Simultaneous interaction, degradation, and kinetic study of sparfloxacin with H2 receptor antagonist.

Sparfloxacin is a quinolone carboxylic acid derivative that shows activity as an antimicrobial agent, against a wide range of Gram-negative and Gram-positive organisms. It is clinically useful for the treatment of urinary tract infections, respiratory tract infections and gynecological infections. In this study in vitro drug-drug interaction of sparfloxacin has been carried out with famotidine and ranitidine. For these studies a two-component spectrophotometric process has been developed for sparfloxacin assay in the presence of famotidine or ranitidine. The reproducibility of the method is within ±5%. The technique has been applied to the development of sparfloxacin in methanol. The interaction studies of sparfloxacin with ranitidine and famotidine were carried out in methanol and methanol: Water mixtures (30:70, v/v; 50:50, v/v) and the kinetics of sparfloxacin degradation were evaluated in the presence and absence of famotidine and ranitidine. The decrease in the rate of degradation of sparfloxacin in the presence of famotidine or ranitidine, compared to that of sparfloxacin alone, indicated the possibility of interaction between the sparfloxacin and famotidine or ranitidine. The Thin layer chromatography (TLC) of the degraded solution showed the presence of a degradation product of sparfloxacin. The studies show that complexation with famotidine or ranitidine may affect the bioavailability of sparfloxacin.

In Vitro Analysis of N-Nitrosodimethylamine (NDMA) Formation From Ranitidine Under Simulated Gastrointestinal Conditions.

Importance: A publication reported that N-nitrosodimethylamine (NDMA), a probable human carcinogen, was formed when ranitidine and nitrite were added to simulated gastric fluid. However, the nitrite concentrations used were greater than the range detected in acidic gastric fluid in prior clinical studies. Objective: To characterize NDMA formation following the addition of ranitidine to simulated gastric fluid using combinations of fluid volume, pH levels, and nitrite concentrations, including physiologic levels. Design, Setting, and Participants: One 150-mg ranitidine tablet was added to 50 or 250 mL of simulated gastric fluid with a range of nitrite concentrations from the upper range of physiologic (100 µmol/L) to higher concentrations (10 000 µmol/L) with a range of pH levels. NDMA amounts were assessed with a liquid chromatography-mass spectrometry method. Main Outcomes and Measures: NDMA detected in simulated gastric fluid 2 hours after adding ranitidine. Results: At a supraphysiologic nitrite concentration (ie, 10 000 µmol/L), the mean (SD) amount of NDMA detected in 50 mL simulated gastric fluid 2 hours after adding ranitidine increased from 222 (12) ng at pH 5 to 11 822 (434) ng at pH 1.2. Subsequent experiments with 50 mL of simulated gastric fluid at pH 1.2 with no added nitrite detected a mean (SD) of 22 (2) ng of NDMA, which is the background amount present in the ranitidine tablets. Similarly, at the upper range of physiologic nitrite (ie, 100 µmol/L) or at nitrite concentrations as much as 50-fold greater (1000 or 5000 µmol/L) only background mean (SD) amounts of NDMA were observed (21 [3] ng, 24 [2] ng, or 24 [3] ng, respectively). With 250 mL of simulated gastric fluid, no NDMA was detected at the upper physiologic range (100 µmol/L) or 10-fold physiologic (1000 µmol/L) nitrite concentrations, while NDMA was detected (mean [SD] level, 7353 [183] ng) at a 50-fold physiologic nitrite concentration (5000 µmol/L). Conclusions and Relevance: In this in vitro study of ranitidine tablets added to simulated gastric fluid with different nitrite concentrations, ranitidine conversion to NDMA was not detected until nitrite was 5000 µmol/L, which is 50-fold greater than the upper range of physiologic gastric nitrite concentrations at acidic pH. These findings suggest that ranitidine is not converted to NDMA in gastric fluid at physiologic conditions.

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.

Development of a Validated Comparative Stability-Indicating Assay Method for Some H2-Receptor Antagonists.

A comparative force degradation high performance thin layer chromatography (HPTLC) method was developed and validated for some H2-receptor antagonists. The studied H2-receptor antagonists were ranitidine (RAN), nizatidine (NIZ) and famotidine (FAM). The degradation behaviors of the studied H2-receptor antagonists were studied under different stress conditions (hydrolytic, thermal and oxidative) conditions as well as storage conditions according to International Conference on Harmonization (ICH) recommendations. A stability-indicating HPTLC method was optimized in order to separate the analyte from the degradation products formed under various stress conditions. Full separation of the drugs from their degradation products was successfully achieved on an HPTLC precoated silica gel plates. Densitometric measurements were carried out using a Camag TLC Scanner III in the absorbance mode at 320 nm for RAN and NIZ, and 280 nm for FAM. The limits of detection and limits of quantitation range were 5.47-9.37 and 16.30-31.26 ng/band, respectively, for all investigated drugs. The validation studies were performed according to ICH requirements. The developed method was simple, rapid and reliable hence it could be applied for routine quality control analysis of the investigated H2-receptor antagonists in dosage forms. The kinetic behavior, degradation rate constants and half-lives of the degradation of the investigated drugs were studied and compared at different stress conditions. The present study provides, for the first time, a new vision to compare the degradation kinetics of H2-receptor antagonists at the same degradation procedures.

Highly luminescent S,N co-doped carbon quantum dots-sensitized chemiluminescence on luminol-H2 O2 system for the determination of ranitidine.

S,N co-doped carbon quantum dots (N,S-CQDs) with super high quantum yield (79%) were prepared by the hydrothermal method and characterized by transmission electron microscopy, photoluminescence, UV-Vis spectroscopy and Fourier transformed infrared spectroscopy. N,S-CQDs can enhance the chemiluminescence intensity of a luminol-H2 O2 system. The possible mechanism of the luminol-H2 O2 -(N,S-CQDs) was illustrated by using chemiluminescence, photoluminescence and ultraviolet analysis. Ranitidine can quench the chemiluminescence intensity of a luminol-H2 O2 -N,S-CQDs system. So, a novel flow-injection chemiluminescence method was designed to determine ranitidine within a linear range of 0.5-50 µg ml-1 and a detection limit of 0.12 µg ml-1 . The method shows promising application prospects.

Validation of four different spectrophotometric methods for simultaneous determination of Domperidone and Ranitidine in bulk and pharmaceutical formulation.

Four simple, specific, accurate and precise spectrophotometric methods were developed and validated for simultaneous determination of Domperidone (DP) and Ranitidine Hydrochloride (RT) in bulk powder and pharmaceutical formulation. The first method was simultaneous ratio subtraction (SRS), the second was ratio subtraction (RS) coupled with zero order spectrophotometry (D(0)), the third was first derivative of the ratio spectra ((1)DD) and the fourth method was mean centering of ratio spectra (MCR). The calibration curve is linear over the concentration range of 0.5-5 and 1-45 µg mL(-1) for DP and RT, respectively. The proposed spectrophotometric methods can analyze both drugs without any prior separation steps. The selectivity of the adopted methods was tested by analyzing synthetic mixtures of the investigated drugs, also in their pharmaceutical formulation. The suggested methods were validated according to International Conference of Harmonization (ICH) guidelines and the results revealed that; they were precise and reproducible. All the obtained results were statistically compared with those of the reported method, where there was no significant difference.

Extraction of ranitidine and nizatidine with using imidazolium ionic liquids prior spectrophotometric and chromatographic detection.

A new extraction medium was proposed for liquid-liquid extraction of the histamine H2 receptor antagonists ranitidine (RNT) and nizatidine (NZT). The ionic liquids with low vapor pressure and favorable solvating properties for a range of compounds such as 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C4mim][Tf2N] were tested for isolation of analytes. The extraction parameters of RNT and NZT, namely, amount of ionic liquid, pH of sample solution, shaking and centrifugation time were optimized. The isolation processes were performed with 1 mL of the ionic liquids. The extracted samples (pH values near 4) were shaken at 1750 rpm. The influence of interfering substances on the efficiency of extraction process was also studied. Methods for the histamine H2 receptor antagonists (ranitidine and nizatidine) determination after their separation using imidazolium ionic liquids by high performance liquid chromatography (HPLC) combined with UV spectrophotometry were developed. The application of ionic liquids in extraction step allows for selective isolation of analytes from aqueous matrices and their preconcentration. The above methods were applied to the determination of RNT and NZT in environmental samples (river water and wastewater after treatment).

A new strategy to eliminate sample mixing during in-tube solid phase microextraction.

During in-tube solid phase microextraction, sample mixing with mobile phase contained in the autosampler tubing during extraction may result in some amount of sample becoming entrained in the mobile phase rather than returning to the sample vial or being directed to waste after extraction. In cases where target analytes have relatively low affinity for the sorbent on the wall of the capillary, mixing can impact data quality. Where the sample contains components that may interfere with either the separation (e.g. proteins) or detection (e.g. ions with MS detection), additional difficulties can arise. In the current research, the magnitude of the sample mixing effect was illustrated by analyzing ranitidine and a series of polycyclic aromatic hydrocarbons (PAH). The sample volume equivalent of mixing was calculated as 37 µL for ranitidine and 20 µL for PAHs using the same inner diameter of capillary. To address this issue, a novel approach involving adding a switching valve located between the metering pump and the capillary was developed. Capillary flush conditions, draw/eject speed and extraction time were optimized for ranitidine with the result that in the final method, no mixing of sample with mobile phase was apparent in the detected amounts. To provide information on a compound class with intermediate polarity, two -blockers were also extracted using the optimized washing conditions respectively. The results indicated that the issue of sample mixing had been resolved for these as well. Finally, in-tube SPME calibration of these three analyte classes was shown to be highly linear, providing further indication that sample mixing was not impacting data quality. Available literature on the subject was surveyed, and a discussion on the rational selection of conditions to guide method development was also provided.

Electrochemical sensor for ranitidine determination based on carbon paste electrode modified with oxovanadium (IV) salen complex.

The preparation and electrochemical characterization of a carbon paste electrode modified with the N,N-ethylene-bis(salicyllideneiminato)oxovanadium (IV) complex ([VO(salen)]) as well as its application for ranitidine determination are described. The electrochemical behavior of the modified electrode for the electroreduction of ranitidine was investigated using cyclic voltammetry, and analytical curves were obtained for ranitidine using linear sweep voltammetry (LSV) under optimized conditions. The best voltammetric response was obtained for an electrode composition of 20% (m/m) [VO(salen)] in the paste, 0.10 mol L(-1) of KCl solution (pH 5.5 adjusted with HCl) as supporting electrolyte and scan rate of 25 mV s(-1). A sensitive linear voltammetric response for ranitidine was obtained in the concentration range from 9.9×10(-5) to 1.0×10(-3) mol L(-1), with a detection limit of 6.6×10(-5) mol L(-1) using linear sweep voltammetry. These results demonstrated the viability of this modified electrode as a sensor for determination, quality control and routine analysis of ranitidine in pharmaceutical formulations.

Direct rapid analysis of multiple PPCPs in municipal wastewater using ultrahigh performance liquid chromatography-tandem mass spectrometry without SPE pre-concentration.

Ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was utilized to develop a rapid, sensitive and reliable method without solid phase extraction (SPE) pre-concentration for trace analysis of 11 pharmaceuticals and personal care products (PPCPs) in influent and effluent from municipal wastewater treatment plants (WWTPs). This method not only shortened the analysis time but also reduced analysis cost significantly by omitting SPE process and avoiding the consumption of SPE cartridge. Detection parameters for UHPLC-MS/MS analysis were optimized, including sample pH, eluent, mobile phase (solvent and additive), column temperature, and flow rate. Under the optimal conditions, all analytes were well separated and detected within 8.0min by UHPLC-MS/MS. The method quantification limits (MQLs) for the 11 PPCPs ranged from 0.040 to 88ngL(-1) and from 0.030 to 90ngL(-1) for influent and effluent, respectively. The matrix effect was systematically investigated and quantified for different types of samples. The analysis of influent and effluent samples of two WWTPs in Hong Kong revealed the presence of 11 PPCPs, including acyclovir, benzophenone-3, benzylparaben, carbamazepine, ethylparaben, fluconazole, fluoxetine, methylparaben, metronidazole, propylparaben, and ranitidine. Their concentrations ranged from 9.1 to 1810ngL(-1) in influent and from 6.5 to 823ngL(-1) in effluent samples collected from Hong Kong WWTPs.

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.

A novel method for ranitidine hydrochloride determination in aqueous solution based on fluorescence quenching of functionalised CdS QDs through photoinduced charge transfer process: spectroscopic approach.

A novel method for the quantitative determination of ranitidine hydrochloride (RNH) based on the fluorescence quenching of functionalised CdS quantum dots (QDs) by RNH in aqueous solution was proposed. The method is simple, rapid, specific and highly sensitive with good precision. The thioglycolic acid (TGA)-capped CdS QDs were synthesized from cadmium nitrate and sodium sulfide in alkaline solution. Under the optimal conditions, the Stern-Volmer calibration plot of F(0)/F against concentration of RNH was linear in the range of 0.50-15.0 µg mL(-1) with a correlation coefficient of 0.996. The limit of detection (LOD) was 0.38 µg mL(-1). The method was satisfactorily applied to the direct determination of RNH in pharmaceutical formulations with no significant interference from excipients. The results were found to be in good agreement with those obtained by the reference method and the claimed value. The accuracy and reliability of the method were further ascertained by recovery studies via the standard-addition method, with percentage recoveries in the range of 98.47 to 102.30%. The possible fluorescence quenching mechanism for the reaction was also discussed.

Development and validation of a RP-HPLC method for simultaneous estimation of naproxen and ranitidinehydrochloride.

A simple, specific and accurate reverse phase liquid chromatographic method has been developed for the simultaneous determination of naproxen and ranitidine HCl. Both the drugs are official with British Pharmacopoeia 2007, but do not involve simultaneous determination of naproxen and ranitidine HCl. The separation was carried out using 4.6 × 250 mm Symmetry Shield TM RP 18 with a particle diameter of 5 µm and mobile phase containing 0.1M orthophosphoric acid: methanol (35:65, pH 3.1) in isocratic mode. The flow rate was 1.00 ml/min and effluent was monitored at 240 nm. The retention times (average) of ranitidine HCl and naproxen were 2.36 min and 12.39 min, respectively. The linearity for naproxen and ranitidine HCl was in the range of 5-35 µg/ml and 1.5-12 µg/ml, respectively. The potencies of naproxen and ranitidine HCl were found 99.40 % and 99.48 %, respectively. The proposed method was validated and successfully applied to the estimation of naproxen and ranitidine HCl in newly formulated combined tablet and in plasma.

An environmentally friendly reflectometric method for ranitidine determination in pharmaceuticals and human urine.

This paper describes an environmentally friendly method for quantitative determination of ranitidine using diffuse reflectance spectroscopy. This method is based on the reflectance measurements of the colored product produced from the spot test reaction between ranitidine and p-dimethylaminocinnamaldehyde (p-DAC), in acid medium, using filter paper as solid support. Experimental design methodologies were used to optimize the optimal conditions. All reflectance measurements were carried out at 590 nm and the linear range was from 1.42x10(-3) to 3.42x10(-2) mol L(-1), with a correlation coefficient of 0.997. The limit of detection was estimated to be 1.09x10(-3) mol L(-1) (R.S.D.=1.9%). The proposed method was successfully applied to the determination of ranitidine in commercial brands of pharmaceuticals and no interferences were observed from the common excipients in formulations. The results obtained by the proposed method were favorably compared with those obtained by an official procedure at 95% confidence level. Additionally, the method was also applied to the determination of ranitidine in human urine showing excellent recoveries (99.6-100.3%).

Solid state characterization and crystal structure from X-ray powder diffraction of two polymorphic forms of ranitidine base.

Ranitidine hydrochloride (RAN-HCl), a known anti-ulcer drug, is the product of reaction between HCl and ranitidine base (RAN-B). RAN-HCl has been extensively studied; however this is not the case of the RAN-B. The solid state characterization of RAN-B polymorphs has been carried out using different analytical techniques (microscopy, thermal analysis, Fourier transform infrared spectrometry in the attenuated total reflection mode, (13)C-CPMAS-NMR spectroscopy and X-ray powder diffraction). The crystal structures of RAN-B form I and form II have been determined using conventional X-ray powder diffraction in combination with simulated annealing and whole profile pattern matching, and refined using rigid-body Rietveld refinement. RAN-B form I is a monoclinic polymorph with cell parameters: a = 7.317(2), b = 9.021(2), c = 25.098(6) A, beta = 95.690(1) degrees and space group P2(1)/c. The form II is orthorhombic: a = 31.252(4), b = 13.052(2), c = 8.0892(11) A with space group Pbca. In RAN-B polymorphs, the nitro group is involved in a strong intramolecular hydrogen bond responsible for the existence of a Z configuration in the enamine portion of the molecules. A tail to tail packing motif can be denoted via intermolecular hydrogen bonds. The crystal structures of RAN-B forms are compared to those of RAN-HCl polymorphs. RAN-B polymorphs are monotropic polymorphic pairs.

[Determination of dichloromethane and trichloromethane residues in ranitidine hydrochloride by headspace liquid phase microextraction coupled with gas chromatography].

A method for the determination of residual dichloromethane and trichloromethane in ranitidine hydrochloride by headspace liquid phase microextraction coupled with gas chromatography (GC) was developed. A homemade device was used to protect the organic drop. The effects of the nature of extraction solvent, extraction time, extraction temperature and microdrop volume on the extraction efficiency were investigated separately. The optimal experimental conditions were as follows: 2 microL of n-tridecane as extraction solvent, 30 min of extraction time, 60 degrees C of extraction temperature. The correlation coefficients of linear calibration curve were 0.9733 and 0.9724 within the concentration ranges of dichloromethane (1-10 microg/g) and trichloromethane (1-10 microg/g), respectively. The detection limits of dichlormethane and trichloromethane were 0.0273 microg/g and 0.0410 microg/g, respectively, the relative standard deviations were lower than 4.36% and 5.89%, and the recoveries of the method were 93.6%-102% and 98.1% respectively. The method is simple and reliable.

Development and validation of a method for active drug identification and content determination of ranitidine in pharmaceutical products using near-infrared reflectance spectroscopy: a parametric release approach.

In this paper we describe the strategy used in the development and validation of a near-infrared diffuse reflectance spectroscopy method for identification and quantification of ranitidine in pharmaceutical products (granulates, cores and coated tablets) at-line, with a fiber optic probe. This method was developed in a pharmaceutical industry for routine application, to replace reference methods and was submitted and approved to the National Medicine Regulatory Agency (Infarmed). We consider that this is the first step of a broader parametric release approach to pharmaceutical products.

Simultaneous determination of macrolides, sulfonamides, and other pharmaceuticals in water samples by solid-phase extraction and LC-(ESI) MS.

This paper describes a method for determining 11 pharmaceuticals in various water sources by SPE followed by LC-(ESI) MS. SPE was carried out with Oasis HLB and the recoveries were 33-67% for 250 and 100 mL sewage water, 55-77% for 500 mL river water and 72-98% for 1 L tap water, with the exception of sulfamethoxazole and omeprazole which showed lower recoveries in all kinds of sample. The LODs in river water were of 5 ng/L for sulfadiazine, trimethoprim, sulfamethazine, sulfamethoxazole, and ranitidine and 10 ng/L for the other compounds. The highest concentrations found in river waters were for sulfamethoxazole (50 ng/L). In influent sewage waters, ranitidine was the most commonly detected compound with a maximum value of 0.24 microg/L.

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.