A microfabricated potentiometric sensor for metoclopramide determination utilizing a graphene nanocomposite transducer layer.

In the recent drug analysis arena, optimizing a green, eco-friendly, and cost-effective technique is the main target. In order to cope with green analytical chemistry principles and the trending development of miniaturized portable and handheld devices, an innovative microfabricated ion-selective electrode for the analysis of metoclopramide (MTP) was developed. The fabricated electrode adopted a two-step optimization process. The first step of optimization depended on screening different ionophores in order to enhance the sensor selectivity. Calix-4-arene showed the maximal selectivity towards MTP. The second step was utilizing a graphene nanocomposite as an ion-to-electron transducer layer between the calix-4-arene polymeric membrane and the microfabricated copper solid-contact ion-selective electrode. The graphene nanocomposite layer added more stability to electrode potential drift and short response times (10 s), probably due to the hydrophobic behavior of the graphene nanocomposite, which precludes the formation of a water layer at the Cu electrode/polymeric membrane interface. The proposed MTP sensor has been characterized according to IUPAC recommendations and the linear dynamic range estimated to be 1 × 10-6 to 1 × 10-2 M with LOD of 3 × 10-7 M. The proposed sensor has been successfully employed in the selective determination of MTP in bulk powder, pharmaceutical formulation, and biological fluid. No statistical significant difference was observed upon comparing the results with those of the official method. The Eco-score of the method was assessed using the Eco-Scale tool and was compared with that of the official method. Graphical abstract.

Validated ecofriendly chromatographic method for quantitative determination of anti-migraine quaternary mixture.

A novel ecofriendly, cost and time saving high-performance thin-layer chromatographic method was developed and validated for simultaneous determination of metoclopramide, ergotamine, caffeine, and paracetamol in bulk and pharmaceutical formulation. The separation was carried out on silica gel plates, using ethyl acetate:ethanol:ammonia (9:1:0.1, v/v/v) as a developing system. Ultraviolet detection was carried out at 272 nm. The resulting retention times were 0.15, 0.36, 0.49, and 0.74 min for metoclopramide, ergotamine, caffeine, and paracetamol, respectively. The greenness profile assessment was achieved to the proposed method to evaluate its greenness characters to the environment with acceptable results. Validation parameters were checked according to International Conference of Harmonization guidelines to achieve the international requirements for quality control analysis of the proposed drugs.

A green approach for metoclopramide quantification in pharmaceutical products: new HPLC and spectrophotometric methods.

Green spectrophotometric and HPLC methods have been developed for the quantification of metoclopramide. In the spectrophotometric method, it was determined by direct absorbance measurement at 273 nm wavelength using ultrapure water as solvent. The Extend C18 column was used for the HPLC method. The mobile phase system consisted of a combination of ethanol and formic acid solution (pH 2.0; 30:70 v/v). Isocratic elution was applied and the flow rate was set at 1.0 mL min-1. Metoclopramide was detected at 273 nm. The methods performed were economical, rapid, environmentally friendly, and simple, providing metoclopramide analysis within 5 min. The methods have been successfully applied in pharmaceutical products without matrix interference. The results of the application of the developed methods to pharmaceutical products were statistically compared and no significant difference was observed between the methods. In addition, the greenness assessment of the developed methods was performed using AGREE software. Our developed methods, based on the use of solvents such as ethanol and water, are proposed as a more environmentally and analyst-friendly option for the quantification of metoclopramide in pharmaceutical products than other methods currently in use.

Validation and application of RP-HPLC method for the quantification of metoclopramide hydrochloride in oral formulations prepared for IVIVC studies.

The objective of this study is to develop sensitive and cost effective reverse phase high performance liquid chromatographic method for the estimation of Metoclopramide Hydrochloride in oral solid dosage formulations. A reverse chromatographic method was used with the mobile phase of Acetonitrile, 20m M Potassium dihydrogen phosphate buffer solution (pH 3 adjusted with orthophosphoric acid) in the ratio of 40:60. The column used was Waters C18 3.9×300mm µBondapak (RP). The flow rate of the mobile phase was 2ml/minute. The detector was set at the wavelength of 275nm.This method showed good sensitivity. The linearity was also found to be excellent (γ(2)=0.997) in the range of 5-75 µg/ml. No interfering peaks were observed at the retention time of Metoclopramide Hydrochloride when both placebo and blank samples were injected (Retention time =1.93min). The parameters such as specificity, linearity, range, accuracy, precision, system suitability, solution stability, detection and quantification limits were evaluated to validate this method. This method can effectively be used for quantitative analysis of Metoclopramide hydrochloride tablet formulations because of its specificity, accuracy and convenience of use.

GC-MS analysis of organic fractions of Chrozophora tinctoria (L.) A.Juss. and their prokinetic propensity in animal models.

Chrozophora tinctoria (L.) A.Juss. is herbaceous, monecious annual plant used traditionally to cure gastrointestinal disorders. The present study was carried out to find the bioactive compounds by Gas Chromatography-Mass Spectrometry, the acetylcholinesterase inhibitory potential acute toxicity, and emetic activity present in the ethyl acetate fraction of Chrozophora tinctoria (EAFCT) and dichloromethane fraction of Chrozophora tinctoria (DCMFCT). The compounds detected in both fractions were mostly fatty acids, with about seven compounds in EAFCT and 10 in DCMFCT. These included pharmacologically active compounds such as imipramine, used to treat depression, or hexadecanoic acid methyl ester, an antioxidant, nematicide, pesticide, hypocholesterolemic, 9,12,15-Octadecatrienoic acid, ethyl ester, (Z,Z,Z)- is used as a cancer preventive, antiarthritic, antihistaminic, hepatoprotective, insectifuge, nematicide, Pentadecanoic acid, 14-methyl-, methyl ester have antifungal, antimicrobial and antioxidant activities, 10-Octadecanoic acid, methyl ester have the property to decrease blood cholesterol, Antioxidant and antimicrobial, 1-Eicosanol is used as an antibacterial, 1-Hexadecene has antibacterial, antioxidant, and antifungal activities. Both DCMFCT and EAFCT fractions inhibited acetylcholinesterase (AChE) activity with IC50 values of 10 µg and 130 µg, respectively. Both the fractions were found to be toxic in a dose-dependent manner, inducing emesis at 0.5g onward and lethargy and mortality from 3-5 g upwards. Both the fractions combined with distilled water showed highly emetic activity. The significant increase in the number of vomits was shown by EAFCT plus distilled water which are 7.50±1.29, 7.25±3.10, and 11.75±2.22 number of vomits at 1g, 2g, and 3g/kg concentration respectively, while DCMFCT plus distilled water showed 5.25±2.22, 7.50±2.52 and 10.25±2.22 number of vomits at 1g, 2, and 3g/kg correspondingly. The antiemetic standard drug metoclopramide has a higher impact against the emesis induced by both the fractions than dimenhydrinate. Metoclopramide decreases the number of vomits caused by EAFCT to 1.00±0.00, 2.00±0.00, 4.00±1.00 at 1g, 2, and 3g/kg sequentially, while dimenhydrinate decreases the number of vomits to 1.33±0.58, 2.33±1.15, 4.33±0.58 at 1g, 2, and 3g respectively. In the same way, Metochloprimide decreases the number of emesis caused by DcmCt from 5.25±2.22, 7.50±2.52, 10.25±2.22 to 1.33±0.58, 2.33±1.1, 4.33±0.58 at 1g, 2, and 3g/kg concentrations. The present study is the first documented report that scientifically validates the folkloric use of Chrozophora tinctoria as an emetic agent.

Thermal FT-IR microspectroscopy for rapid detection of solid-state ion-exchange reaction between metoclopramide HCl monohydrate and potassium bromide.

The combination of Fourier transform infrared (FT-IR) microspectroscopy with a thermal analyzer was applied to quickly investigate the solid-state ion-exchange reaction of metoclopramide HCl monohydrate (MCP H(2)O) by clipping MCP H(2)O powder between two KBr or KCl pellets. The physical and ground mixtures of MCP H(2)O or 150 °C-preheated MCP powder and KBr or KCl powders with a weight ratio of 1 : 100 were also prepared and determined by FT-IR microspectroscopy. The samples of MCP H(2)O or 150 °C-preheated MCP were identified by using differential scanning calorimetry (DSC) and thermogravimetric (TG) analysis. The results of present study indicate that the ion-exchange reaction was easily induced between MCP H(2)O and KBr by grinding and heating processes. The possible mechanism of ion-exchange reaction may take place between the HCl salt of MCP H(2)O and a KBr matrix by grinding or heating to yield a mixture of HCl and HBr salts of the MCP sample in the presence of hydrated water. The crystal hydrate played an important role to improve this ion-exchange reaction between MCP H(2)O and KBr. However, no ion-exchange reaction occurred between MCP H(2)O and KCl or between 150 °C-preheated MCP and KBr. The solid-state ion-exchange reaction was more easily determined by this novel thermal FT-IR microspectroscopy than other conventional methods.

Spectrofluorimetric assessment of metoclopramide hydrochloride using terbium doped in PMMA matrix optical sensor.

A new, simple and accurate spectrofluorimetric method for the determination of metoclopramide hydrochloride was developed. The metoclopramide hydrochloride can remarkably enhance the luminescence intensity of the Tb(3+) ion doped in PMMA matrix at λ(ex)=360 nm in methanol at pH 6.9. The intensity of the emission band at 545 nm of Tb(3+) ion doped in PMMA matrix is increased due to the energy transfer from metoclopramide hydrochloride to Tb(3+) in the excited stated. The effect of different parameters, e.g., pH, temperature, Tb(3+) concentration, foreign ions that control the fluorescence intensity of the produced ion associate was critically investigated. The calibration curve of the emission intensity at 545 nm shows linear response of metoclopramide over a concentration range of 5 × 10(-5)-5.0 × 10(-8) M with detection limit of 8.7 × 10(-10) M. The method was used successfully for the determination of metoclopramide in pharmaceutical preparations and human serum. The average recovery of 99.48% with standard deviation of 0.32% and 96.98% with standard deviation of 0.4%, of pharmaceutical preparations and human serum respectively, were obtained which compared will with the results obtained from standard LC method of average recovery 99.04% and standard deviation of 0.6% and average recovery of 98.19% with standard deviation of 0.6% of pharmaceutical preparations and human serum, respectively.

[Stability of Six Drugs in Total Parenteral Nutrition Solution].

Elneopa NF No. 1 and No. 2 infusions are total parenteral nutrition solutions packaged in four-chambered infusion bags. They have been used as home parenteral nutrition, with various drugs injected into the infusion bags, for treating patient symptoms. In this study, we investigated the stability of six drugs, including famotidine, scopolamine butylbromide, furosemide, bromhexine hydrochloride, betamethasone sodium phosphate, and metoclopramide hydrochloride in the infusion bags under dark conditions at 4℃ for 7 days. Additionally, we developed a high-performance liquid chromatography method to determine drug concentrations in the infusions. The concentrations of injected famotidine, scopolamine butylbromide, and betamethasone sodium phosphate remained unchanged when the four chambers of Elneopa NF No. 1 and No. 2 were opened and the infusions were mixed. Their respective concentrations in the upper and lower chambers also remained unchanged. The concentration of furosemide in the upper chamber of the No. 1 infusion bag decreased after 5 days, although no change was observed in the other chambers and the mixed infusions with the four chambers opened. The concentration of bromhexine hydrochloride slightly decreased in the upper chambers (approximately 3%) after the co-infusion but decreased significantly in the other chambers and the mixed infusions with the four chambers opened. The concentration of metoclopramide hydrochloride significantly decreased in the upper chambers after the co-infusion; however, no change in concentration was observed in the other chambers and the mixed infusion with the four chambers opened. The results of this study provide useful information on home-based parenteral nutrition.

Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies.

Metoclopramide (MCP) is frequently used to treat gastroparesis. Previous studies have documented MCP metabolism, but systematic structural identification of metabolites has not been performed. The aim of this study was to better understand MCP metabolism in humans. For examination of in vivo metabolism, a single oral 20-mg MCP dose was administered to eight healthy male volunteers, followed by complete urine collection over 24 h. In vitro incubations were performed in human liver microsomes (HLM) to characterize metabolism via cytochromes P450 and UDP-glucuronosyltransferases and in human liver cytosol for metabolism via sulfotransferases. Urine and subcellular incubations were analyzed for MCP metabolites on a mass spectrometer with accurate mass measurement capability. Five MCP metabolites were detected in vivo, and five additional metabolites were detected in vitro. The five metabolites of MCP identified both in vitro and in vivo were an N-O-glucuronide (M1), an N-sulfate (M2), a des-ethyl metabolite (M3), a hydroxylated metabolite (M4), and an oxidative deaminated metabolite (M5). To our knowledge, metabolites M1 and M4 have not been reported previously. M2 urinary levels varied 22-fold and M3 levels varied 16-fold among eight subjects. In vitro studies in HLM revealed the following additional metabolites: two ether glucuronides (M6 and M8), possibly on the phenyl ring after oxidation, an N-glucuronide (M7), a carbamic acid (M9), and a nitro metabolite (M10). Metabolites M6 to M10 have not been reported previously. In conclusion, this study describes the identification of MCP metabolites in vivo and in vitro in humans.

Advanced approaches for the treatment and amplification of weak spectral signals produced by critical concentrations in white multicomponent systems.

An analytical investigation was carried out to study the treatment and amplification of the spectral signals produced by critical concentrations with high accuracy and precision using two advanced approaches. The factorized-spectrum approach was applied through two novel methods which were: absorptivity centering technique via both: factorized zero order absorption spectrum (ACT-FSD0ΔA) and factorized ratio spectrum (ACT-FSRΔP). The proposed methods were found to be linear in the ranges of (15-100 µg/mL) and (3-40 µg/mL) for ASP and MTO, respectively. Those methods were compared to the methods following the geometrical standard addition approach: ratio H-point standard addition method (RHPSAM) and geometrical induced amplitude modulation (GIAM). The approaches were applied for the determination of the minor component metoclopramide in its mixture with the major component aspirin in the challengeable ratio of (1,90) respectively in a white multicomponent system. The results obtained from the proposed approaches were statistically compared with each other. The methods were validated according to ICH guidelines where the results were found to be within the acceptable limits. The methods were found to be accurate and reliable for the determination of metoclopramide critical concentration besides aspirin concentration. The results of single factor ANOVA analysis indicated that there is no significant difference among the developed methods. These methods provided simple resolution of this binary combination from synthetic mixtures and pharmaceutical preparation and can be conveniently adopted for routine quality control analysis.

Segmental Hair Analysis-Interpretation of the Time of Drug Intake in Two Patients Undergoing Drug Treatment.

The present study involved segmental testing of hair in two clinical cases with known dosage histories. Hair analysis confirmed the first patient's exposure to the prescribed sertraline and citalopram for several months. Citalopram was generally distributed along the hair shaft in accordance with the drug ingestion period. By contrast, "false" positive results were observed for sertraline in distal hair segments, corresponding to a period of no sertraline exposure, which may indicate incorporation from sweat or sebum, which transport the drugs along the hair surface. The second patient received various drugs during her treatment for brain cancer. Metoclopramide, morphine, oxazepam, paracetamol, sumatriptan, tramadol, and zopiclone, which had been part of the therapy, were all detected in the proximal hair segment. The results of these two cases indicated that results-especially concerning the time of drug intake-must be interpreted with caution and allow for the possibility of incorporation from sweat or sebum.

Electrogenerated chemiluminescence sensor for metoclopramide determination based on Ru(bpy)3 2+-doped silica nanoparticles dispersed in Nafion on glassy carbon electrode.

A novel method for the determination of metoclopramide (MCP) using electrogenerated chemiluminescence (ECL) is presented. A tris(2,2'-bipyridyl)dichlororuthenium(II) (Ru(bpy)3(2+))-doped silica (RuDS) nanoparticle/perfluoinated ion-exchange resin (Nafion) with nanocomposite membrane modified glassy carbon electrode (GCE) is used. The Ru(bpy)3(2+) encapsulation interior of the silica nanoparticle maintains its electrochemical activities and also reduces Ru(bpy)3(2+) leaching from the silica matrix when immersed in water due to the electrostatic interaction. The analytical performance of this ECL sensor for MCP is shown in detail. Under optimal experimental conditions, it has good linearity in the concentration range from 2 x 10(-8)mol/L to 1 x 10(-5)mol/L (R=0.9989) with a detection limit of 7 x 10(-9)mol/L. The relative standard deviation (n=11) is 3.2% for detecting 1.2 x 10(-6)mol/L MCP. The recoveries are in the range of 97.0-104.4% for sample measurements by standard-addition method. This method has been applied successfully to determine MCP in pharmaceutical preparations and in human urine. Statistical analysis (Student's t-test and variance ratio F-test) of the obtained results show no significant difference between this proposed method and the reference method.

Second derivative synchronous fluorescence spectroscopy for the simultaneous determination of metoclopramide and pyridoxine in syrup and human plasma.

A rapid, simple, and highly sensitive second derivative synchronous fluorometric method has been developed for the simultaneous determination of metoclopramide (MT) and pyridoxine (PY) in a binary mixture. The method is based on measurement of the native fluorescence of these drugs at delta lambda = 80 nm in methanol. The different experimental parameters affecting the native fluorescence of the drugs were carefully studied and optimized. The fluorescence-concentration plots were rectilinear over the ranges of 0.02-0.4 and 0.1-2 microg/mL for MT and PY, respectively. The limits of detection were 0.003 and 0.007 microg/mL and the limits of quantification were 0.008 and 0.02 microg/mL for MT and PY, respectively. The proposed method was successfully applied to the determination of MT and PY in synthetic mixtures and in commercial syrup. The results were in good agreement with those obtained with a reported method. The high sensitivity attained by the proposed method allowed the determination of MT in spiked and real human plasma samples. The mean percent recoveries of MT from spiked and real human plasma (n = 3) were 93.72 +/- 3.15 and 89.72 +/- 2.19 respectively.

[Residue analysis of metoclopramide in bovine and swine tissues by HPLC and administration experiment].

A reversed-phase ion-pair HPLC method with ultraviolet detection has been developed for determination of metoclopramide (MCP) in bovine and swine muscle, liver, kidney, fat and intestine. MCP was extracted from samples with acetonitrile, and the extracts were cleaned up on an Oasis HLB cartridge (60 mg) after liquid-liquid extraction. The limit of detection of MCP was 0.002 microg/g and the limit of quantitation was 0.007 microg/g. Recoveries of MCP spiked at 0.03 ppm ranged from 74.1 to 93.3% for bovine tissues and from 86.1 to 92.7% for swine tissues. The present method was used for the analysis of bovine and swine tissues 1 day after withdrawal following drug administration. The MCP concentrations in all tissues were lower than the Japanese provisional MRLs.

Square wave anodic stripping voltammetric determination of metoclopramide in tablet and urine at carbon paste electrode.

A simple, reliable and selective square wave anodic stripping (SWAS) voltammetric method at carbon paste electrode (CPE) of metoclopramide hydrochloride (MCP) in pharmaceutical dosage forms (tablet) and in biological fluids (spiked and real urine samples) has been developed and evaluated. Different parameters such as medium, supporting electrolyte, pH, accumulation potential, scan rate, accumulation time and ionic strength, were tested to optimize the conditions for the determination of MCP. The adsorbed form is oxidized irreversibly under optimal conditions, viz., 0.4M HCl-sodium acetate buffer (pH approximately 6.2), 0.2M KCl, a linear concentration ranges from 0.067 to 0.336, 0.067 to 0.269 and 0.067 to 0.269 ng/mL of MCP, at accumulation times 60, 120 and 180 s, respectively, can be determined successfully. The interferences of some common excipients and some metal ions were studied. The standard addition method was used to determine the MCP in pure solutions, tablets and in biological fluids with satisfactory results. The data obtained are compared with the standard official method.

[Spectral study and determination of metoclopramide and procaine hydrochloride by sequential injection analysis].

A sequential injection spectrophotometric method is proposed for the determination of metoclopramide or procaine hydrochloride, based on the reactions of metoclopramide and procaine hydrochloride with cerium(IV) in sulfuric acid medium. Red intermediate products were observed and were found unstable so that their analytical use is only possible by sequential injection technology. For metoclopramide, the detection limit is 6.5 microg x mL(-1), and the linear range of determination is 9.7-116.6 microg x mL(-1) with a sampling frequency of 45 h(-1). For procaine hydrochloride, the detection limit is 7.4 microg x mL(-1), and the linear range of the determination is 10.0-130.0 microg x mL(-1) with a sampling frequency of 45 h(-1). The method has been applied to the determination of metoclopramide and procaine hydrochloride in tablets and injections with satisfactory results as compared with standard method.

A radioimmunoassay for metoclopramide.

A radioimmunoassay for the anti-emetic drug, metoclopramide, in the pmol range was developed. The immunogen was prepared by photolytic coupling of metoclopramide to bovine serum albumin. A crosslinking reagent, N-hydroxy-succinimidyl-4-azidobenzoate, was first reacted with serum albumin through nucleophilic substitution. Ultraviolet irradiation (lambda greater than 300 nm) of the photoactive serum albumin conjugate in the presence of metoclopramide resulted in covalent attachment of the drug to the protein. An 125I-labelled metoclopramide derivative was prepared by diazotisation of the aromatic amine group and substitution of the resultant diazo group with 125I-. Binding data of the antibody with radioiodinated metoclopramide gave a linear Scatchard plot indicative of a homogeneous antibody population. A dissociation constant of 3 X 10(-11) mol/l was calculated for the antigen-antibody interaction. The antibodies showed negligible cross-reactivity with lignocaine which is structurally closely related to metoclopramide.

Modification of metoclopramide GLC assay: application to human biological specimens.

A modified electron-capture GLC assay for metoclopramide in human biological specimens is reported. This assay involves the incorporation of a back-extraction method to remove endogenous contaminants. Its applicability was demonstrated by studying the time course of metoclopramide in plasma and urine from a human subject. The lowest quantifiable metoclopramide concentration in plasma was 7 ng/ml, provided 0.5 ml of plasma was used.

Sensitive electron-capture GLC determination of metoclopramide in biological fluids.

A highly sensitive and specific electron-capture GLC assay capable of detecting picogram quantities of metoclopramide, a procaine derivative, in biological fluids was developed. This assay consisted of extracting metoclopramide from an alkalinized aqueous layer into benzene. A portion of the organic phase was derivatized with heptafluorobutyric anhydride. Quantitative estimation of the derivative was accomplished by adding diazepam, the internal standard, in bezene (750 ng/ml). A calibration curve was prepared for the plasma extracts. Linearity was observed in the range studied (91-825 ng/ml). No interference from endogenous substances was observed. The minimum detectable amount was 1 pg/injection. The structure of the derivative was confirmed by electron-impact and chemical-ionization mass spectrometry. The applicability of this method was shown by a preliminary study of the elimination kinetics of metoclopramide in rats after a 10-mg/kg iv dose.

Acute and chronic effects of neuroleptic drugs on plasma and brain homovanillic acid in the rat.

In the rat, the acute administration of the neuroleptic drug, haloperidol, produces a parallel increase in brain and plasma concentrations of the dopamine metabolite, homovanillic acid (HVA). The effect of other neuroleptic drugs, which may differ from haloperidol in their central and peripheral actions, on brain and plasma HVA has not been systematically investigated. Therefore, in this report we examine the acute effects of six different neuroleptic drugs, representing most major chemical classes of these drugs, on plasma and brain concentrations of HVA. Metoclopramide, fluphenazine, loxapine, and molindone produce parallel increases in brain and plasma HVA which closely resemble those produced by haloperidol. Compared to these neuroleptics, chlorpromazine produces a much greater increase in plasma HVA but a similar effect on brain HVA. The large chlorpromazine-induced increase in plasma HVA suggests that this drug alters peripheral production or clearance of HVA, perhaps via blockade of peripheral alpha-receptors. Of the available neuroleptics, sulpiride is one of the most specific and potent at blocking the dopamine vascular receptor. Administration of high doses of sulpiride produces only modest increases in both plasma and brain HVA, suggesting that blockade of peripheral dopamine receptors does not substantially alter peripheral clearance of HVA. After chronic administration of haloperidol for up to 21 days, plasma HVA continued to reflect the brain HVA response to drug administration.