A categorical review on electroanalytical determination of non-narcotic over-the-counter abused antitussive drugs

Talanta 142 (2015) 157–163

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Talanta journal homepage: www.elsevier.com/locate/talanta

Review

A categorical review on electroanalytical determination of non-narcotic over-the-counter abused antitussive drugs Neeta Thapliyal a, Harun Patel a, Rajshekhar Karpoormath a,n, Rajendra N. Goyal b, Rajkumar Patel c a Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville Campus), Durban 4000, South Africa b Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India c Division of Physics & Semiconductor Science, Dongguk University, Seoul 100-715, South Korea

art ic l e i nf o

a b s t r a c t

Article history: Received 30 March 2015 Received in revised form 20 April 2015 Accepted 21 April 2015 Available online 29 April 2015

Dextromethorphan (DXM) and diphenhydramine (DPH) are two commonly used over-the-counter nonnarcotic antitussive drugs. Recent reports reveal the widespread abuse of DXM and DPH due to their euphoric and alcohol-like effects. Due to their medicinal importance as well as the apparent increase in their use as abused drugs, it has become critical to determine them in samples of biological, clinical and pharmaceutical interest. The electrochemical techniques for drug analysis have gathered considerable attention due to their pronounced selectivity, sensitivity and simplicity. The given review presents a compilation of published voltammetric and potentiometric methods developed for determination of DXM and DPH. It critically highlights the analytical performances, revealing the recent trends and progress in the specified approach for their analysis. The review forms a basis for further progress in this field and development of improved electrochemical sensors to determine the drug. & 2015 Elsevier B.V. All rights reserved.

Keywords: Dextromethorphan Diphenhydramine Drug abuse Determination Voltammetry Potentiometry

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electroanalytical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Voltammetric methods of analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Dextromethorphan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Diphenhydramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Potentiometric methods of analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Dextromethorphan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

158 158 159 159 159 160 160

Abbreviations: AA, Acrylic acid; BEHS, Bis (2-ethylhexyl) sebacate; BIA, Batch injection analysis; BIA-MPA, Batch injection analysis system with multiple pulse amperometric detection; CDs, β-Cyclodextrins; CGE, Coated graphite electrode; CNP/CPE, Carbon nanoparticles-modified carbon paste electrode; CPE, Carbon paste electrode; CV, Cyclic voltammetry; CWE, Silver coated wire electrode; DBS, Dibutylsebacate; DOP, Dioctylphthalate; DPASV, Differential pulse anodic stripping voltammetry; DPH, Diphenhydramine; DPH-PL, Diphenhydramine-picrolonate; DPH-RN, Diphenhydramine-reineckate; DPH-TPB, Diphenhydramine-tetraphenylborate; DPV, Differential pulse voltammetry; DXM, Dextromethorphan; DXM-PM, Dextromethorphan-phosphomolybdate; DXM-RN, Dextromethorphan-reineckate; DXM-TPB, Dextromethorphan tetraphenylborate; DyNW/CPE, Dysprosium nanowire modified carbon paste electrode; EME, Electromembrane extraction; FFT-CV, Fast Fourier transform-cyclic voltammetry; FFT-SWV, Fast Fourier transform-square wave voltammetry; FIA, Flow injection analysis; GCE, Glassy carbon electrode; ICPE, Carbon paste electrode with sodium tetraphenyl borate ion pairing agent; ICPE, Ionic liquid based carbon paste electrode; INCPE, Carbon nanotube-carbon microparticle-ionic liquid composite carbon paste; IPs, Ion-pairs; ISEs, Ion-selective electrodes; ISPE, Screen-printed electrode with sodium tetraphenyl borate ion pairing agent; LOD, Limit of detection; LOQ, Limit of quantification; MCPE, Carbon paste electrode with DPH-TPB ion pair; MIP, Molecularly imprinted polymers; MSPE, Screen-printed electrode with DPH-TPB ion pair; NaTFPB, Sodium tetrakis (4-fluorophenyl) borate; NaTPB, Sodium tetraphenylborate; NCPE, Carbon nanotubes modified carbon paste electrode; NH4TPB, Ammonium tetraphenylborate; NIP, Nonimprinted polymers; o-NPOE, o-Nitrophenyl octyl ether; PCP, Phencyclidine; PHE, Phenylephrine; PMA, Phosphomolybdic acid; PT, Phosphotungstate; PTA, Phosphotungstic acid; PTp-CIPB, Tetrakis(p-chlorophenyl)borate; PVC, Polyvinyl chloride; RAS, Reineckate ammonium salt; RGO-SPCE, Reduced graphene oxide modified screen-printed carbon electrode; SPEs, Screen printed carbon electrodes; STA, Silicotungstic acid; TCP, Tricresylphosphate; THF, Tetrahydrofuran; TPB, Tetraphenylborate; VPY, Vinyl pyridine n Corresponding author. Tel.: þ 27 312607179; fax: þ 27 312607792. E-mail address: [email protected] (R. Karpoormath). http://dx.doi.org/10.1016/j.talanta.2015.04.061 0039-9140/& 2015 Elsevier B.V. All rights reserved.

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2.2.2. 3. Conclusion . . . Acknowledgement. References . . . . . . .

Diphenhydramine ................ ................ ................

...................................................................................... ...................................................................................... ...................................................................................... ......................................................................................

1. Introduction Dextromethorphan (a synthetic analog of codeine and d-3methoxy-17-methylmorphinan; Fig. 1) (DXM) is effective over the counter antitussive medicine widely used for treating chronic cough since the last four decades [1–3]. It brings relief from non-productive cough by directly acting on the cough centre present in the medulla [4]. Other uses of the drug include treatment of cold, pseudobulbar disorder, methotrexate-induced neurotoxicity, depression and pain relief [5–10]. Upon oral ingestion, dextromethorphan is quickly absorbed from the gastrointestinal tract and it starts exerting its activity within 15–60 min of ingestion [11,12]. The peak plasma concentration (in the range 1–20 mmol L  1) is attained in almost 2–3 h [12]. DXM metabolises rapidly in liver to dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan and is mainly excreted as an unchanged parent drug and dextrorphan [13,14]. The drug is beneficial when administered in recommended doses. However, acute overdosage of DXM affects the central nervous system and may also lead to coma which can be fatal [15]. Administration of dextromethorphan with monoamine oxidase and selective serotonin re-uptake inhibitors is avoided because it may lead to accumulation of excess serotonin in the body causing serotonin syndrome, a life threatening condition [16,17]. Though DXM is a very effective safe-to-use medicament, a high dose of the drug replicates phencyclidine and alcohol like effect such as hallucination, paranoia, euphoria and suicidal tendency [18]. It is for this reason that the drug is massively abused worldwide for recreational purposes [19]. Popularly known as “skittles,” “robos,” “rojos,” “velvet,” “CCC” and “poor man's PCP” among recreational users, unrestricted access and low cost of the drug has made it an inexpensive alternative to illegal psychotropic drugs leading to a considerable increase in its abuse in recent years [20]. Frequent ingestion of extremely high doses of DXM has been reported to result in impaired motor function, increased heart rate and blood pressure, rhabdomyolysis and drug accumulation eventually leading to toxicity [21–23]. Hypoxic brain damage, though rare, may also occur [24]. According to the Drug Abuse Warning Network Report, almost 1% of all emergency room drugrelated visits are related to DXM abuse [25]. Diphenhydramine, 2-(diphenylmethoxy)-N,N-dimethylamine (Fig. 1) (DPH), is widely used as an antiallergic, antiemetic and antitussive drug [26,27]. DPH can cause strong sedation and hence, is widely used for insomnia as well [28]. It is also used to manage drug-induced Parkinsonism [29]. Being an anticholinergic agent, it may cause side effects such as increased heart rate, dehydration, enlarged pupils, blurred vision, ringing in the ears and constipation

Fig. 1. Chemical structures of Dextromethorphan and Diphenhydramine.

161 162 162 162

[30]. Acute overdosage may lead to complications like kidney failure, pancreatitis, cardiac arrest, coma, or even death within 2–18 h [31–33]. The drug is widely distributed throughout the body and the peak plasma concentration is attained in about 2–3 h after dosage, with 5–15% of a therapeutic dose of the drug excreted unchanged in human urine [34,35]. Being easily available, DPH is sometimes used as a recreational drug due to its euphoria and delirium-induced hallucination properties, which can be fatal in case of serious overdose [36,37]. On account of medical and pharmacological importance of DXM and DPH as well as the increasing trend of their abuse, there is a need to develop reliable, highly selective and sensitive analytical methods to quantify the drugs in pharmaceutical products and in human body fluids. An efficacious drug analysis requires achieving sensitivities at micromolar or even lower levels along with appreciable selectivity in real samples. Several analytical methods have been employed for the determination of the drugs. Most of these rely on chromatographic techniques such as highperformance liquid chromatography [38–41], gas chromatography [42–44] and thin-layer chromatography [45–47]. These methods require time-consuming sample preparation steps, expensive instruments and complex procedures. Currently, the area of development and application of electrochemical methods in pharmaceutical and biomedical analysis is under rapidly growing interest for the determination of extremely low concentration of drugs and/or their metabolites in clinical samples. The electroanalytical methods possess simplicity, high sensitivity, excellent selectivity, and low cost and are easy to use allowing direct analysis of analyte without the need of any separation or pre-treatment steps, thus making it an appealing method of choice for drug analysis [48]. The present paper aims to reveal the trends in the development of electrochemical methods for the determination of DXM and DPH to date. Various voltammetric and potentiometric methods used to determine the drug in bulk, pharmaceutical formulations and biological fluids have been discussed in the present review. To the best of our knowledge, this is the first attempt to summarise the electroanalytical methodologies reported for quantification of the over-the-counter non-narcotic antitussive drugs, DXM and DPH.

2. Electroanalytical methods Electroanalytical methods belong to a group of techniques in analytical chemistry, wherein the analyte of interest is studied by measuring the voltage (potential) and/or current signals in an electrochemical cell. Their extensive use is attributed to relatively cheap instrumentation, high accuracy, precision and sensitivity, rapid analysis time, and ability to simultaneously determine various analytes in a solution [49]. Also, the technique boasts of direct analysis of the sample without any tedious and long preparative steps [50]. Hence, it is being increasingly used for drug analysis in pharmaceutical formulations and biological samples. There are a variety of electrochemical methods, the principal ones being voltammetry and potentiometry. The given review critically discusses the voltammetric and potentiometric methods reported in literature for the determination of the over-the-counter abused antitussive drugs, DXM and DPH.

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2.1. Voltammetric methods of analysis Voltammetry is a versatile analytical technique based on measuring the current that flows through an electrode dipped in electroactive species containing solution, as the potential is varied. The measured current is directly proportional to the analyte concentration in a given range, and this forms the basis of routine use of voltammetric techniques for the quantitative determination of a range of organic and inorganic compounds. Voltammetric methods of analysis have been receiving considerable attention since the past few decades due to their simplicity, efficiency and low cost. It is well-known that modification of the conventional working electrode surface imparts high sensitivity and selectivity to the analyte response. Advent of chemically modified electrodes has further enhanced the scope and analytical applicability of the technique in the field of drug analysis. However, in spite of the intense research and immense development in the voltammetry-based techniques, literature search revealed that these methods have rarely been used for the quantification of the non-narcotic antitussive drugs, DXM and DPH. 2.1.1. Dextromethorphan One of the first reports that used voltammetry to determine DXM was proposed by Lin et al. [51] in 2010. The voltammetric behaviour of DXM was investigated in Britton–Robinson buffer solution at a glassy carbon electrode (GCE) using cyclic voltammetry (CV) and differential pulse anodic stripping voltammetry (DPASV). A single anodic peak was observed at 1.0 V at a pH of 6.5. The practical analytical applicability of the method was tested in DXM hydrobromide tablets and good recovery was detected in the range from 98.6% to 102.9%. The method was fast, simple and had practical applicability. Later, Heli and co-workers [52] studied the electrooxidation of dextromethorphan at carbon paste electrode (CPE), carbon nanotubes modified CPE (NCPE), ionic liquid based CPE (ICPE) and carbon nanotube-carbon microparticle-ionic liquid composite electrode (INCPE) in a 0.1 mol L  1 phosphate buffer solution. The cyclic voltammogram displayed an irreversible oxidation peak at all the four electrodes. An improved current response was observed at the ionic liquid based electrodes with the INCPE displaying the highest peak current and the lowest peak potential value. The best voltammetric response at INCPE was due to the presence of the nanocomposite that incorporated the unique characteristics of both the ionic liquid and carbon nanotubes. The effect of some common interferents and pharmaceutical excipients was checked on the voltammetric response of DXM and it was found that none of the selected interferents/excipients affected the current response of the drug. The method was then successfully validated for DXM quantification in pharmaceutical formulations (tablets, syrups and oral drops). The method was simple, selective and reliable. However, the report failed to mention the reproducibility and stability of INCPE. The detection limit (LOD) and limit of quantification (LOQ) were also comparatively higher. Another drawback of the method was that it required stirring the solution for few seconds after each amperometric injection in order to increase solution homogenisation.

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Electromembrane extraction (EME) was combined for the first time with differential pulse voltammetry (DPV) and used for the determination of DXM at a reduced graphene oxide modified screen-printed carbon electrode (RGO-SPCE) resulting in enhanced electrochemical signals [53]. This new strategy of coupling EME with DPV encompassed the benefits of both the techniques making the method highly selective, inexpensive, having short analysis time and simple. The electrochemical behaviour of the drug was investigated using CV. A single anodic peak was observed at both the bare and modified electrodes indicating the irreversible nature of the electrochemical oxidation. A significant enhancement in the peak current value was observed at RGO-SPCE which was attributed to the increased real surface area at the modified electrode. The practical analytical applicability of the method was successfully evaluated in spiked human plasma and urine samples. The method was found to be comparable to other analytical methods reported in the literature for DXM determination in terms of LOD, broad linear concentration range and recoveries. The method, however, failed to specify the effect of interferents on the electrochemical response of DXM. Recently, Amiri et al. [54] developed a tosyl carbon nanoparticles based voltammetric sensor for determination of DXM in presence of phenylephrine (PHE) and paracetamol. The carbon nanoparticles-modified carbon paste electrode (CNP/CPE) successfully separated the overlapping oxidation peaks of PHE and DXM at bare electrode into two distinct voltammetric peaks. The method displayed easy fabrication of electrode, fast electron transfer, good reproducibility and appreciable sensitivity. The method was validated in human serum and commercial tablets using DPV. However, the effect of interferents on the voltammetric response of the drug was not evaluated. A list of voltammetric methods along with their basic parameters for the determination of DXM is depicted in Table 1. 2.1.2. Diphenhydramine Daneshgar et al. [55] fabricated a dysprosium nanowire modified carbon paste electrode (DyNW/CPE) to determine trace levels of the drug using fast Fourier transform square-wave voltammetry (FFT-SWV) technique. The method was simple, fast and sensitive having appreciable precision and accuracy. DPH was successfully quantified in tablets, spiked human plasma and urine samples. No interference from drug excipients as well as the matrix of biological fluids was observed, indicating the non-requirement of any prior extraction steps. The method overcomes the limitations of material waste and time consumption of earlier reported methods. Norouzi et al. [56] adopted a new electrochemical method based on flow injection analyis (FIA) and Fast Fourier Transform cyclic voltammetry (FFT-CV) for determination of DPH at gold microelectrode. The method was rapid, highly efficient and exhibited significant sensitivity, accuracy and precision. The formulation compounds did not show any interference to the determination of diphenhydramine, confirming the selectivity of the method. No prior extraction step was required during quantification of the drug in spiked plasma and urine. The disadvantage of the technique was that before each experiment, the electrode surface required to be polished first for a minute using extra fine

Table 1 Comparative characteristics of the voltammetric methods for determination of DXM. Electrode

Technique

Linear concentration range (mol L  1)

LOD (mmol L  1)

LOQ (mmol L  1)

pH

Ref.

GCE INCPE RGO-SPCE CNP/CPE

DPASV CV EME- DPV CV

4.0  10  6–8.0  10  5 3.0  10  5–3.3  10  3 5.0  10  6–1.5  10  3 8.0  10  6–8.0  10  4

0.56 8.81 1.50 2.89

N/R 29.36 N/R N/R

6.5 7.4 6.0 7.0

[51] [52] [53] [54]

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Table 2 Response characteristics of the voltammetric methods for determination of DPH. Electrode

Technique

Linear concentration range (mol L  1)

LOD (mmol L  1)

LOQ (mmol L  1)

pH

Ref.

DyNW/CPE Gold microelectrode BDD

FFT-SWV FFT-CV BIA-MPA

1.0  10  10–1.0  10  7 1.0  10  11–4.0  10  7 1.0  10  5–6.0  10  5

4.0  10  5 5.0  10  6 0.15

8.0  10  5 4.0  10  5 0.50

7.0 2.0 4.7

[55] [56] [57]

carborundum paper and then for 10 min with 0.3 μm alumina, which was highly time-consuming. Also, there was possibility of desorption of the adsorbed DPH from the electrode surface during the potential scanning. Recently, Freitas et al. [57] investigated the electrochemical behaviour of diphenhydramine at boron-doped diamond electrode using CV. DPH was then determined in presence of 8-chlorotheophylline used batch injection analysis system with multiple pulse amperometric detection (BIA-MPA). The advantages associated with the technique are simplicity, low cost and high analysis speed. However, the method fails to demonstrate its feasibility to determine DPH in human body fluids. Table 2 displays the performance characteristics of the voltammetric methods reported for determination of DPH. 2.2. Potentiometric methods of analysis Potentiometry is one of the well-established electroanalytical techniques offering a rapid and simple procedure to determine a varied range of inorganic and organic substances. The method generally involves a transducer/ion-selective electrode that possesses high specificity towards an ion or a class of ions, thus enabling the selective detection of analyte in presence of other substances. Potentiometric detection based on ion-selective electrodes (ISEs) offers a number of advantages that includes ease of preparation and procedures, fast response, appreciable selectivity and low cost. Recent improvements in potentiometric sensors have resulted in effective trace analysis at sub-nanomolar concentrations [58]. A considerable number of papers have been reported for the determination of DXM and DPH using these methods. 2.2.1. Dextromethorphan The first study highlighting the use of potentiometry for determination of dextromethorphanium ion was performed at a simple plastic membrane electrode by Higuchi et al. [59]. Analysis of the drug was conducted at a polyvinyl chloride (PVC) – amide indicating electrode by titrating with sodium tetraphenylboron. Almost two decades later, simple plasma-polymerised membrane electrodes having ammonium tetraphenylborate (NH4TPB) as the ionexchanger were constructed and optimised for successful quantification of DXM in bulk and pharmaceutical formulations [60]. On evaluating the selectivity of the sensor it was observed that though selective over a number of interfering species (Na þ , K þ , Ca2 þ , glucose, urea, glycine, histidine, lysine, and acetylcholine), slight interference was observed from NH4 þ , tetraethyl ammonium ion, creatinine and atropine. The electrode exhibited a life-term of six months. However, it was necessary to store the electrode in dioctylphthalate (DOP) when not in use. El-Naby [61] developed a potentiometric sensor for the selective detection of DXM using dextromethorphan-reineckate (DXM-RN) or dextromethorphan-phosphomolybdate (DXM-PM) complex as the electroactive material. The sensor was fabricated by incorporating the ion-association complex in a PVC matrix plasticized with DOP or dibutylsebacate (DBS). The best response was attained with the DXM-PM based sensor plasticized with DOP. No interference was observed from several opiate and non-opiate alkaloids, amides,

amino acids, inorganic cations and xanthines confirming the remarkable selectivity of the sensor for DXM. The analytical applicability of the method was validated by successful analysis of DXM in the working range from 5  10  5 to 5  10  3 mol L  1 in pharmaceutical dosage forms. A potentiometric method under batch and flow injection analysis conditions was described by Khaled et al. [62] for the determination of DXM in pure and pharmaceutical preparations. Novel CPE and PVC electrodes were fabricated by incorporating ion pairing agents or ion-pairs (IPs) viz. phosphomolybdic acid (PMA), phosphotungstic acid (PTA), reineckate ammonium salt (RAS), sodium tetraphenylborate (NaTPB) and silicotungstic acid (STA). Both CPE and PVC electrodes plasticized with o-nitrophenyl octyl ether (o-NPOE) and modified with varying DXM-IPs gave Nernstian slopes in the concentration range from 10  5 to 10  2 mol L  1. A fast response time was noted for all developed CPEs. For PVC electrodes, the best response time (5 s) was noted for the electrode having DXM-TPB as the electroactive material. The PVC electrodes showed a relatively shorter lifetime (14–28 days) as compared to the different modified CPEs which displayed a 30–60 days lifeterm. Appreciably high selectivity of the sensors was noticed for many inorganic cations (Na þ , K þ , Li þ , Ca2 þ , Mg2 þ and NH4 þ ) and various other interferents/additives usually present in pharmaceutical preparations (caffeine, citrate, glycine, maltose, starch and sucrose). Being solid, CPE was found to be easier to incorporate in FIA system as compared to PVC electrode. The FIA system was preferred, since it allowed high sampling output with a relatively short analysis time ( 1 min). Later, the same team developed disposable DXM sensitive potentiometric sensors based on screen printed electrodes (SPEs) using home-made carbon ink utilising the same IPs [63], as mentioned above. The modified electrodes were in the form of a bi-electrode strip having both working and reference electrodes. Among the developed SPEs modified with different DXM ion-pairs, DXM-TPB incorporated electrode displayed the best response. Further evaluation of the response parameters revealed that SPEs modified with DXM-TPB exhibited better response as compared to the SPEs having ion-pairing agents, which exhibited a Nernstian slope, fast response time and an operational lifetime of 4 weeks. No significant interference was observed from various inorganic cations as well as additives commonly found in pharmaceutical formulations. The proposed electrodes were then effectively employed for DXM assay in pharmaceutical formulations (tablets and drops) under BIA and FIA conditions. β-Cyclodextrins (CDs) based silver coated wire electrode (CWE), coated graphite electrode (CGE) and PVC membrane electrodes were developed as potentiometric sensors for the quantification of DXM [64]. The fabricated DXM sensors exhibited Nernstian response with an enhanced sensitivity that was attributed to the ability of CDs to form inclusion complexes (by encapsulating DXM molecule). Various β-CD ionophores (pure β-CD, heptakis (2, 6-di-omethyl)-β-CD, heptakis (2, 3, 6-tri-o-methyl)-β-CD and 2-hydroxypropyl-β-CD) were used, among which the best response was shown by the CWE sensors fabricated with heptakis (2, 6-di-omethyl)-β-CD ionophores and sodium tetrakis (4-fluorophenyl) borate (NaTFPB) with o-NPOE as the plasticizer. DXM determination was found to be free from any interference from inorganic cations

161

5–10 10 5 1.6 1.6 4 60 60 2 5–7 2.5–6.5 3–8 3–7 3–7 4–7 2–9 2–9 3–9 59.1 59.5 7 0.6 56.4 7 0.7 55.7 7 0.9 58.1 7 0.5 59.0 7 0.2 55.9 52.4 57.2 1.0  10  5–1.0  10  2 NH4TPB, DOP DXM-PM, DOP, PVC, THF 2.0  10  6–1.0  10  2 DXM-TPB, o-NPOE, THF, PVC 1.0  10  5–1.0  10  2 DXM-TPB, o-NPOE, carbon powder 1.0  10  5–1.0  10  2 DXM-TPB, o-NPOE, PVC, carbon powder 1.0  10  5–1.0  10  2 heptakis (2,3,6-tri-o-methyl)-β-CD, NaTFPB, o-NPOE, PVC, THF 1.0  10  7–1.0  10  2 VPY, BEHS, PVC, THF 1.0  10  5–1.0  10  2 AA, DOP, PVC, THF, graphite rod 5.0  10  7–1.0  10  2 DXM PTp-CIPB ion pair complex, DOP, PVC 5.0  10  6–1.0  10  2 Plasma-polymerized membrane PVC-matrix PVC-matrix CPE SPE CWE MIP based liquid electrode MIP based graphite electrode PVC-matrix

N/R 1 7.9 10 6 0.07 3 0.2 2

Composition Type of electrode/sensor

Table 3 Summary of potentiometric sensors for the determination of DXM.

2.2.2. Diphenhydramine Coated wire and polymer membrane based DPH sensors were fabricated by incorporating the DPH-TPB ion pair in a plasticized PVC film [67]. The sensors exhibited Nernstian response in specific concentration ranges depending on electrode type and were found to be highly selective for DPH with respect to various interfering species commonly present in biological fluids and commercial pharmaceutical formulations. Analytical applicability of the sensor was then successfully evaluated by determining the drug in antihistaminic syrups. Later, Shen et al. [68] developed DPH-selective electrodes using various ion-pair complexes, namely diphenhydramine-reineckate (DPH-RN), diphenhydramine-picrolonate (DPH-PL), diphenhydramine-tetraphenylborate (DPH-TPB) and DPH-[HgI4]2 as the active material. It was found that the electrode with DPH-TPB ionpair complex exhibited the best response characteristics. Upon investigating the selectivity coefficients of the electrode towards various interferents, only quinine, levamisole and dibazole showed noticeable interference. The proposed electrode was simple, fast and displayed good reproducibility. The performance of DPH-selective electrodes using various ionpair complexes of DPH were compared by Erdem et al. [69]. The investigated ion-pairing agents were tetraphenylborate (TPB), phosphotungstate (PT) and reineckate (RN). Based on the response characteristics of the electrodes, the one with DPH-TPB ion-pair complex in PVC membrane was selected to determine the drug in

Linear concentration range (mol L  1) LOD (mmol L  1) Slope (mV decade  1) Working pH range Response time (s) Ref.

as well as additives/interferents usually present in pharmaceutical preparations. The proposed method was then applied for DXM assay in pharmaceutical dosage forms under potentiometric titration and FIA conditions. Novel molecularly imprinted (MIP) and non-imprinted polymers (NIP) based liquid and graphite coated DXM hydrobromide selective electrodes were developed incorporating bis(2-ethylhexyl) sebacate (BEHS) and DOP as plasticizers in a PVC matrix [65]. Vinyl pyridine (VPY) and acrylic acid (AA) were used as monomers for the synthesis of MIP. All the liquid electrodes, except the ones based on BEHS and AA, exhibit a rapid near Nernstian response in linear concentration ranges between 10  2 and 10  5 mol L  1. VPY and BEHS based liquid electrode gave the best result with a detection limit of 3 mmol L  1 and was thus used further to determine dextromethorphan concentration in antitussive and cold syrup samples. Among the MIP and NIP based graphite coated electrodes having 0.5 mm membrane thickness, a near Nernstian response was observed at only the AA and DOP based MIP electrode. The electrode displayed a fast response time with a low detection limit of 2.0  10  7 mol L  1 and hence was further used for quantitative determination of DXM in pharmaceutical preparations. Interference studies revealed that amoxicillin, glucose, ketorolac, paracetamol, sodium bromide, potassium nitrate and barium nitrate did not interfere with the determination of DXM. However, ciprofloxacin was found to interfere at low concentrations. The developed electrodes were stable and possessed a life term of three months. Recently, Elmosallamy and Amin [66] fabricated a simple potentiometric DXM sensor based on ion-pair complex of DXM tetrakis (p-chlorophenyl)borate (PTp-CIPB) as the ion-exchanger in a plasticized PVC matrix membrane and o-NPOE or DOP as plasticizer. The DXM sensor showed a near Nernstian response with a detection limit of 2 mmol L  1. The lifetime of the DOP and o-NPOE based sensor was 11 and 12 weeks, respectively. Significant selectivity to DXM was observed in presence of inorganic cations, urea, glucose, codeine, morphine, ephedrine, pharmaceutical additives and diluents commonly present in pharmaceutical formulations. Since DOP based DXM sensor was found to exhibit higher selectivity, it was applied for determination of DXM in pharmaceutical preparations. Table 3 shows the overview of potentiometric sensors reported till date for the determination of DXM.

[60] [61] [62] [62] [63] [64] [65] [65] [66]

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Table 4 Summary of potentiometric sensors for the quantification of DPH. Type of electrode/ sensor

Composition

Linear concentration range ( mol L  1)

PVC-matrix PVC-matrix PVC-matrix SPE CPE MSPE ISPE MCPE ICPE

TPB, PVC 3.2  10  6–1.0  10  1 TPB, PVC, DOS 3.5  10  5–1.0  10  2 BiI, PVC 2.6  10  5–1.0  10  1 NaTPB, TCP, o-NPOE 1.0  10  6–1.0  10  2 NaTPB, TCP, o-NPOE 1.0  10  6–1.0  10  2 NaTPB, TPB, TCP 1.0  10  6–1.0  10  1 NaTPB, TPB, TCP 1.0  10  6–1.0  10  1 NaTPB, TPB, TCP 1.0  10  6–1.0  10  1 NaTPB, TPB, TCP 1.0  10  6–1.0  10  1

bulk and pharmaceutical preparations. The developed sensor was also used for dissolution study of DPH released from tablets. The sensor showed good selectivity for the drug with respect to lactose, glucose, sucrose, glycine, NH4 þ , Ca2 þ , K þ , Na þ , trisodium citrat-5,5 dihydrate, papaverine, ephedrine and codeine, normally present in biological fluids or with DPH in pharmaceutical preparations. The developed sensor exhibited an additional application of determining the amount of drug released from dosage form in dissolution test. However, the observed detection limit was high as compared to other reported methods. Li et al. [70] reported a PVC membrane-DPH selective electrode based on bismuth iodide and DPH molecular association complex. The electrode exhibited analytical characteristics with nearNernstian response towards the drug and applied for the determination of DPH in pharmaceutical preparations tablet using the standard curve method. The analytical characteristics of screen-printed electrodes (SPE) and CPEs were evaluated for the determination of diphenhydramine in pure, capsules, urine and serum samples [71]. Based on the ion-pair formation between DPH and NaTPB as electroactive material and o-NPOE as plasticizer in DPH matrix, the sensors showed near-Nernstian sensitivity with a low detection limit. The SPE exhibited better performance as compared to CPE with respect to total potential change, potential break at the end point and the response time. The SPE and CPE sensors showed a lifetime of 63 and 55 days, respectively. Though disposable, the electrodes could be successfully used for at least 50 consecutive measurements, suggesting good stability. The effect of interfering species (pharmaceutical excipients and fillers in drug formulations, carbohydrates and nitrogenous compounds such as amines, glycine, and some inorganic cations) was investigated and the sensor was found to show good selectivity. The method was easy, fast and inexpensive; however it required prior separation steps before quantifying the drug in biological fluids Recently, Akl et al. [72] introduced new potentiometric DPH sensor based on the ion-pair formation between DPH and NaTPB as electroactive material and tricresylphosphate (TCP) as plasticizer in DPH matrix. The sensor displayed near-Nernstian sensitivity with a low detection limit. The electrodes exhibited good stability with a life time of up to 76, 71, 62 and 57 days for ISPE, MSPE, ICPE and MCPE sensors, respectively. An appreciable selectivity for DPH was observed in the presence of pharmaceutical excipients, various carbohydrates and nitrogenous compounds such as amines, glycine, and some inorganic cations. The method was then validated in commercial pharmaceutical formulations. However, the developed electrodes were not applied to determine the drug in biological fluids. Table 4 lists the response characteristics of potentiometric methods reported till date for the determination of DPH.

LOD (mmol L  1) Slope (mV decade  1)

Working pH range

Response time (s)

Ref.

1.6 30.0 19 0.97 0.98 0.965 0.968 0.978 0.976

2.5–5.5 2.0–7.5 – 3.0–8.0 3.0–7.0 2.5–8.0 3.0–9.0 2.5–7.0 3.0–8.0

– r 20 – 10 16 5 6 10 11

[68] [69] [70] [71] [71] [72] [72] [72] [72]

60.0 51.0 48 55.2 7 1.0 54.7 7 1.0 56.20 7 0.65 59.14 70.90 55.86 7 1.12 60.03 7 1.32

3. Conclusion Given the rapid surge in non-narcotic antitussive drug abuse cases, the development of simple yet highly proficient methods for their analysis is vital. Owing to simple instrumentation, economical, no prerequisite of sample pre-treatment, fast response time, and excellent sensitivity and selectivity, the electrochemical techniques are being preferred over highly complex and costly chromatographic techniques for drug determination in medicinal and biological samples. Substantial progress was observed in the development of potentiometric sensors for DXM and DPH. PVC membrane based sensors were most extensively used with a wide linear concentration and fast response time. With respect to the use of voltammetric techniques, very few articles were reported for the quantification of DXM and DPH, with rare usage of modified electrodes. Considering the increasing use of nanotechnology and CMEs for electroanalysis of drugs, there is an immense scope for development of highly efficient and improved voltammetric methods for the analysis of these drugs. This review is expected to provide crucial information that will immensely accelerate real progress in determination of over the counter abused antitussive drugs.

Acknowledgement The authors are thankful to College of Health Sciences, University of KwaZulu-Natal, South Africa (Grant no. CS 78), Westville Campus, Durban, South Africa for providing financial support.

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