Voltammetric determination of lidocaine and its toxic metabolite using C18 silica modified carbon paste electrode: Application to pharmaceutical dosage form and milk
Ahmed S. Saad, Amal M. Abou Al-Alamein, Maha M. Galal*, and Hala E. Zaazaa
Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562-Cairo, Egypt
Corresponding author’s e-mail: [email protected] +201117486474, Fax.+20223635140
Voltammetric assay of lidocaine and its milk-secreted toxic metabolite
Abstract
A new voltammetric method was developed for the simultaneous determination of lidocaine hydrochloride (LH) and its toxic metabolite 2, 6-dimethylaniline (DMA) based on their oxidation and adsorption on C18 silica modified carbon paste electrode (SMCPE). Several experimental factors including effect of pH of Britton Robinson buffer solution (BRB), scan rate, percentage of silica, accumulation potential and time were studied and the optimum conditions were found to be: pH 11±0.10 (BRB), scan rate 100 mV/s, accumulation potential -0.6V, accumulation time 150 s and 5 % C18 silica. Under the optimized conditions, square wave voltammetry (SWV) showed two signals for DMA and LH at 0.56 and 0.87 V, respectively. The method revealed satisfactory results in terms of linearity (7.94 x10-6 to 1.07 x 10-4 M) for LH and (1.20 x 10-6 to 1.07 x 10-5 M) for DMA, accuracy, and precision. The limit of detection was found to be 2.19 x 10-6 and 2.15 x 10-7 M for LH and DMA in pure forms, respectively. The method was further applied for the determination of LH in its pharmaceutical dosage form and for the assay of DMA in spiked milk samples.
Keywords: Lidocaine hydrochloride; 2,6-Dimethylaniline; toxic metabolite; C18 silica modified carbon paste electrode; square wave voltammetry
Introduction
Lidocaine hydrochloride monohydrate (LH) , chemically known as 2-(Diethylamino)-N-(2,6-dimethylphenyl) acetamide hydrochloride monohydrate ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “id” : “ITEM-1”, “issued” : { “date-parts” : “2014” }, “title” : “The British Pharmacopoeia, London: The stationary office Vol. 2.”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=b4b21132-a59b-48fb-affc-dd06c16f6ff0” } , “mendeley” : { “formattedCitation” : “(1)”, “plainTextFormattedCitation” : “(1)”, “previouslyFormattedCitation” : “(1)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(1),ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “id” : “ITEM-1”, “issued” : { “date-parts” : “2011” }, “title” : “The United States Pharmacopeia USP 34-NF 29”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=fca67579-8e22-449a-be2f-4eefbf074894” } , “mendeley” : { “formattedCitation” : “(2)”, “plainTextFormattedCitation” : “(2)”, “previouslyFormattedCitation” : “(2)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(2) (See Supplementary data Fig.1) is used as a local anesthetic.

It exerts its action by preventing the generation and conduction of nerve impulse as its main site of action is the cell membrane where it interferes with the permeability of the membrane to sodium ions ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Brunton”, “given” : “Laurance L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Lazo”, “given” : “John S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Parker”, “given” : “Keith L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “edition” : “11”, “editor” : { “dropping-particle” : “”, “family” : “Brunton”, “given” : “Laurance L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-1”, “issued” : { “date-parts” : “2006” }, “publisher” : “McGraw-Hill”, “publisher-place” : “New York, USA,”, “title” : “Goodman and Gilman’s The pharmacological basis of therapeutics.”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=2bcb8cb6-b35f-4d63-a224-0af5b04e5aad” } , “mendeley” : { “formattedCitation” : “(3)”, “plainTextFormattedCitation” : “(3)”, “previouslyFormattedCitation” : “(3)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(3). DMA is the main official impurity of LH as mentioned in both the British ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “id” : “ITEM-1”, “issued” : { “date-parts” : “2014” }, “title” : “The British Pharmacopoeia, London: The stationary office Vol. 2.”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=b4b21132-a59b-48fb-affc-dd06c16f6ff0” } , “mendeley” : { “formattedCitation” : “(1)”, “plainTextFormattedCitation” : “(1)”, “previouslyFormattedCitation” : “(1)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(1) and United States pharmacopeias ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “id” : “ITEM-1”, “issued” : { “date-parts” : “2011” }, “title” : “The United States Pharmacopeia USP 34-NF 29”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=fca67579-8e22-449a-be2f-4eefbf074894” } , “mendeley” : { “formattedCitation” : “(2)”, “plainTextFormattedCitation” : “(2)”, “previouslyFormattedCitation” : “(2)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(2). Moreover, DMA is reported to be the hydrolytic degradation product of LH ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “M. Riad”, “given” : “Safaa.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “M. Abdul-Azim”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “O. Mohamed”, “given” : “Afaf”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Bull.Fac.Pharm. Cairo Univ.”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2008” }, “page” : “35-48”, “title” : “Stability indicating methods for the determination of lidocaine and prilocaine in presence of their degradation products”, “type” : “article-journal”, “volume” : “46” }, “uris” : “http://www.mendeley.com/documents/?uuid=3caea95c-9ff7-40e9-acbe-7dc77a620425” } , “mendeley” : { “formattedCitation” : “(4)”, “plainTextFormattedCitation” : “(4)”, “previouslyFormattedCitation” : “(4)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(4) besides being its toxic metabolite ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “abstract” : “Human liver slices, in vitro, were used to establish whether lidocaine (LIDO) can be converted by human liver tissue to 2,6-xylidine (XYL), a compound shown to be carcinogenic in rodents. XYL was identified by GC/MS as a major metabolite in human liver slices from five individual donors after incubation with either LIDO (100 microM) or its deethylated metabolite, monoethylglycinexylidide (MEGX; 100 microM). Similar media XYL concentrations (9.8 microM +/- 2.1 SD and 7.9 microM +/- 2.1 SD) were achieved after either LIDO or MEGX incubation for 4 hr, respectively. With LIDO, the mean media XYL to MEGX ratios were 1.1 at 1-hr and 1.0 at 4-hr incubation times. In contrast, when LIDO (> 500 microM) was incubated with human liver microsomes for 1 hr, the XYL to MEGX ratio was approximately 0.01. No XYL was detected when LIDO (100 microM) was incubated with either human liver S9 fractions or whole liver homogenates. These results suggest that the enzyme primarily responsible for hydrolysis of LIDO may be labile in subcellular fractions. Kinetic analysis of the data suggests that XYL can be produced from either LIDO directly, or sequentially through MEGX. Although these metabolic data are helpful in addressing issues of LIDO toxicity, the overall risk assessment for LIDO is determined in large part by other factors, including the relative rates of activation to other potentially toxic species such as 4-HO-2,6-XYL as well as inactivation by detoxification pathways. The results presented emphasize the important role human liver slices can play in drug metabolism studies.”, “author” : { “dropping-particle” : “”, “family” : “Parker RJ, Collins JM”, “given” : “Strong JM.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Drug Metab Dispos.”, “id” : “ITEM-1”, “issue” : “(11)”, “issued” : { “date-parts” : “1996” }, “page” : “1167-73.”, “title” : “Identification of 2,6-xylidine as a major lidocaine metabolite in human liver slices.”, “type” : “article-journal”, “volume” : “24” }, “uris” : “http://www.mendeley.com/documents/?uuid=88565c62-47a7-4e5d-b0e4-852c9ac7f79f” } , “mendeley” : { “formattedCitation” : “(5)”, “plainTextFormattedCitation” : “(5)”, “previouslyFormattedCitation” : “(5)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(5) which may lead to urinary bladder cancer ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1021/tx060082q”, “ISSN” : “0893228X”, “PMID” : “16918249”, “abstract” : “Aromatic amines such as 2-naphthylamine and 4-aminobiphenyl are established human bladder carcinogens. Experimental evidence for carcinogenicity of monocylic aromatic amines is limited mostly to other organs, but a recent epidemiologic study of bladder cancer found that 2,6-dimethyl- (2,6-DMA), 3,5-dimethyl- (3,5-DMA), and 3-ethylaniline (3-EA) may play a significant role in the etiology of this disease in man. The present work was undertaken to test whether a genotoxic mechanism can account for the presumptive activity of 2,6-DMA, 3,5-DMA, and 3-EA by quantifying the binding of these compounds to DNA in vivo. Each of these three (14)Calkylanilines was administered at approximately 100 microg/kg to C57BL/6 mice, which were subsequently sacrificed 2, 4, 8, 16, and 24 h post-dosing. Bladder, colon, kidney, liver, lung, and pancreas were harvested from each animal, and DNA was isolated from each tissue. Adduct levels were determined by quantifying bound isotope using accelerator mass spectrometry. Adducts were detectable in the bladder and liver DNA samples from every animal at every time point at levels that ranged from 3 per 10(9) to 1.5 per 10(7) nucleotides. Adduct levels were highest in animals given 3,5-DMA and lowest in those given 3-EA. Levels in both bladder and liver declined by severalfold over the course of the experiment. Adducts were detected less frequently in the other four tissues. Taken together, the results strongly suggest that these three alkylanilines are metabolized in vivo to electrophilic intermediates that covalently bind to DNA and that adducts are formed in the DNA of bladder, which is a putative target organ for these alkylanilines.”, “author” : { “dropping-particle” : “”, “family” : “Skipper”, “given” : “Paul L”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Trudel”, “given” : “Laura J”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kensler”, “given” : “Thomas W”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Groopman”, “given” : “John D”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Egner”, “given” : “Patricia A”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Liberman”, “given” : “Rosa G”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Wogan”, “given” : “Gerald N”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Tannenbaum”, “given” : “Steven R”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Chemical Research in Toxicology”, “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2006” }, “page” : “1086-1090”, “title” : “DNA adduct formation by 2,6-dimethyl-, 3,5-dimethyl-, and 3-ethylaniline in vivo in mice”, “type” : “article-journal”, “volume” : “19” }, “uris” : “http://www.mendeley.com/documents/?uuid=5413db36-d4eb-4fd1-8b01-eeee196c7246” } , “mendeley” : { “formattedCitation” : “(6)”, “plainTextFormattedCitation” : “(6)”, “previouslyFormattedCitation” : “(6)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(6) and is stated to cause nasal carcinogencity in rats where its estimated cancer potency was found to be 0.0063 mg/kg body weight/day ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “PMID” : “11765029”, “abstract” : “2,6-Dimethylaniline (2,6-xylidine; 2,6-DMA) is a nasal carcinogen in rats. Humans may be exposed to this compound via several routes: 2,6-DMA is found in cigarette smoke; it is a pharmacologically inactive metabolite of some drugs (e.g., the local anesthetic lidocaine) and pesticides (e.g., metalaxyl); and it is an impurity in technical grade metalaxyl. The potential transfer of 2,6-DMA from mother to nursing infant via milk is of toxicological concern. Solid-phase microextraction with separation and detection using gas chromatography-mass spectrometry was optimized and used for the analysis of 2,6-DMA in milk. 2,6-DMA-d9 was synthesized and used for quantitation by the isotope ratio method. At a concentration of 5 ppb 2,6-DMA, the method detection limit was 0.20 ppb, and the relative standard deviation was 3.6%. Samples of milk were obtained from bovines administered lidocaine (2.9-3.9 mg/kg) during surgery. A breast milk sample was also obtained from a human donor who received 36 mg lidocaine during dental work. 2,6-DMA was present at levels ranging from 14.5 to 66.0 ppb in bovine milk and was detected at 1.6 ppb in the human milk sample. Our results demonstrate that 2,6-DMA, formed by the metabolism of lidocaine, is transferable to bovine and human milk.”, “author” : { “dropping-particle” : “”, “family” : “Puente NW”, “given” : “Josephy PD”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “J Anal Toxicol.”, “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2001” }, “page” : “711-5”, “title” : “Analysis of the lidocaine metabolite 2,6-dimethylaniline in bovine and human milk.”, “type” : “article-journal”, “volume” : “25” }, “uris” : “http://www.mendeley.com/documents/?uuid=0275e72a-184c-4175-9211-9942aa2af5f7” } , “mendeley” : { “formattedCitation” : “(7)”, “plainTextFormattedCitation” : “(7)”, “previouslyFormattedCitation” : “(7)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(7).
Diverse analytical techniques were reported in the literature for the determination of LH whether alone or in combination with other drugs including: spectrophotometric methods ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “M. Riad”, “given” : “Safaa.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “M. Abdul-Azim”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “O. Mohamed”, “given” : “Afaf”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Bull.Fac.Pharm. 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Cairo Univ.”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2008” }, “page” : “35-48”, “title” : “Stability indicating methods for the determination of lidocaine and prilocaine in presence of their degradation products”, “type” : “article-journal”, “volume” : “46” }, “uris” : “http://www.mendeley.com/documents/?uuid=3caea95c-9ff7-40e9-acbe-7dc77a620425” } , “mendeley” : { “formattedCitation” : “(4)”, “plainTextFormattedCitation” : “(4)”, “previouslyFormattedCitation” : “(4)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(4), high performance liquid chromatography (HPLC) ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1002/bmc.3619”, “ISSN” : “02693879”, “abstract” : “A simple, isocratic, high-resolution and prompt HPLC-PDA method was developed and validated for the simultaneous quantification of prilocaine (PCL) and lidocaine (LCL) hydrochlorides in in vitro buccal iontophoresis-driven permeation studies. A reversed-phase C18 column (250 mm x 4.6 mm, 3mum, 110A) was used for the chromatographic separation. The mobile phase contained acetonitrile: 0.1M sodium phosphate buffer, pH 7.0 (1:1, v/v), plus 0.05% (v/v) diethylamine. The isocratic flow rate was set at 1 mL/min and the detection wavelength was 203 nm. PCL and LCL eluted in 8.9 min and 13 min, respectively, and the system suitability parameters varied within an acceptable range. The method was selective, sensitive, precise, accurate and robust, producing a linear plot at the concentration range of 0.25 to 10 microg/mL. The application of this method was demonstrated by a significant enhancement of the permeation of PCL and LCL with the application of iontophoresis (1 mA/cm(2) per 1 h) through isolated porcine esophageal epithelium. The amount of the drug retained in the epithelium also increased with the application of an electrical current.”, “author” : { “dropping-particle” : “”, “family” : “Couto”, “given” : “Renu00ea O.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Cubayachi”, “given” : “Camila”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “V.”, “family” : “Lopez”, “given” : “Renata F.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gaitani”, “given” : “Cristiane M.”, “non-dropping-particle” : “de”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Pedrazzi”, “given” : “Vinu00edcius”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Freitas”, “given” : “Osvaldo”, “non-dropping-particle” : “de”, “parse-names” : false, “suffix” : “” } , “container-title” : “Biomedical Chromatography”, “id” : “ITEM-1”, “issue” : “6”, “issued” : { “date-parts” : “2016”, “6” }, “page” : “857-866”, “title” : “A simple and high-resolution HPLC-PDA method for simultaneous quantification of local anesthetics in in vitro buccal permeation enhancement studies”, “type” : “article-journal”, “volume” : “30” }, “uris” : “http://www.mendeley.com/documents/?uuid=43ed6b12-8ebf-43f5-8692-804c0d3fc425” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1039/C4AY01196A”, “ISSN” : “1759-9660”, “author” : { “dropping-particle” : “”, “family” : “Chamseddin”, “given” : “Chamseddin”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jira”, “given” : “Thomas”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Analytical Methods”, “id” : “ITEM-2”, “issue” : “17”, “issued” : { “date-parts” : “2014” }, “page” : “6702-6710”, “publisher” : “Royal Society of Chemistry”, “title” : “Multifactorial design principles applied for the simultaneous separation of local anesthetics using chromatography modeling software”, “type” : “article-journal”, “volume” : “6” }, “uris” : “http://www.mendeley.com/documents/?uuid=19ab34f0-3fe0-4f80-96e5-1c9db745c325” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1016/j.aca.2004.03.062”, “ISBN” : “0003-2670”, “ISSN” : “00032670”, “abstract” : “A set of 17 samples containing a constant amount of lidocaine (667 ??M) and a decreasing amount of prilocaine (667-0.3 ??M) was analysed by LC-DAD at three different levels of separation, followed by parallel factor analysis (PARAFAC) of the data obtained. In Case 1 no column was connected, the chromatographic resolution (Rs) therefore being zero, while Cases 2 and 3 had partly separated peaks (Rs=0.7 and 1.0). The results showed that in Case 1, analysed without any separation, the PARAFAC decomposition with a model consisting of two components gave a good estimate of the spectral and concentration profiles of the two compounds. In Cases 2 and 3, the use of PARAFAC models with two components resolved the underlying chromatographic, spectral and concentration profiles. The loadings related to the concentration profile of prilocaine were used for regression and prediction of the prilocaine content. The results showed that prediction of prilocaine content was possible with satisfactory prediction (RMSEP<0.01). This study shows that PARAFAC is a powerful technique for resolving partly separated peaks into their pure chromatographic, spectral and concentration profiles, even with completely overlapping spectra and the absence or very low levels of separation. ?? 2004 Elsevier B.V. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Wiberg”, “given” : “Kent”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jacobsson”, “given” : “Sven P.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Analytica Chimica Acta”, “id” : “ITEM-3”, “issue” : “2”, “issued” : { “date-parts” : “2004” }, “page” : “203-209”, “title” : “Parallel factor analysis of HPLC-DAD data for binary mixtures of lidocaine and prilocaine with different levels of chromatographic separation”, “type” : “article-journal”, “volume” : “514” }, “uris” : “http://www.mendeley.com/documents/?uuid=c3345068-12da-4bf7-ace2-f95bebb64637” }, { “id” : “ITEM-4”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Juan”, “given” : “SUN Shu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “Da”, “family” : “Jian”, “given” : “GU”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Li”, “given” : “YANG Jiu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Chinese Journal of Hospital Pharmacy”, “id” : “ITEM-4”, “issued” : { “date-parts” : “2002” }, “title” : “Measurement of lidocaine and prilocaine in compound cream by HPLC”, “type” : “article-journal”, “volume” : “11” }, “uris” : “http://www.mendeley.com/documents/?uuid=ef7b080b-1548-4364-b567-27b0d6850a77” } , “mendeley” : { “formattedCitation” : “(9u201312)”, “plainTextFormattedCitation” : “(9u201312)”, “previouslyFormattedCitation” : “(9u201312)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(9–12) , gas chromatography ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.2298/CICEQ120124064A”, “ISSN” : “14519372”, “abstract” : “A novel analytical method was developed and validated for determination of prilocaine HCl in bulk drug and pharmaceutical formulation by gas chromatography- nitrogen phosphorus detection (GC-NPD). The chromatographic separation was performed using a HP-5MS column. The calibration curve was linear over the concentration range of 40-1000 ng ml-1 with a correlation coefficient of 0.9998. The limits of detection (LOD) and quantification (LOQ) of the method were 10 and 35 ng ml-1, respectively. The within-day and between-day precision, expressed as the percent relative standard deviation (RSD%) were less than 5.0%, and the accuracy (percent relative error) was better than 4.0%. The developed method can be directly and easily applied for determination of prilocaine HCl in bulk drug and pharmaceutical formulation using internal standard methodology.”, “author” : { “dropping-particle” : “”, “family” : “Atila”, “given” : “Alptug”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Kadioglu”, “given” : “Yucel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Chemical Industry and Chemical Engineering Quarterly”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2013” }, “page” : “313-319”, “title” : “Determination of prilocaine hcl in bulk drug and pharmaceutical formulation by GC-NPD method.”, “type” : “article-journal”, “volume” : “19” }, “uris” : “http://www.mendeley.com/documents/?uuid=bcd748d0-2cec-4837-bd0d-b83c98e33842” }, { “id” : “ITEM-2”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Stockmann”, “given” : “Svetlana”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Elsner”, “given” : “Oliver”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Spies”, “given” : “Ellen”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dibbelt”, “given” : “Leif”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gehring”, “given” : “Hartmut”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-2”, “issued” : { “date-parts” : “2012” }, “title” : “Gas Phase Analysis of Lidocaine and Prilocaine by Solid Phase Micro Extraction (SPME) and Gas Chromatography – Mass Spectrometry (GS-MS): A Feasibility Study”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=dc2c83f5-e5b9-4622-a744-8f4730cbea99” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1002/bmc”, “ISBN” : “1881-7831 (Print)\n1881-7831 (Linking)”, “ISSN” : “1881-7831”, “PMID” : “22504396”, “author” : { “dropping-particle” : “”, “family” : “Kadioglu”, “given” : “Yucel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Atila”, “given” : “Alptug”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “BIOMEDICAL CHROMATOGRAPHY”, “id” : “ITEM-3”, “issued” : { “date-parts” : “2007” }, “page” : “1077-1082”, “title” : “Development and validation of gas chromatographyu2013mass spectroscopy method for determination of prilocaine HCl in human plasma using internal standard methodology”, “type” : “article-journal”, “volume” : “21” }, “uris” : “http://www.mendeley.com/documents/?uuid=f4b2899d-d0b4-4d07-8db2-86bce01e1917” }, { “id” : “ITEM-4”, “itemData” : { “DOI” : “10.1046/j.1365-2133.2001.04408.x”, “ISSN” : “00070963”, “abstract” : “Background: Although the lignocaine (lidocaine)-prilocaine cream EMLA(registered trademark) has been extensively studied for the relief of acute treatment-related pain from sharp leg ulcer debridement, no data exist on systemic absorption from prolonged application in patients with chronically painful ulcers. Objectives: To study the plasma concentrations of lignocaine and prilocaine resulting from prolonged application of EMLA to leg ulcers. Methods: A single 24-h application of 5-10 g (median 6.75) of EMLA was given to 10 patients with painful leg ulcers measuring 50-100 cm2. Venous blood samples, drawn between 0.5 and 27 h after cream application, were analysed by gas chromatography using a nitrogen-sensitive detector. Results: The peak plasma levels were in the range 185-705 ng mL-1 and 62-277 ng mL-1 for lignocaine and prilocaine, respectively, and were observed 2-4 h (in one patient 6-8 h) after application. The peak plasma concentration of lignocaine, but not of prilocaine, increased significantly with increasing dose. The cream was well tolerated by the patients. Conclusions: The results indicate that a 24-h application of 5-10 g EMLA results in peak plasma concentrations of the two local anaesthetics, which combined are less than one-fifth of those associated with toxic reactions. The analgesic efficacy of EMLA for the relief of chronic ulcer pain deserves further study.”, “author” : { “dropping-particle” : “”, “family” : “Stymne”, “given” : “B.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Lillieborg”, “given” : “S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “British Journal of Dermatology”, “id” : “ITEM-4”, “issue” : “4”, “issued” : { “date-parts” : “2001” }, “page” : “530-534”, “title” : “Plasma concentrations of lignocaine and prilocaine after a 24-h application of analgesic cream (EMLAu00ae) to leg ulcers”, “type” : “article-journal”, “volume” : “145” }, “uris” : “http://www.mendeley.com/documents/?uuid=e592c2bf-fe72-4e1f-9319-e733d415e844” } , “mendeley” : { “formattedCitation” : “(13u201316)”, “plainTextFormattedCitation” : “(13u201316)”, “previouslyFormattedCitation” : “(13u201316)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(13–16) and capillary zone electrophoresis ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Valese”, “given” : “Andressa C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Spudeit”, “given” : “Daniel A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Dolzan”, “given” : “Maressa D.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bretanha”, “given” : “Lizandra C.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Vitali”, “given” : “Luciano”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Micke”, “given” : “Gustavo A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Analytical Methods in Chemistry”, “id” : “ITEM-1”, “issued” : { “date-parts” : “2016” }, “title” : “High-Throughput Analysis of Lidocaine in Pharmaceutical Formulation by Capillary Zone Electrophoresis Using Multiple Injections in a Single Run”, “type” : “article-journal” }, “uris” : “http://www.mendeley.com/documents/?uuid=dc4bd398-4995-425f-89b1-ed7594efa903” }, { “id” : “ITEM-2”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Franco”, “given” : “Marina”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jasionowska”, “given” : “Renata”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “American Journal of Analytical Chemistry”, “id” : “ITEM-2”, “issue” : “March”, “issued” : { “date-parts” : “2013” }, “page” : “117-124”, “title” : “Quick Single Run Capillary Zone Electrophoresis Determination of Active Ingredients and Preservatives in Pharmaceutical Products”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=46c66bf3-b488-4a3c-8618-c57deff1565e” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1002/elps.201100575”, “ISSN” : “01730835”, “PMID” : “22736349”, “abstract” : “In this study, the influence of the capillary inner diameter (id) on the efficiency and sensitivity of a capillary zone electrophoresis separation was investigated. Four local anaesthetic drugs (lidocaine, prilocaine hydrochloride, procaine and tetracaine) were separated with a validated method using capillaries of different id. The separation parameter N and the resolution of the critical peak pair were monitored. It was found that N increases in tighter capillaries, while sensitivity decreases indicated by the increased detection limit for lidocaine. This loss in sensitivity can partially be compensated by loading more sample into the capillary by means of an increased injection time and pressure. However, when it comes to the evaluation of the drug quality according to a monograph in the European Pharmacopoeia, we cannot recommend to vary the capillary id in order to meet the system suitability criteria.”, “author” : { “dropping-particle” : “”, “family” : “Ilko”, “given” : “David”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Holzgrabe”, “given” : “Ulrike”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Electrophoresis”, “id” : “ITEM-3”, “issue” : “11”, “issued” : { “date-parts” : “2012” }, “page” : “1494-1498”, “title” : “Influence of the capillary diameter on the separation efficiency and sensitivity: A systematic approach”, “type” : “article-journal”, “volume” : “33” }, “uris” : “http://www.mendeley.com/documents/?uuid=b01a1877-3b16-421c-bba6-41e6065d8898” }, { “id” : “ITEM-4”, “itemData” : { “ISSN” : “03654877”, “abstract” : “The potential of nonaqueous capillary electrophoresis was investigated for the separation of selected anesthetic drugs. The effect of parameters, such as methanol-acetonitrile composition, temperature, apparent pH* and ionic strength of the electrophoretic media on migration times and selectivity was discussed. The capillary electrophoresis separation of these drugs was compared in aqueous and nonaqueous media. The best separation was achieved with a fused silica capillary (48.5 cm total length x 50 u03bcm 1.D.), a buffer electrolyte solution composed of 25 mM ammonium acetate in methanol, an applied voltage of 30 kV and a temperature of 10 u00b0C. Replicate injections under the optimal nonaqueous conditions gave acceptable precision data for migration times and peak areas.”, “author” : { “dropping-particle” : “”, “family” : “Cherkaoui”, “given” : “S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Veuthey”, “given” : “J.-L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Analusis”, “id” : “ITEM-4”, “issue” : “9”, “issued” : { “date-parts” : “1999” }, “page” : “765-771”, “title” : “Separation of selected anesthetic drugs by nonaqueous capillary electrophoresis”, “type” : “article-journal”, “volume” : “27” }, “uris” : “http://www.mendeley.com/documents/?uuid=85012c88-1af2-4f35-ae82-392460330c95” } , “mendeley” : { “formattedCitation” : “(17u201320)”, “plainTextFormattedCitation” : “(17u201320)”, “previouslyFormattedCitation” : “(17u201320)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(17–20). Electrochemical methods such as ion selective electrodes (ISE) ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.3390/pharmaceutics4030366”, “ISSN” : “19994923”, “abstract” : “Polyvinyl chloride (PVC)-based solid-contact ion-selective electrodes \r\n(SC-ISEs), responding to propranolol hydrochloride (Pr+) and lidocaine hydrochloride (Ld+) cations as the model drugs with potassium tetrakis(4-chlorophenyl) borate (KTpClPB) as the ion exchanger, were studied. Different drug-polymer solutions were prepared with the model drugs, using different blend ratios of ethylcellulose (EC) and hydroxypropyl cellulose (HPC). Two different solid dosage forms were used. Polymer films were produced by solvent casting method and drug containing porous cellulose samples were prepared by depositing the drug-polymer solutions onto filter paper substrates. The quality of the electrodes and the release profile of Pr+ and Ld+ were investigated with \r\nthe potentiometric method. The results were compared to UV spectrophotometry. The electrodes were found to be sensitive, precise and functional with a Nernstian behavior over the range of 1.0 u00d7 10u22123u20133.1 u00d7 10u22126 M (9.2 u00d7 10u22124u20133.0 u00d7 10u22121 mg/mL) and \r\n1 u00d7 10u22123u20132 u00d7 10u22126 M (5.4 u00d7 10u22124u20132.7 u00d7 10u22121 mg/mL) at 25 u00b0C for Pr+ and Ld+ sensitive electrodes, respectively. The dynamic response time for the electrodes was less than 10 s. The Pr+ release from porous filter paper was always higher than its equivalent film formulation. Also, lidocaine had higher and faster release from the samples with higher drug concentration. The comparison of the two analytical methods showed near \r\nidentical results. The ISEs provided a powerful and flexible alternative to UV method \r\nin determination of drug release from porous cellulose substrates in a small scale \r\ndissolution testing.”, “author” : { “dropping-particle” : “”, “family” : “Vakili”, “given” : “Hossein”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Genina”, “given” : “Natalja”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ehlers”, “given” : “Henrik”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bobacka”, “given” : “Johan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Sandler”, “given” : “Niklas”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Pharmaceutics”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “2012” }, “page” : “366-376”, “title” : “Using ion-selective electrodes to study the drug release from porous cellulose matrices”, “type” : “article-journal”, “volume” : “4” }, “uris” : “http://www.mendeley.com/documents/?uuid=bee19d06-61b7-4aa2-aa4b-3f0d59d2668a” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1134/S106193480902018X”, “ISSN” : “1061-9348”, “author” : { “dropping-particle” : “”, “family” : “Giahi”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Pournaghdy”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Rakhshaee”, “given” : “R.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Analytical Chemistry”, “id” : “ITEM-2”, “issue” : “2”, “issued” : { “date-parts” : “2009” }, “page” : “195-200”, “title” : “A new lidocaine-selective membrane electrode based on its sulfathiazole ion-pair”, “type” : “article-journal”, “volume” : “64” }, “uris” : “http://www.mendeley.com/documents/?uuid=dbe5bec3-434c-4758-ac0b-4805c63dd81b” }, { “id” : “ITEM-3”, “itemData” : { “ISSN” : “10619348”, “author” : { “dropping-particle” : “”, “family” : “Kulapina”, “given” : “E G”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “V”, “family” : “Barinova”, “given” : “O”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Analytical Chemistry”, “id” : “ITEM-3”, “issue” : “5”, “issued” : { “date-parts” : “2001” }, “page” : “457-460”, “title” : “Ion-Selective Electrodes for the Determination of Nitrogen-Containing Medicinal Substances”, “type” : “article-journal”, “volume” : “56” }, “uris” : “http://www.mendeley.com/documents/?uuid=0a0d62f5-9e3b-4992-a16d-7fc872785f3a” }, { “id” : “ITEM-4”, “itemData” : { “DOI” : “10.1016/S0039-9140(99)00178-2”, “ISBN” : “0039-9140”, “ISSN” : “00399140”, “PMID” : “18967786”, “abstract” : “2,6 Didodecyl ?? cyclodextrin (2,6dd??CD) modified ion-selective electrodes (ISEs) were used in discrete solutions and in a flow injection analysis manifold for monitoring the local anaesthetic lidocaine hydrochloride (lignocaine) in the presence of endogenous cations and proteins. Membrane matrices comprised of either high molecular weight poly (vinyl chloride) (PVC) or polyurethane (Tecoflex SG 80) were compared. The behaviour of these electrodes in the presence of bovine serum albumin (BSA), ??1 acid glycoprotein (AAG) and human serum (HS) indicate that the Tecoflex- based membrane matrices are preferable to PVC as the drift induced by proteins on baseline lines and peak height reproducibility was considerably reduced in the former. Interference from ‘serum’ levels of sodium, potassium and calcium (145 mmol dm-3 Na+, 1.26 mmol dm-3 Ca2+, 4.30 mmol dm-3 K+) was negligible (-Log K(ij)/(POI) (overall) ??? 4.0). The major organic interferents were molecules of similar size and structure, which caused reduced slope and drift in baseline potentials, at equimolar concentration levels. A reduction in interferent concentration by a factor of 10 negated these effects.”, “author” : { “dropping-particle” : “”, “family” : “Kataky”, “given” : “Ritu”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Toth”, “given” : “Klara”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Palmer”, “given” : “Simon”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Feher”, “given” : “Zsofia”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Talanta”, “id” : “ITEM-4”, “issue” : “5”, “issued” : { “date-parts” : “1999” }, “page” : “939-946”, “title” : “A study of the effect of proteins and endogenous cations on a lipophilic ??-cyclodextrin-based potentiometric lidocaine sensor using discrete solution and flow-injection analysis”, “type” : “article-journal”, “volume” : “50” }, “uris” : “http://www.mendeley.com/documents/?uuid=8405ac44-002e-4c41-a600-fb7120b259ad” } , “mendeley” : { “formattedCitation” : “(21u201324)”, “plainTextFormattedCitation” : “(21u201324)”, “previouslyFormattedCitation” : “(21u201324)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(21–24) and voltammetry ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.cclet.2016.04.017”, “ISSN” : “10018417”, “abstract” : “In this research, copper oxide nanoparticles modified carbon paste electrode was developed for the voltammetric determination of lidocaine. The square wave voltammogram of lidocaine solution showed a well-defined peak between +0.5 and +1.5 V. Instrumental and chemical parameters influencing voltammetric response were optimized by both one at a time and Box-Behnken model of response surface methodology. The results revealed that there was no significant difference between two methods of optimization. The linear range was 1-2500 ??mol L-1 (Ip = 0.11CLH + 17.38, R2 = 0.999). The LOD and LOQ based on three and ten times of the signal to noise (S/N) were 0.39 and 1.3 ??mol L-1 (n = 10), respectively. The precision of the method was assessed for 10 replicate square wave voltammetry (SWV) determinations each of 0.05, 0.5 and 1 mmol L-1 of lidocaine showing relative standard deviations 4.1%, 3.7% and 2.1%, respectively. The reliability of the proposed method was established by application of the method for the determination of lidocaine in two pharmaceutical preparations, namely injection and gel.”, “author” : { “dropping-particle” : “”, “family” : “Rahbar”, “given” : “Nadereh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ramezani”, “given” : “Zahra”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ghanavati”, “given” : “Jamalaldin”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Chinese Chemical Letters”, “id” : “ITEM-1”, “issue” : “6”, “issued” : { “date-parts” : “2016” }, “page” : “837-842”, “publisher” : “Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences”, “title” : “CuO-nanoparticles modified carbon paste electrode for square wave voltammetric determination of lidocaine: Comparing classical and Box-Behnken optimization methodologies”, “type” : “article-journal”, “volume” : “27” }, “uris” : “http://www.mendeley.com/documents/?uuid=b70be7e8-1804-48f4-aa7f-ecf456bfa6fc” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.3906/kim-1112-6”, “ISSN” : “13000527”, “author” : { “dropping-particle” : “”, “family” : “Tan”, “given” : “Gamze”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bolat”, “given” : “Gu00fclu00e7in”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Onur”, “given” : “Mehmet Ali”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abaci”, “given” : “Serdar”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Turkish Journal of Chemistry”, “id” : “ITEM-2”, “issue” : “4”, “issued” : { “date-parts” : “2012” }, “page” : “593-600”, “title” : “Determination of lidocaine based on electrocatalysis of a chemically modified electrode”, “type” : “article-journal”, “volume” : “36” }, “uris” : “http://www.mendeley.com/documents/?uuid=b15cf555-c6ee-4554-b7b7-eb150a66ffa3” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1002/1521-4109(200008)12:12<901::AID-ELAN901>3.0.CO;2-6”, “ISSN” : “10400397”, “abstract” : “Voltammetric measurements are used to study the transfer of protonated forms of local anesthetics (procaine, tetracaine, prilocaine, bupivacaine, lidocaine, dibucaine) across a supported o-nitrophenyl octyl ether (o-NPOE) membrane. Ion diffusion coefficients and ion transfer potentials were obtained which are comparable with those inferred from measurements at a water-o-NPOE interface. It is shown that the pharmacological potency of local anesthetics correlates with standard ion transfer potentials of their protonated forms. It is proposed that the drug propagation involves the transfer of the ionic rather than uncharged anesthetic across the cell membrane.”, “author” : { “dropping-particle” : “”, “family” : “Samec”, “given” : “Zdenak”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Trojanek”, “given” : “Antonin”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jan”, “given” : “Langmaier”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Eva”, “given” : “Samcova”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Jiri”, “given” : “Malek”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Electroanalysis”, “id” : “ITEM-3”, “issue” : “12”, “issued” : { “date-parts” : “2000” }, “page” : “901-904”, “title” : “Voltammetry of protonated anesthetics at a liquid membrane: Evaluation of the drug propagation”, “type” : “article-journal”, “volume” : “12” }, “uris” : “http://www.mendeley.com/documents/?uuid=672bd9c1-47e8-4152-8f5c-2a9d33ad6240” } , “mendeley” : { “formattedCitation” : “(25u201327)”, “plainTextFormattedCitation” : “(25u201327)”, “previouslyFormattedCitation” : “(25u201327)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(25–27) were also reported. Simultaneous or selective quantitation of LH and DMA was described using TLC ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “M. Riad”, “given” : “Safaa.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “M. Abdul-Azim”, “given” : “Mohammad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “O. Mohamed”, “given” : “Afaf”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Bull.Fac.Pharm. Cairo Univ.”, “id” : “ITEM-1”, “issue” : “2”, “issued” : { “date-parts” : “2008” }, “page” : “35-48”, “title” : “Stability indicating methods for the determination of lidocaine and prilocaine in presence of their degradation products”, “type” : “article-journal”, “volume” : “46” }, “uris” : “http://www.mendeley.com/documents/?uuid=3caea95c-9ff7-40e9-acbe-7dc77a620425” } , “mendeley” : { “formattedCitation” : “(4)”, “plainTextFormattedCitation” : “(4)”, “previouslyFormattedCitation” : “(4)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(4), ISE ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1002/elan.201800132”, “ISSN” : “15214109”, “abstract” : “u00a9 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Sustainable chemistry has attracted the attention of scientists during the last decades owing to the great advantages encountered by its application. These include: waste reduction, energy conservation and substitution of hazardous substances with more eco-friendly ones. Following this approach, a new sensitive and selective membrane sensor was developed and investigated for the determination of lidocaine hydrochloride (LD) and its carcinogenic metabolite 2,6-dimethylaniline (DMA). Several polyvinyl chloride (PVC) based sensors were tried using different plasticizers as well as different cation exchangers. The best response was achieved upon using dioctylphthalate (DOP) as solvent mediator and phosphotungstate (PT) as cation exchanger. LD was selectively determined at pH6 without interference from its carcinogenic metabolite, while DMA that had been reported to be the toxic inactive metabolite of LD secreted in the milk was determined in the milk at pH2. Fast, stable Nernstian responses were achieved by the proposed sensors over a concentration range of 2.66u00d710 -5 M to 1u00d710 -2 M for both LD and DMA. The method was validated according to the IUPAC recommendations and was successfully applied for the determination of LD in pure form and pharmaceutical dosage form, whereas DMA was successfully determined in pure form and spiked milk samples.”, “author” : { “dropping-particle” : “”, “family” : “Saad”, “given” : “A.S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Alamein”, “given” : “A.M.A.A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Galal”, “given” : “M.M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Zaazaa”, “given” : “H.E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Electroanalysis”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2018” }, “title” : “Novel Green Potentiometric Method for the Determination of Lidocaine Hydrochloride and its Metabolite 2, 6-Dimethylaniline; Application to Pharmaceutical Dosage Form and Milk”, “type” : “article-journal”, “volume” : “5” }, “uris” : “http://www.mendeley.com/documents/?uuid=56525074-edb2-47e7-8acd-8182cc2c5ce1” } , “mendeley” : { “formattedCitation” : “(28)”, “plainTextFormattedCitation” : “(28)”, “previouslyFormattedCitation” : “(31)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(28) and HPLC ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/j.jpba.2004.09.025”, “ISSN” : “07317085”, “PMID” : “15862666”, “abstract” : “A method for the determination of local anaesthetics and their impurities – 2,6-dimethylaniline and o-toluidine – by high-performance liquid chromatographic method with amperometric detection has been developed. The analysis was performed in an isocratic mode on a reversed phase Luna column 5 u03bcm C-18 (100 mm u00d7 4.6 mm). A mobile phase 0.01 mol l-1 Tris buffer of pH 7.9:acetonitrile (45:55) was selected for the separation and determination of studied anaesthetics and their impurities. Chromatograms were recorded for 500 s by means of an amperometric detector at a potential of +1.0 V of the glassy carbon electrode versus the reference electrode Ag/AgCl. The proposed liquid chromatographic method was successfully applied to the analysis of commercially available pharmaceutical preparations. The limit of the detection for 2,6-dimethylaniline and o-toluidine was 0.8 ng ml-1. The limit of qantitation, considering a signal to noise ratio was 1.5 ng ml -1. The method developed in this study is sensitive and selective and can be applied to routine studies of pharmaceuticals in the form of cream and injection. u00a9 2004 Elsevier B.V. All rights reserved.”, “author” : { “dropping-particle” : “”, “family” : “Fijau0142ek”, “given” : “Zbigniew”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Baczyu0144ski”, “given” : “Emil”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Piwou0144ska”, “given” : “Agata”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Warowna-Grzeu015bkiewicz”, “given” : “Mau0142gorzata”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Pharmaceutical and Biomedical Analysis”, “id” : “ITEM-1”, “issue” : “5”, “issued” : { “date-parts” : “2005” }, “page” : “913-918”, “title” : “Determination of local anaesthetics and their impurities in pharmaceutical preparations using HPLC method with amperometric detection”, “type” : “article-journal”, “volume” : “37” }, “uris” : “http://www.mendeley.com/documents/?uuid=37cb4fd3-54cb-41b4-a7dd-8e78c323493c” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1365/s10337-009-1274-x”, “ISSN” : “0009-5893”, “author” : { “dropping-particle” : “”, “family” : “Mohammad”, “given” : “Mohammad Abdul-Azim”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Chromatographia”, “id” : “ITEM-2”, “issue” : “3-4”, “issued” : { “date-parts” : “2009” }, “page” : “563-568”, “title” : “LC Determination of Lidocaine and Prilocaine Containing Potential Risky Impurities and Application to Pharmaceuticals”, “type” : “article-journal”, “volume” : “70” }, “uris” : “http://www.mendeley.com/documents/?uuid=08e965a3-bad1-48bd-9dd8-b103978fbaed” }, { “id” : “ITEM-3”, “itemData” : { “DOI” : “10.1093/chromsci/bmv170”, “ISSN” : “00219665”, “abstract” : “Two sensitive and selective analytical methods were developed for simultaneous determination of aminoacridine hydrochloride and lidocaine hydrochloride in bulk powder and pharmaceutical formulation. Method A was based on HPLC separation of the cited drugs with determination of the toxic lidocaine-related impurity 2,6-dimethylaniline. The separation was achieved using reversed-phase column C18, 250 + 4.6 mm, 5 ufffdm particle size and mobile phase consisting of 0.05 M disodium hydrogen phosphate dihydrate (pH 6.0 ufffd 0.2 adjusted with phosphoric acid) and acetonitrile (55 : 45, v/v). Quantitation was achieved with UV detection at 240 nm. Linear calibration curve was in the range of 1.00-10.00, 13.20-132.00 and 1.32-13.20 ufffdg mL?1 for aminoacridine hydrochloride, lidocaine hydrochloride and 2,6-dimethylaniline, respectively. Method B was based on TLC separation of the cited drugs followed by densitometric measurement at 365 nm on the fluorescent mode for aminoacridine hydrochloride and 220 nm on the absorption mode for lidocaine hydrochloride. The separation was carried out using ethyl acetate-methanol-acetic acid (65 : 30 : 5 by volume) as a developing system. The calibration curve was in the range of 25.00-250.00 ng spot?1 and 0.99-9.90 ufffdg spot?1 for aminoacridine hydrochloride and lidocaine hydrochloride, respectively. The results obtained were statistically analyzed and compared with those obtained by applying the manufacturer’s method.”, “author” : { “dropping-particle” : “”, “family” : “Bebawy”, “given” : “Lories I.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Elghobashy”, “given” : “Mohamed R.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abbas”, “given” : “Samah S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shokry”, “given” : “Rafeek F.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Chromatographic Science”, “id” : “ITEM-3”, “issue” : “4”, “issued” : { “date-parts” : “2016” }, “page” : “492-499”, “title” : “Chromatographic Determination of Aminoacridine Hydrochloride, Lidocaine Hydrochloride and Lidocaine Toxic Impurity in Oral Gel”, “type” : “article-journal”, “volume” : “54” }, “uris” : “http://www.mendeley.com/documents/?uuid=1f2b6320-9fad-440a-b76e-73505b3961ed” } , “mendeley” : { “formattedCitation” : “(29u201331)”, “plainTextFormattedCitation” : “(29u201331)”, “previouslyFormattedCitation” : “(28u201330)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(29–31). As far as to our Knowledge no voltammetric method is reported for the simultaneous determination of LH and DMA. Therefore the aim of this work was to develop a simple, accurate and sensitive voltammetric method for the simultaneous determination of LH and DMA in pure form and in pharmaceutical dosage. Being the inactive toxic, milk-secreted metabolite of LH, DMA was further quantified in milk samples using the proposed method ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “PMID” : “11765029”, “abstract” : “2,6-Dimethylaniline (2,6-xylidine; 2,6-DMA) is a nasal carcinogen in rats. Humans may be exposed to this compound via several routes: 2,6-DMA is found in cigarette smoke; it is a pharmacologically inactive metabolite of some drugs (e.g., the local anesthetic lidocaine) and pesticides (e.g., metalaxyl); and it is an impurity in technical grade metalaxyl. The potential transfer of 2,6-DMA from mother to nursing infant via milk is of toxicological concern. Solid-phase microextraction with separation and detection using gas chromatography-mass spectrometry was optimized and used for the analysis of 2,6-DMA in milk. 2,6-DMA-d9 was synthesized and used for quantitation by the isotope ratio method. At a concentration of 5 ppb 2,6-DMA, the method detection limit was 0.20 ppb, and the relative standard deviation was 3.6%. Samples of milk were obtained from bovines administered lidocaine (2.9-3.9 mg/kg) during surgery. A breast milk sample was also obtained from a human donor who received 36 mg lidocaine during dental work. 2,6-DMA was present at levels ranging from 14.5 to 66.0 ppb in bovine milk and was detected at 1.6 ppb in the human milk sample. Our results demonstrate that 2,6-DMA, formed by the metabolism of lidocaine, is transferable to bovine and human milk.”, “author” : { “dropping-particle” : “”, “family” : “Puente NW”, “given” : “Josephy PD”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “J Anal Toxicol.”, “id” : “ITEM-1”, “issue” : “8”, “issued” : { “date-parts” : “2001” }, “page” : “711-5”, “title” : “Analysis of the lidocaine metabolite 2,6-dimethylaniline in bovine and human milk.”, “type” : “article-journal”, “volume” : “25” }, “uris” : “http://www.mendeley.com/documents/?uuid=0275e72a-184c-4175-9211-9942aa2af5f7” } , “mendeley” : { “formattedCitation” : “(7)”, “plainTextFormattedCitation” : “(7)”, “previouslyFormattedCitation” : “(7)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(7).
Carbon paste electrodes (CPE) have found their place in modern electroanalysis owing to their versatility, ease of preparation, low ingredients cost, reasonable reproducibility, high sensitivity and broad potential range. Several modifications have been carried out to CPE inorder to improve the analytical performance through increasing the selectivity and sensitivity of the determination ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.2298/JSC0910021V”, “ISSN” : “03525139”, “abstract” : “An overview is given dealing with the applications of carbon paste electrodes in equilibrium potentiometry as well as in electrochemical stripping analysis using both voltammetric and potentiometric modes. Various modifica-tions of carbon pastes and carbon paste-based biosensors are also mentioned. The main emphasis in this article is directed at summarizing recent results of the authors’ research group during the past few years.”, “author” : { “dropping-particle” : “”, “family” : “Vytu0159as”, “given” : “Karel”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “u0160vancara”, “given” : “Ivan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Metelka”, “given” : “Radovan”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of the Serbian Chemical Society”, “id” : “ITEM-1”, “issue” : “10”, “issued” : { “date-parts” : “2009” }, “page” : “1021-1033”, “title” : “Carbon paste electrodes in electroanalytical chemistry”, “type” : “article-journal”, “volume” : “74” }, “uris” : “http://www.mendeley.com/documents/?uuid=0aa50278-cf49-4628-8886-ffb7ec253066” } , “mendeley” : { “formattedCitation” : “(32)”, “plainTextFormattedCitation” : “(32)”, “previouslyFormattedCitation” : “(32)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(32). Silica gel is one of the reported modifiers that has been used for the determination of some drugs owing to its attractive properties as high adsorption capability, thermal constancy and insolubility in many solvents ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1039/c5ra06292f”, “ISSN” : “20462069”, “abstract” : “<p>A novel irreversible anodic voltammetric method was introduced for selective determination of diminazene aceturate in the presence of phenazone as a stabilizer.</p>”, “author” : { “dropping-particle” : “”, “family” : “Zaazaa”, “given” : “Hala E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Salama”, “given” : “Nahla N.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Azab”, “given” : “Shereen M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Atty”, “given” : “Shimaa A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “El-Kosy”, “given” : “Naglaa M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Salem”, “given” : “Maissa Y.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “RSC Advances”, “id” : “ITEM-1”, “issue” : “60”, “issued” : { “date-parts” : “2015” }, “page” : “48842-48850”, “publisher” : “Royal Society of Chemistry”, “title” : “A novel surfactant silica gel modified carbon paste electrode in micellar media for selective determination of diminazene aceturate in the presence of its stabilizer”, “type” : “article-journal”, “volume” : “5” }, “uris” : “http://www.mendeley.com/documents/?uuid=7f5abde0-46c1-4380-8f6d-6cb4956c9cd1” }, { “id” : “ITEM-2”, “itemData” : { “DOI” : “10.1080/00032719408002634”, “ISSN” : “0003-2719”, “author” : { “dropping-particle” : “”, “family” : “Chicharro”, “given” : “M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Zapardiel”, “given” : “A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Bermejo”, “given” : “E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Pu00e9rez”, “given” : “J. A.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hernu00e1ndez”, “given” : “L.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Analytical Letters”, “id” : “ITEM-2”, “issue” : “10”, “issued” : { “date-parts” : “1994” }, “page” : “1809-1831”, “title” : “Ephedrine Determination in Human Urine Using a Carbon Paste Electrode Modified with C <sub>18</sub> Bonded Silica Gel”, “type” : “article-journal”, “volume” : “27” }, “uris” : “http://www.mendeley.com/documents/?uuid=de925a18-a238-487d-b9ec-0200c0768f42” }, { “id” : “ITEM-3”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “V”, “given” : “Elsevier Science Publishers B”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gonzalez”, “given” : “E”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hernandez”, “given” : “P”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hernandez”, “given” : “L”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “id” : “ITEM-3”, “issued” : { “date-parts” : “1990” }, “page” : “265-272”, “title” : “Cyclic voltammetry of Tifluadom at a C,,-modified carbon-paste electrode”, “type” : “article-journal”, “volume” : “228” }, “uris” : “http://www.mendeley.com/documents/?uuid=142dcc01-8057-4a26-812e-b54a1d4abaf0” } , “mendeley” : { “formattedCitation” : “(33u201335)”, “plainTextFormattedCitation” : “(33u201335)”, “previouslyFormattedCitation” : “(33u201335)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(33–35). The developed method is based upon using C18 silica modified carbon paste electrode (CPE) for the simultaneous determination of LH and DMA.

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Experimental
Materials and reagents
LH was kindly supplied by Egyptian International Pharmaceuticals Industries Co (EIPICO) Cairo- Egypt with 100.95% ± 1.210 purity ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “id” : “ITEM-1”, “issued” : { “date-parts” : “2014” }, “title” : “The British Pharmacopoeia, London: The stationary office Vol. 2.”, “type” : “book” }, “uris” : “http://www.mendeley.com/documents/?uuid=b4b21132-a59b-48fb-affc-dd06c16f6ff0” } , “mendeley” : { “formattedCitation” : “(1)”, “plainTextFormattedCitation” : “(1)”, “previouslyFormattedCitation” : “(1)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(1). DMA, graphite (; 20 ?m), paraffin oil were purchased from Sigma-Aldrich (Germany). Bondesil C18 Silica (230-400 mesh, 40 ?m) was purchased from Agilent (USA). Britton–Robinson buffer (BRB) was prepared by mixing different volumes of 0.04 mol/L each phosphoric acid, acetic acid and boric acid (Adwic Co., Egypt). The pH was adjusted to the range of (2.0–12.0) using appropriate volumes of 0.2 mol/L NaOH (Adwic Co., Egypt). Milli-Q deionized water was used.

Standard solutions
Stock standard solution of LH (10-2 M) Accurately weighed amount of LH (0.288 g) was quantitatively transferred into a volumetric flask (100 mL) containing 50 mL deionized water and completing to the mark with the same solvent. Working standard solution of 10-3 M LH was prepared by suitable dilution from the stock standard solution.

Stock standard solution of DMA (10-2 M) Accurate amount of DMA (0.121 g) was quantitatively transferred into a volumetric flask (100 mL) containing 50 mL water and completing to the mark with the same solvent. Working standard solutions of 10-3 M DMA was prepared by suitable dilution from the stock standard solution.
Pharmaceutical formulation
Vials of Lidocaine HCl 1% batch number (140573), manufactured by Egyptian International Pharmaceuticals Industries Co (EIPICO), were obtained from the local market. Each vial is labeled to contain 10 mg/mL LH.
Preparation of electrode
The used working electrode was a cylinderical teflon body (6 cm in length) with an orifice of 6 mm diameter and 5 mm length followed directly by a cylindrical copper rod (6 mm in diameter) to perform as an electric contact. The orifice of the electrode was packed with the prepared pastes either bare carbon paste, C18 silica modified carbon paste or polar silica modified carbon pastes. The bare carbon paste was prepared by mixing graphite powder with paraffin oil in a glassy morter in a ratio of 7: 3. Where as the modified carbon pastes were prepared by mixing graphite powder with either C18 silica or polar silica followed by the addition of paraffin oil.

Instrumental and experimental set up
For voltammetric measurements, a Metrohm (AUTOLAB, model AUT204FRA32) electrochemical device was employed. A three electrode arrangement was applied throughout. Ag/AgCl reference electrode was used together with a platinum electrode serving as the counter electrode and finally C18 silica modified carbon paste electrode as a working electrode. Adjustment of pH was carried out using a pH-meter (JENWAY model 3505 – UK).

Construction of calibration curves
Aliquots equivalent to 200 ?L LH (10-3 M) were successively added to 25 mL BRB buffer (pH 11±0.1) in the electrolytic cell. Square wave voltammetry (SWV) was applied at deposition potential -0.6 V, deposition time 150 seconds and scan rate 100 mV/s. A calibration curve was constructed relating the different concentrations to the peak current. The same procedure was applied for DMA but by adding successive increments of 30 ?L (10-3 M) solution.

Application to pharmaceutical dosage form and milk
Lidocaine hydrochloride vials labeled to contain 10 mg/mL LH. A suitable dilution was made to obtain a concentration of 1×10-5M then SWV was applied and the recovery was calculated. The accuracy of the method was also checked by applying the standard addition technique.

Skimmed milk was purchased from the local market and without any treatment it was diluted with the buffer (pH 11±0.1) in a ratio (1:1, v/v). A volume of 25 mLwas transferred to the electrolytic cell then successive aliquots of DMA were added and SWV was recorded. A calibration graph was then constructed relating the concentration to the peak current.
Results and discussion
Primary analysis using cyclic voltammetry of 4 x 10-3 mol/L of LH in BRB pH 10 at scan rate 100 mV/s showed an irreversible oxidation peak at +0.85 V which is attributed to the oxidation of the tertiary amino group as reported in the literature ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “author” : { “dropping-particle” : “”, “family” : “Rahbar”, “given” : “Nadereh”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Ramezani”, “given” : “Zahra”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Babapour”, “given” : “Ahmad”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Natural Pharmaceutical Products”, “id” : “ITEM-1”, “issue” : “1”, “issued” : { “date-parts” : “2015” }, “page” : “1-7”, “title” : “Electro-Oxidation Mechanism and Direct Square-Wave Voltammetric Determination of Lidocaine With a Carbon-Paste Electrode”, “type” : “article-journal”, “volume” : “10” }, “uris” : “http://www.mendeley.com/documents/?uuid=ce8a4aaa-f2d4-4f00-8c59-5fe20fe7adcc” } , “mendeley” : { “formattedCitation” : “(36)”, “plainTextFormattedCitation” : “(36)”, “previouslyFormattedCitation” : “(36)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(36). The applied potential range was +0.02 to +1.5 V at room temperature at bare carbon paste electrode (Fig.1). Optimization of cyclic voltammetric conditions included studying the effect of different modifiers, effect of pH, effect of silica concentration, deposition potential, accumulation time and effect of scan rate. After the conditions were optimized, square wave voltammetry was applied for the simultaneous determination of LH and DMA.

Effect of different modifiers
Two types of silica were tested, polar silica and C18 silica. It was found that C18 silica gave higher current intensity than bare carbon paste and polar silica modified electrodes (Fig.2). Morphological study of the three electrodes using scanning electron microscope (SEM) (Fig.3), revealed that C18 silica electrode had the most homogeneous porosity and particles distribution with an almost flat morphology producing the best oxidation in addition to highest current density.
Effect of pH
Cyclic voltammograms (CV) of LH were recorded at C18 silica carbon paste electrode in BRB over pH range (2.0-12.0) at a scan rate 100 mV/s. By increasing the pH of the solution, it was observed that the peak potential shifted to lower values signifying that oxidation greatly depends on pH and that protons are involved in the reaction ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1002/elan.201500437”, “ISSN” : “10400397”, “author” : { “dropping-particle” : “”, “family” : “Rizk”, “given” : “Mohamed”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Abouu2005El-Alamin”, “given” : “Maha M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Hendawy”, “given” : “Hassan A. M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Moawad”, “given” : “Mervat I.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Electroanalysis”, “id” : “ITEM-1”, “issue” : “4”, “issued” : { “date-parts” : “2016” }, “page” : “770-777”, “title” : “Highly Sensitive Differential Pulse and Square Wave Voltammetric Methods for Determination of Strontium Ranelate in Bulk and Pharmaceutical Dosage Form”, “type” : “article-journal”, “volume” : “28” }, “uris” : “http://www.mendeley.com/documents/?uuid=d8b67602-29c1-4ff4-9406-90281cba6894” } , “mendeley” : { “formattedCitation” : “(37)”, “plainTextFormattedCitation” : “(37)”, “previouslyFormattedCitation” : “(37)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(37) (See Supplementary data Fig.2). By plotting the pH against the potential a straight line was obtained which fitted to the following equation: E=1.3609-0.0465 pH (r2= 0.9867) with a slope near 59 mV indicating equal number of electrons and protons involved in the reaction (See Supplementary data Fig.3). The peak current showed its maximum value at pH 11 and thus it was used in further investigation and in quantitation.

Effect of different concentrations of silica
Different electrodes containing different concentrations of C18 silica (2.5, 5 and 7.5 %) were tried. The CVs were recorded and it was found that 5 % silica gave maximum current intensity (Fig. 4).
Effect of scan rate
Different scan rates were recorded for LH (4 x 10-3 M) starting from 20 to 200 mV/s inorder to study the reaction mechanism and determine whether it is adsorption or diffusion controlled. A linear relationship was obtained by plotting the logarithm of scan rate against the logarithm of current (See Supplementary data Fig. 4). The regression equation was found to be: log Ip (?A) =0.8418 log (v)-7.6908 (r2=0.9979) showing a value of slope between 0.5 and 1, implying that LH is transported by both adsorption and diffuion processes ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1021/ac60210a007”, “ISBN” : “0003-2700”, “ISSN” : “15206882”, “PMID” : “10984”, “abstract” : “The theory of stationary electrode polarography for both single scan and cyclic triangular wave experiments has been extended to systems in which preceding, folowing, or catalytic (cyclic) chemical reactions are coupled with reversible or irreversible charge transfers. A numerical method was developed for solving the integral equations obtained from the boundary value problems, and extensive data were calcuated wich permit construction of stationary electrode polarograms from theory. Correlations of kinetic and experimental parameters made it possible to develop diagnostic criteria so that unknown systems can be characterized by studying the variation of peak current, half-peak potential, or ratio of anodic to cathodic peak currents as a function of rate of voltage scan.”, “author” : { “dropping-particle” : “”, “family” : “Nicholson”, “given” : “Richard S.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Shain”, “given” : “Irving”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Analytical Chemistry”, “id” : “ITEM-1”, “issue” : “4”, “issued” : { “date-parts” : “1964” }, “page” : “706-723”, “title” : “Theory of Stationary Electrode Polarography: Single Scan and Cyclic Methods Applied to Reversible, Irreversible, and Kinetic Systems”, “type” : “article-journal”, “volume” : “36” }, “uris” : “http://www.mendeley.com/documents/?uuid=2c9dfc4e-7f19-4cf4-88e9-34e80fcc4bdf” } , “mendeley” : { “formattedCitation” : “(38)”, “plainTextFormattedCitation” : “(38)”, “previouslyFormattedCitation” : “(38)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(38). The evidence of diffusion is also supported by the linear relationship obtained by plotting peak current against the square root of scan rate (See Supplementary data Fig.5). A scan rate of 100 mV/s was chosen for the quantitative determination of LH as it showed well-shaped peak with relatively narrow peak width.

The number of electrons involved in the oxidation reaction was calculated from Laviron equation ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1016/S0022-0728(74)80448-1”, “ISBN” : “0022-0728”, “ISSN” : “00220728”, “abstract” : “The effects of a strong adsorption of the depolarizer and/or of the product of the electrochemical reaction on the currents obtained in polarography and in linear potential sweep voltammetry (l.p.s.v.) are considered.(a)A study of the surface electrochemical reaction (reaction of molecules in the adsorbed state) is presented. Mathematical expressions are derived for the current when the reaction is reversible (Brdicka prewaves or postwaves) for polarography and l.p.s.v. The case where the product of the reaction undergoes an irreversible chemical reaction of the first or second order in l.p.s.v. has been treated. Experimental examples are given: the theory accounts for the characteristics of the Brdicka prewaves and postwaves and of the adsorption peaks obtained in l.p.s.v.(b)The electrochemical process is modified by a film of adsorbed molecules (autoinhibition or autocatalysis). Three types of autoinhibition are considered: (I) The inhibiting film is constituted of the molecules of the depolarizer itself. (II) The molecules of the film result from a chemical reaction which occurs parallel with the inhibited electrochemical reaction. (III) The film is made of the final product of the inhibited electrochemical reaction. Mathematical expressions for the i-t curves and for the polarograms have been derived and experimental examples are given. In case III, autoinhibition waves similar in shape to Brdicka prewaves are often observed (pseudo-prewaves); criteria permitting a distinction to be made between prewaves and pseudo-waves are discussed. The case of an autocatalysis by the product of the reaction has been treated; an experimental example is given. The equations of the i-t curves (polarography) and i-E curves (l.p.s.v.) have also been calculated when the electrochemical reaction is irreversible. These equations are obeyed for small coverages. When the film of the depolarizer is compact anomalies appear, which are due to interactions between the molecules. u00a9 1974 Elsevier Sequoia S.A.”, “author” : { “dropping-particle” : “”, “family” : “Laviron”, “given” : “E.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Journal of Electroanalytical Chemistry”, “id” : “ITEM-1”, “issue” : “3”, “issued” : { “date-parts” : “1974” }, “page” : “355-393”, “title” : “Adsorption, autoinhibition and autocatalysis in polarography and in linear potential sweep voltammetry”, “type” : “article-journal”, “volume” : “52” }, “uris” : “http://www.mendeley.com/documents/?uuid=d1dc977b-3c4f-45e6-9dae-afce3b77e402” } , “mendeley” : { “formattedCitation” : “(39)”, “plainTextFormattedCitation” : “(39)”, “previouslyFormattedCitation” : “(39)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(39) using the slope obtained by plotting oxidation peak potential against the logarithm of scan rate. The value of the slope was found to be 0.132 indicating the transfer of one electron which is in accordance with the reported literature on electro-oxidation of tertiary amines ADDIN CSL_CITATION { “citationItems” : { “id” : “ITEM-1”, “itemData” : { “DOI” : “10.1021/la049194c”, “ISSN” : “0743-7463”, “abstract” : “Abstract Image The electrochemical oxidation of aliphatic amines (primary, secondary, and tertiary) has been investigated by cyclic voltammetry and preparative electrolysis. The oxidation mechanisms have been established, and the lifetimes of the radical cations have been measured for secondary and tertiary amines. These results have been put in parallel with the attachment of amines to glassy carbon, Au, and Pt electrodes by cyclic voltammetry, X-ray photoelectron spectroscopy (XPS), and infrared reflectionu2212absorption spectroscopy (IRRAS). It is then possible to show that it is not the radical cation but the radical obtained after the deprotonation which reacts with the electrode surface. XPS results also point to the existence of a covalent bond between Au or Pt and the organic moiety.”, “author” : { “dropping-particle” : “”, “family” : “Adenier”, “given” : “Alain”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Chehimi”, “given” : “Mohamed M.”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Gallardo”, “given” : “Iluminada”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Pinson”, “given” : “Jean”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” }, { “dropping-particle” : “”, “family” : “Vilu00e0”, “given” : “Neus”, “non-dropping-particle” : “”, “parse-names” : false, “suffix” : “” } , “container-title” : “Langmuir”, “id” : “ITEM-1”, “issue” : “19”, “issued” : { “date-parts” : “2004”, “9” }, “page” : “8243-8253”, “title” : “Electrochemical Oxidation of Aliphatic Amines and Their Attachment to Carbon and Metal Surfaces”, “type” : “article-journal”, “volume” : “20” }, “uris” : “http://www.mendeley.com/documents/?uuid=f06fd41e-0988-3713-8226-36e1dc131380” } , “mendeley” : { “formattedCitation” : “(40)”, “plainTextFormattedCitation” : “(40)”, “previouslyFormattedCitation” : “(40)” }, “properties” : { }, “schema” : “https://github.com/citation-style-language/schema/raw/master/csl-citation.json” }(40).

Effect of deposition potential and accumulation time
Deposition potential and accumulation time may have a great impact on the sensitivity of the determination by controlling the amount of drug adsorbed at the electrode surface. Different deposition potentials were scanned in the range of -1.2 to -0.2 V and the cyclic wave voltammograms were recorded. Results revealed that the current intensity of LH was greatly enhanced upon applying a potential of -0.6 V. Upon applying this potential for different time intervals, maximum peak current of LH was obtained after accumulation time of 150 seconds as shown in (See Supplementary data Fig.6).
Cyclic voltammetry is primarily used as a tool for fundamental and diagnostic studies which provides qualitative information only about electrochemical processes. More sensitive methods such as SWV are used for the quantitative determination of electroactive substances. Thus a mixture of DMA and LH was analyzed using the optimized conditions of 5% C18 silica in BRB (pH 11±0.10) applying deposition potential of -0.6 V for 150 seconds at scan rate of 100 mV/s using SWV where two peaks were observed at 0.56 V and 0.87 V for DMA and LH respectively (Fig.5).

Method validation
Linearity: using the optimized conditions, good linearity was achieved by plotting the concentration of LH and DMA against the peak current showing good correlation coefficients, in ranges of (7.94 x10-6 to 1.07 x 10-4 M) and (1.20 x 10-6 to 1.07 x 10-5 M) for LH and DMA, respectively (See Supplementary data Fig.7 and Fig.8). The parameters of the regression equations are shown in Table 1.

Accuracy: three different samples of LH and DMA were analyzed using the same procedure under linearity and the concentrations were calculated from the regression equations showing reasonable recoveries as shown in Table 1.

Precision: intraday and interday precision were assessed by analyzing three different samples in triplicates on the same day and on three successive days respectively. RSD% was calculated and was less than 2% as shown in Table 1.

Specificity and selectivity: the proposed method was successfully applied for the determination of LH and DMA in their laboratory prepared mixtures as shown in Table 2. The method was also applied for the determination of LH in dosage form without any interference from excipients or additives. Validation of the method was further checked by applying the standard addition technique as shown in Table 3.
Limit of detection (LOD) and limit of quantitation (LOQ): LOD was determined using the following equation: LOD= 3.3 x (SD of the response/slope) while LOQ was calculated using this equation LOQ = 10 x (SD of the response/slope) where SD is the standard deviation. Results are shown in Table 1.

Application to spiked milk
Being a toxic metabolite of LH and reported to be secreted in human and bovine milk, DMA was determined in spiked milk samples by the developed SWV method where good linearity was acheived in the range of 2.39 x 10-6 – 8.33 x 10-6 M with detection limit of 2.42 x 10-7 M as shown in Table 4.

Comparison with reported method
The results of the proposed method were statistically compared to those obtained from the reported HPLC method and no significant difference was found between them as shown in Table 5.

4. Conclusion
In this work, a new sensor was developed based on carbon paste electrode modified with C18 silica for the simultaneous determination of LH and its toxic metabolite DMA. Different conditions were studied and under the optimized conditions square wave voltammetry was used for the quantitation of both LH and DMA in pure form and pharmaceutical dosage form. DMA was also determined in spiked milk samples with good recoveries. The proposed method is sensitive, accurate and precise. Complete validation was done regarding linearity, accuracy, precision, specificity and selectivity. The proposed method can be used in the quality control laboratories giving satisfactory results compared to other sophisticated, time consuming and expensive methods.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Table 1: Regression and validation data of the calibration curves for the quantitative determination of lidocaine hydrochloride and 2,6- dimethylaniline in pure form
Parameters LH DMA
Accuracy ± RSD% 99.57 ± 0.810 101.96 ± 1.104
LOD (M) 2.19 x 10-6 2.15 x 10-7
LOQ (M) 6.65 x 10-6 6.52 x 10-7
Precision
Repeatability 1.361 0.554
Intermediate precision 1.704 1.126
Linearity
Range (M) 7.94 x 10-6 – 1.07 x 10-4 1.20 x 10-6 – 1.07 x 10-5
Mean 99.12 99.92
SD 1.884 1.352
RSD 1.901 1.353
Slope 0.115 0.2176
Intercept 6 x 10-7 6 x 10-10
Correlation coefficient (r) 0.9997 0.9998
Table 2: Recovery of lidocaine hydrochloride and 2,6-dimethylaniline from different laboratory prepared mixtures by the proposed SWV method
LH DMA
Concentration
(M) Found concentration
(M) Recovery% Concentration
(M) Found concentration
(M) Recovery %
1 x 10 -5 1.03 x 10 -5 103.00 5 x 10 -6 4.99 x 10-6 99.90
4 x 10 -5 4.00 x 10 -5 100.00 4 x 10-6 3.84 x 10-6 96.00
5 x 10 -5 5.05 x 10 -5 101.00 2 x 10-6 1.95 x 10-6 97.50
Mean 101.33 Mean 97.80
SD 1.528 SD 1.967
RSD 1.508 RSD 2.011

Table 3: Application of the proposed SWV method for the determination of lidocaine hydrochloride in pharmaceutical dosage form
Pharmaceutical formulation Recovery % ± SD* Standard addition
Lidocaine Hydrochloride ampoule B.N. 140573 99.67 ± 1.258 Claimed taken (M) Standard added
(M) Standard found
(M) Recovery of Standard added*
1 x 10-5 3.980 x 10-6 3.950 x 10-6 99.20
7.936 x 10-6 8.079 x 10-6 102.00
1.185 x 10-5 1.184 x 10-5 99.90
1.574 x 10-5 1.562 x 10-5 99.20
1.960 x 10-5 1.970 x 10-5 101.00
Mean ± SD 100.14 ± 1.068
RSD 1.067
*Average of three determinations

Table 4: Regression and validation data of the calibration curve for the determination of 2,6-dimethylaniline in milk
Parameters DMA
Linearity (M) 2.39 x 10-6 – 8.33 x 10-6
Mean 99.25
SD 1.770
RSD 1.783
LOD (M) 2.42 x 10-7
LOQ (M) 7.32 x 10-7
Slope 0.0794
Intercept 6 x 10-8
Correlation coefficient (r) 0.9994

Table 5: Statistical comparison between the proposed SWV method and the reported HPLC method
Parameter Voltammetry Reported*
LH DMA LH DMA
Mean 99.12 99.92 100.05 100.12
SD 1.884 1.352 1.246 1.275
Variance 3.549 1.828 1.553 1.626
n 9 6 6 6
Student’s t test 1.369
(1.771)** 0.491
(1.812)** F-value 2.29
(4.82)** 1.124
(5.05)** *values between parenthesis correspond to the reported HPLC method using Hypersil C18 column. The mobile phase consisted of Britton Robinson buffer pH 7: methanol: acetonitrile (40:45:15, by volume), flow rate 1.2 ml/min and UV detection at 225 nm.
**values between parenthesis correspond to F and t values at p=0.05

Fig.1: Cyclic voltammograms of lidocaine hydrochloride (4 x 10-3 M) at bare carbon paste electrode

Fig.2: Cyclic voltammograms of lidocaine hydrochloride (4 x 10-3 M) at different electrodes
left26035C18 Silica CPE
Polar Silica CPE
Bare CPE
0C18 Silica CPE
Polar Silica CPE
Bare CPE

Fig.3: Scanning electron microscope images of the three prepared electrodes

Fig. 4: Effect of silica concentration on the oxidation peak of lidocaine hydrochloride (4 x 10-3 M) in BR buffer pH 11 at scan rate 100 mV/s

419989046863000Fig.5: Square wave voltammogram of lidocaine hydrochloride (…….), 2,6-dimethylaniline (—-) and a mixture of both ( )

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