Development and validation of RP-HPLC method for simultaneous determination of cefpodoxime proxetil and H2 receptor antagonists in pharmaceutical dosage forms.

A new method on RP-HPLC is devised and validated, as per ICH guidelines, for the synchronous estimation of cefpodoxime proxetil and H2-receptor antagonits that are Cimetidine, Famotidine and Ranitidine. The method is simple, accurate, expeditious, reproducible, robust and precise. Chromatography was done on a C18 (250 x 4.6mm) column with methanol: water as mobile phae in the ratio of 70:30 (v/v), pumped at a flow rate of 1ml/min and pH was maintained using 85% ortho-phosphoric acid at 3. The λ max 240 nm was preferred for UV detection. A good linear relationship was attained, over the concentration ranges of 20-70 µg/ml and 5-30µg/ml, for cefpodoxime proxetil and H2 blockers respectively, with a correlation coefficient of R= 0.9987 to 0.9992. The method was validated and found precised (i.e. intra day and interday analysis) with RSD <2%. LOD and LOQ observations were under 0.4806 to 2.6069µg/ml which proved the method to be sensitive. The method provided satisfactory results of robustness and reproducibility, when validated and applied successfully for analysis of dosage forms.

Ultrasensitive chemiluminescence assay for cimetidine detection based on the synergistic improving effect of Au nanoclusters and graphene quantum dots.

A novel and sensitive chemiluminescence (CL) procedure based on the synergetic catalytic effects of gold nanoclusters (Au NCs) and graphene quantum dots (GQDs) was developed for the reliable measurement of cimetidine (CM). The initial experiments showed that the KMnO4 -based oxidation of alkaline rhodamine B (RhoB) generated a very weak CL emission, which was intensively enhanced in the simultaneous presence of Au NCs and GQDs. CL intermediates can be adsorbed and gathered on the surface of Au NCs, becoming more stable. GQDs participate in the energy transferring processes and facilitate them. These improving effects were simultaneously obtained by adding both Au NCs and GQDs into the RhoB-KMnO4 reaction. Consequently, the increasing effect of the Au NCs/GQDs mixture was more than that of pure Au NCs or GQDs, and a new nano-assisted powerful CL system was achieved. Furthermore, a marked quenching in the emission of the introduced CL system was observed in the presence of CM, so the system was examined to design a sensitive sensor for CM. After optimization of influencing parameters, the linear lessening in CL emission intensity of KMnO4 -RhoB-Au NCs/GQDs was verified for CM concentrations in the range 0.8-200 ng ml-1 . The limit of detection (3Sb /m) was 0.3 ng ml-1 . Despite being a simple CL method, good sensitivity was obtained for CM detection with reliable results for CM determination in human urine samples.

Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy.

The lower detection limit for 2 distinct crystalline phases by 1H magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) is investigated for a minority amount of cimetidine (anhydrous polymorph A) in a physical mixture with the anhydrous HCl salt of cimetidine. Specifically, 2-dimensional 1H double-quantum (DQ) MAS NMR spectra of polymorph A and the anhydrous HCl salt constitute fingerprints for the presence of each of these solid forms. For solid-state NMR data recorded at a 1H Larmor frequency of 850 MHz and a MAS frequency of 30 kHz on ∼10 mg of sample, it is shown that, by following the pair of cross-peaks at a 1H DQ frequency of 7.4 + 11.6 = 19.0 ppm that are unique to polymorph A, the level of detection for polymorph A in a physical mixture with the anhydrous HCl salt is a concentration of 1% w/w.

Qualitative and simultaneous quantitative analysis of cimetidine polymorphs by ultraviolet-visible and shortwave near-infrared diffuse reflectance spectroscopy and multivariate calibration models.

The object of the present study was to investigate the feasibility of applying ultraviolet-visible and shortwave near-infrared diffuse reflectance spectroscopy (UV-vis-SWNIR DRS) coupled with chemometrics in qualitative and simultaneous quantitative analysis of drug polymorphs, using cimetidine as a model drug. Three polymorphic forms (A, B and D) and a mixed crystal (M1) of cimetidine, obtained by preparation under different crystallization conditions, were characterized by microscopy, X-ray powder diffraction (XRPD) and infrared spectroscopy (IR). The discriminant models of four forms (A, B, D and M1) were established by discriminant partial least squares (PLS-DA) using different pretreated spectra. The R and RMSEP of samples in the prediction set by discriminant model with original spectra were 0.9959 and 0.1004. Among the quantitative models of binary mixtures (A and D) established by partial least squares (PLS) and least squares-support vector machine (LS-SVM) with different pretreated spectra, the LS-SVM models based on original and MSC spectra had better prediction effect with a R of 1.0000 and a RMSEP of 0.0134 for form A, and a R of 1.0000 and a RMSEP of 0.0024 for form D. For ternary mixtures, the established PLS quantitative models based on normalized spectra had relatively better prediction effect for forms A, B and D with R of 0.9901, 0.9820 and 0.9794 and RMSEP of 0.0471, 0.0529 and 0.0594, respectively. This research indicated that UV-vis-SWNIR DRS can be used as a simple, rapid, nondestructive qualitative and quantitative method for the analysis of drug polymorphs.

A quantitative HPLC-MS/MS method for studying internal concentrations and toxicokinetics of 34 polar analytes in zebrafish (Danio rerio) embryos.

An analytical method using high-performance liquid chromatography-tandem mass spectrometry was developed to determine internal concentrations of 34 test compounds such as pharmaceuticals and pesticides in zebrafish embryos (ZFE), among them, cimetidine, 2,4-dichlorophenoxyacetic acid, metoprolol, atropine and phenytoin. For qualification and quantification, multiple reaction monitoring mode was used. The linear range extends from 0.075 ng/mL for thiacloprid and metazachlor and 7.5 ng/mL for coniine and clofibrate to 250 ng/mL for many of the test compounds. Matrix effects were strongest for nicotine, but never exceeded ±20 % for any of the developmental stages of the ZFE. Method recoveries ranged from 90 to 110 % from an analysis of nine pooled ZFE. These findings together with the simple sample preparation mean this approach is suitable for the determination of internal concentrations from only nine individual ZFE in all life stages up to 96 h post-fertilization. Exemplarily, the time course of the internal concentrations of clofibric acid, metribuzin and benzocaine in ZFE was studied over 96 h, and three different patterns were distinguished, on the basis of the speed and extent of uptake and whether or not a steady state was reached. Decreasing internal concentrations may be due to metabolism in the ZFE.

Controlled-pH tissue cleanup protocol for signal enhancement of small molecule drugs analyzed by MALDI-MS imaging.

The limit of detection of low-molecular weight compounds in tissue sections, analyzed by matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), was significantly improved by employing sample washing using a pH-controlled buffer solution. The pH of the washing solutions were set at values whereby the target analytes would have low solubility. Washing the tissue sections in the buffered solution resulted in removal of endogenous soluble ionization-suppressing compounds and salts, while the target compound remained in situ with minor or no delocalization during the buffered washing procedure. Two pharmaceutical compounds (cimetidine and imipramine) and one new protease inhibitor compound were successfully used to evaluate the feasibility of the pH-controlled tissue washing protocol for MALDI-MSI. Enhancement in signal-to-noise ratio was achieved by a factor of up to 10.

The physiology of the normal human breast: an exploratory study.

The physiology of the nonlactating human breast likely plays a key role in factors that contribute to the etiology of breast cancer and other breast conditions. Although there has been extensive research into the physiology of lactation, few reports explore the physiology of the resting mammary gland, including mechanisms by which compounds such as hormones, drugs, and potential carcinogens enter the breast ducts. The purpose of this study was to explore transport of exogenous drugs into ductal fluid in nonlactating women and determine if their concentrations in the fluid are similar to those observed in the breast milk of lactating women. We selected two compounds that have been well characterized during lactation, caffeine and cimetidine. Caffeine passively diffuses into breast milk, but cimetidine is actively transported and concentrated in breast milk. After ingestion of caffeine and cimetidine, 14 nonlactating subjects had blood drawn and underwent ductal lavage at five time points over 12 h to measure drug levels in the fluid and blood. The concentrations of both caffeine and cimetidine in lavage fluid were substantially less than those observed in breast milk. Our results support recent evidence that the cimetidine transporter is not expressed in the nonlactating mammary gland, and highlight intriguing differences in the physiology and molecular transport of the lactating and nonlactating breast. The findings of this exploratory study warrant further exploration into the physiology of the nonlactating mammary gland to elucidate factors involved in disease initiation and progression.

Determination of ranitidine, nizatidine, and cimetidine by a sensitive fluorescent probe.

A validated, simple, and sensitive fluorescence quenching method for the determination of ranitidine, nizatidine, and cimetidine in tablets and biological fluids is presented. This is the first single fluorescence method reported for the analysis of all three H(2) antagonists. The competitive reaction between the investigated drug and the palmatine probe for the occupancy of the cucurbit[7]uril (CB[7]) cavity was studied using spectrofluorometry. CB[7] was found to react with the probe to form a stable complex. The fluorescence intensity of the complex was also enhanced greatly. However, the addition of the drug dramatically quenched the fluorescence intensity of the complex. Accordingly, a new fluorescence quenching method for the determination of the studied drugs was established. The different experimental parameters affecting the fluorescence quenching intensity were studied carefully. At optimum reaction conditions, the rectilinear calibration graphs between the fluorescence quenching values (ΔF) and the medicament concentration were obtained in the concentration range of 0.04-1.9 µg mL(-1) for the investigated drugs. The limits of detection ranged from 0.013 to 0.030 µg mL(-1) at 495 nm using an excitation wavelength of 343 nm. The proposed method can be used for the determination of the three H(2) antagonists in raw materials, dosage forms and biological fluids.

Colorimetric assay of cimetidine in the presence of its oxidative degradates.

Three simple, accurate, and sensitive colorimetric methods for the determination of cimetidine (Cim) in pure form, in dosage forms, and in the presence of its oxidative degradates were developed. These methods are indirect, involve the addition of excess oxidant [N-bromosuccinimide (NBS) for method A; cerric sulfate [Ce(SO4)2] for methods B and C] of known concentration in acid medium to Cim, and the determination of the unreacted oxidant by measurement of the decrease in absorbance of amaranth dye for method A, chromotrope 2R for method B, and rhodamine 6G, for method C at a suitable maximum wavelength, lambda max: 520, 528, and 525 nm, for the 3 methods, respectively. Regression analysis of the Beer plots showed good correlation in the concentration ranges of 0.2-4.4 microg/mL for method A, and 0.2-3.4 microg/mL for methods B and C. The apparent molar absorptivity, Sandell sensitivity, and detection and quantitation limits were evaluated. The stoichiometric ratio between the drug (Cim) and the oxidant (NBS or Ce4+) was estimated. The validity of the proposed methods was tested by analyzing pure and dosage forms containing Cim with relative standard deviation < or = 1.18. The proposed methods could successfully determine the studied drug with varying excess of its oxidative degradation products, with recovery between 99.2 and 101.8, 100.2 and 102.8, and 99.8 and 102.0% for methods A-C, respectively.

Enantioselective in-line and off-line CE methods for the kinetic study on cimetidine and its chiral metabolites with reference to flavin-containing monooxygenase genetic isoforms.

An in-line screening and an off-line chiral CE method were developed to determine the stereoselectivity of flavin-containing monooxygenase (FMO) isoforms using cimetidine (CIM) as a substrate. The S-oxygenation of CIM was investigated using achiral chemical oxidants and (human supersomes) enzymatic metabolism procedures. In the off-line setup, the chiral selector sulfobutylether-beta-CD was chosen to separate the CIM S-oxide (CSO) metabolites. The electrophoretic migration order of CSO was confirmed to be (+) before (-) through the use of single enantiomers obtained by preparative chromatography. For the electrophoretically mediated microanalysis method, the in-line enzymatic reaction was performed in 100 mM phosphate reaction buffer (pH 8.3), whereas 50 mM phosphate buffer with 30 mM chiral selector (pH 2.5) was used as a BGE. During the screening of FMO isoenzymes by the electrophoretically mediated microanalysis method, formation of the new chiral center on the CIM sulfur was found to be stereoselective. FMO1 produces more (-)-CSO-enantiomer, while FMO3 generates mainly (+)-CSO-enantiomer. On the other hand, FMO5 shows no activity. The kinetic constants of FMO1 and FMO3 were measured by the off-line method. A K(m)=4.31 mM for the formation of the (+)-CSO-enantiomer and a K(m)=4.56 mM for the (-)-CSO-enantiomer are reported for the first time for FMO1.

Spectrophotometric determination of H(2)-receptor antagonists via their oxidation with cerium(IV).

A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H(2)-receptor antagonists: cimetidine, famotidine, nizatidine and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium(IV) in presence of perchloric acid and subsequent measurement of the excess Ce(IV) by its reaction with p-dimethylaminobenzaldehyde to give a red colored product (lambda(max) at 464nm). The decrease in the absorption intensity of the colored product (DeltaA), due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9990-0.9994) were found between DeltaA values and the concentrations of the drugs in a concentration range of 1-20microgml(-1). The assay limits of detection and quantitation were 0.18-0.60 and 0.54-1.53microgml(-1), respectively. The method was validated, in terms of accuracy, precision, ruggedness and robustness; the results were satisfactory. The proposed method was successfully applied to the determination of the investigated drugs in pure and pharmaceutical dosage forms (recovery was 98.3-102.6+/-0.57-1.90%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.

A new sensitive flow-injection chemiluminescence method for the determination of H(2)-receptor antagonists.

Based on the chemiluminescence (CL) intensity generated from the potassium ferricyanide [K(3)Fe(CN)(6)]-rhodamine 6G system in sodium hydroxide (NaOH) medium, a new sensitive flow-injection chemiluminescence (FI-CL) method has been developed, validated and applied for the determination of three kinds of H(2)-receptor antagonists: cimetidine (CIMT), ranitidine (RANT) hydrochloride and famotidine (FAMT). Under the optimum conditions, the linear range for the determination was 1.0 x 10(-9)-7.0 x 10(-5) g/ml for CIMT, 1.0 x 10(-9)-5.0 x 10(-5) g/mL for RANT hydrochloride and 5.0 x 10(-9)-7.0 x 10(-5) g/mL for FAMT. During 11 repeated measurements of 1.0 x 10(-6) g/mL sample solutions, the relative standard deviations (RSDs) were all <5%. The detection limit was 8.56 x 10(-10) g/mL for CIMT, 8.69 x 10(-10) g/mL for RANT hydrochloride and 2.35 x 10(-9) g/mL for FAMT (S:N = 3). This method has been successfully implemented for the analysis of H(2)-receptor antagonists in pharmaceuticals.

Exantema y epigastralgia recidivantes: a propósito de un caso / Recedivating exanthema and epigastralgia: about a case

No disponible

Photochemical fate of pharmaceuticals in the environment: cimetidine and ranitidine.

The photochemical fates of the histamine H2-receptor antagonists cimetidine and ranitidine were studied. Each of the two environmentally relevant pharmaceuticals displayed high rates of reaction with both singlet oxygen (1O2, O2(1delta(g))) and hydroxyl radical (*OH), two transient oxidants formed in sunlit natural waters. For cimetidine, the bimolecular rate constant for reaction with *OH in water is 6.5 +/- 0.5 x 10(9) M(-1) s(-1). Over the pH range 4-10, cimetidine reacts with 1O2 with bimolecular rate constants ranging from 3.3 +/- 0.3 x 10(6) M(-1) s(-1) at low pH to 2.5 +/- 0.2 x 10(8) M(-1) s(-1) in alkaline solutions. The bimolecular rate constants for ranitidine reacting with 1O2 in water ranges from 1.6 +/- 0.2 x 10(7) M(-1) s(-1) at pH 6-6.4 +/- 0.2 x 10(7) M(-1) s(-1) at pH 10. Reaction of ranitidine hydrochloride with *OH proceeds with a rate constant of 1.5 +/- 0.2 x 10(10) M(-1) s(-1). Ranitidine was also degraded in direct photolysis experiments with a half-life of 35 min under noon summertime sunlight at 45 degrees latitude, while cimetidine was shown to be resistant to direct photolysis. The results of these experiments, combined with the expected steady-state near surface concentrations of 1O2 and *OH, indicate that photooxidation mediated by 1O2 is the likely degradation pathway for cimetidine in most natural waters, and photodegradation by direct photolysis is expected to be the major pathway for ranitidine, with some degradation caused by 1O2. These predictions were verified in studies using Mississippi River water. Model compounds were analyzed by laser flash photolysis experiments to assess which functionalities within ranitidine and cimetidine are most susceptible to singlet-oxygenation and direct photolysis. The heterocyclic moieties of the pharmaceuticals were clearly implicated as the sites of reaction with 1O2, as evidenced by the high relative rate constants of the furan and imidazole models. The nitroacetamidine portion of ranitidine has been shown to be the moiety active in direct photolysis.

Desorption/ionization on silicon time-of-flight/time-of-flight mass spectrometry.

Desorption/ionization on silicon (DIOS) tandem time-of-flight (TOF/TOF) mass spectrometry (MS) provides high accuracy and significant fragmentation information, particularly in the characterization of biomolecules. DIOS TOF/TOF offers a high-throughput surface-based ionization platform as well as complete fragmentation through high collision energies. The absence of matrix interference in DIOS allows for the MS and MS/MS analysis of small molecules well below m/z 300. In addition, sample preparation is minimal, and the DIOS chips can be stored and reanalyzed for fragmentation information or accurate mass measurements. The combined benefits of robustness, minimal sample preparation, good sensitivity, high throughput, and sequencing capability make DIOS TOF/TOF a powerful tool for small molecule characterization and protein identification.

Determination of cimetidine, famotidine, and ranitidine hydrochloride in the presence of their sulfoxide derivatives in pure and dosage forms by high-performance thin-layer chromatography and scanning densitometry.

A selective, precise, and accurate method was developed for the determination of cimetidine (C), famotidine (F), and ranitidine hydrochloride (R x HCl) in the presence of their sulfoxide derivatives. The method involves quantitative densitometric evaluation of mixtures of the drugs and their derivatives after separation by high-performance thin-layer chromatography on silica gel plates (10 x 20 cm) with ethyl acetate-isopropanol-20% ammonia (9 + 5 + 4, v/v) as the mobile phase for both C and F and ethyl acetate-methanol-20% ammonia (10 + 2 + 2, v/v) as the mobile phase for R x HCl; Rf values for C, F, and R x HCl and their corresponding derivatives were 0.85 and 0.59, 0.73 and 0.41, and 0.56 and 0.33, respectively. Developing time was approximately 20 min. For densitometric evaluation, peak areas were recorded at 218, 265, and 313 nm for C, F, and R x HCl, respectively. The relationship between concentration and the corresponding peak area was plotted for the ranges of 5-50 microg/spot for C and 2-20 microg/spot for F and R x HCl. Mean recoveries were 100.39 +/- 1.33, 99.77 +/- 1.30, and 100.09 +/- 0.69% for C, F, and R x HCl, respectively. The proposed method was used successfully for stability testing of the pure drugs in the presence of up to 90% of their degradates, in bulk powder and dosage forms. The results obtained were analyzed statistically and compared with those obtained by the official methods.

Voltammetric determination of nitrosocimetidine in simulated gastric juice.

OBJECTIVE: To develop a voltammetric method for the determination of nitrosocimetidine in simulated gastric juice (SGJ). METHOD: Measurement of the polarographic wave of the nitroso derivative at the dropping mercury electrode in 0.1 m HCl. RESULTS: A well-defined diffusion-controlled cathodic wave was obtained at -0.34 V vs. Ag/AgCl electrode. The current-concentration relationship was found to be rectilinear over the range 10-80 microg/mL and 2-50 microg/mL with percentage recovery of 101.24 +/- 0.79 and 100.79 +/- 0.56 for the direct current (DCt) and differential pulse polarography (DPP) modes, respectively, with a minimum detectability (S/N=2) of 0.16 microg/ml (5.6 x 10-7 m) using DPP mode. CONCLUSION: The proposed method was successfully applied to study the nitrosation of cimetidine in SGJ.

Preparation of a cimetidine ion-selective electrode and its application to pharmaceutical analysis.

A novel cimetidine ion-selective electrode is prepared, characterized and used in pharmaceutical analysis. The electrode incorporates PVC-membrane with cimetidine-phospohotungstate ion pair complex. The electrode exhibits a Nernstian response for cimetidine in the concentration range 1.0 x 10(-5)-1.0 x 10(-2) M with a slope of 58+/-1 mV per decade. The limit of detection is 5.0 x 10(-6) M. The electrode displays a good selectivity for cimetidine with respect to a number of common foreign inorganic and organic species. It can be used in the pH range 3.0-5.5. The membrane sensor was successfully applied to the determination of cimetidine in its tablets as well as its recovery from a urine sample.

Sulfur-specific detection of impurities in cimetidine drug substance using liquid chromatography coupled to high resolution inductively coupled plasma mass spectrometry and electrospray mass spectrometry.

The use of liquid chromatography coupled to sector field inductively coupled plasma mass spectrometry (SF-ICP-MS) for the specific detection of sulfur-containing compounds is described. In the sulfur-containing drug substance cimetidine, structurally related impurities well below the 0.1% mass fraction level relative to the main drug substance could easily be detected. The structure of most of the impurities was confirmed by electrospray mass spectrometry (ESI-MS), and thus, the complementarity of the two techniques for drug analysis is shown. The limit of detection by SF-ICP-MS for cimetidine in solution was approximately 4-20 ng x g(-1), but it was blank-limited.

Simultaneous determination of cimetidine, famotidine, nizatidine, and ranitidine in tablets by capillary zone electrophoresis.

A simple capillary zone electrophoresis (CZE) method is described for the simultaneous determination of cimetidine (CIM), famotidine (FAM), nizatidine (NIZ), and ranitidine (RAN). The analysis of these drugs was performed in a 100 mM phosphate buffer, pH 3.5. Several parameters were studied, including wavelength for detection, concentration and pH of phosphate buffer, and separation voltage. The quantitative ranges were 100-1,000 microM for each analyte. The intra- and interday relative standard deviations (n = 5) were all less than 4%. The detection limits were found to be about 10 microM for CIM, 20 microM for RAN, 20 microM for NIZ, and 10 microM for FAM (S/N = 3, injection 1 s) at 214 nm. All recoveries were greater than 92%. Applications of the method to the assay of these drugs in tablets proved to be feasible.