.

Table 3 The effect of Interference material on the electro-analytical determination of PAR and MCP by SWVs in BRB pH 7.0 at ZrO2NP/IL/CPE
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3.5.4 Determination of PAR and MCP in drug product

The suggested SWV approach was effectively employed to detect PAR and MCP in pharmaceutical formulations after confirming its validity, as shown in Table 4.

Table 4 Determination of PAR and MCP in three different pharmaceutical formulations (i, ii, and iii) using the new proposed modified electrode and application of standard addition technique
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3.5.5 Application in urine and plasma

In addition, we used the SWV method to measure PAR and MCP in spiked human plasma and urine samples, with the findings presented in Table 5. Both medications PAR and MCP recovered well in BR buffer at pH 7.0, according to the results shown in Table 5.

Table 5 Determination of PAR and MCP in plasma and urine using the new proposed sensing protocol
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3.5.6 Statistical comparison of obtained results with the reported method

The accuracy of proposed method was further examined utilizing the student t test and F value to compare the results produced by the suggested approach to a published method [41], which showed no statistically notable difference between the two approaches in terms of accuracy and precision, as shown in Table 6. Moreover, the figures of merit of the sensor were compared to other reported methods as shown in supporting information Table S1.

Table 6 Statistical comparison between the results of determination of pure PAR and MCP by the proposed voltammetric method and a reported ratio subtraction spectrophotometric method
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3.5.7 Reproducibility

Ten electrodes were produced in parallel (as stated in the experimental section) to test the reproducibility of the proposed sensor. For a 0.1 mmol L−1 of two drugs, the relative standard deviation (RSD) for the Ip between electrodes is 2.11% showing that the modified electrodes are reproducible. The relative standard deviation (RSD) of the peak current was 2.30% after the ZrO2NP/IL/CPE was stored dry in air for two weeks, indicating excellent stability of the modified electrodes. Based on the results, the proposed sensor is suitable for regular analysis of PAR and MCP in their combined medicinal dose form. The suggested method provided promising results for further investigations to determine both compounds in plasma and urine.

4 Conclusion

The proposed electrochemical sensor is a simple, selective, and reliable approach for determining PAR and MCP simultaneously using nanocomposite of both ZrO2NP- and IL-modified CPE. The modification of the CPE with nanocomposite increased the electrode surface area and enhanced electron transfer kinetics that resulted in improved sensitivity toward both drugs. The novel approach for electrochemical detection of both PAR and MCP is stable, highly selective, has a wide linear dynamic range, and a low detection limit, with high reproducibility. The suggested sensor was successfully used to determine PAR and MCP in a variety of pharmaceutical formulations (tablets and syrup), as well as spiked human plasma and urine samples, with good results. When compared to other approaches for determining PAR and MCP that have been reported, the suggested method is simple, selective, and quick, as well as possibly portable, and might be utilized for quality control, clinical analysis, as point-of-care in hospital emergency for early detection of PAR overdose and routine drug testing in pharmaceutical formulations.