Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking.

The liability of the H2-receptor antagonist nizatidine (NZ) to nitrosation in simulated gastric juice (SGJ) and under WHO-suggested conditions was investigated for the first time. For monitoring the nitrosatability of NZ, a hydrophilic interaction liquid chromatography (HILIC) method was optimized and validated according to FDA guidance. A Cosmosil HILIC® column and a mobile phase composed of acetonitrile: 0.04 M acetate buffer pH 6.0 (92:8, v/v) were used for the separation of NZ and its N-nitroso derivative (NZ-NO) within 6 min with LODs of 0.02 and 0.1 µg/mL, respectively. NZ was found highly susceptible to nitrosation in SGJ reaching 100% nitrosation in 10 min, while only 18% nitrosation was observed after 160 min under the WHO-suggested conditions. The chemical structure of NZ-NO was clarified by ESI+/MS. In silico toxicology study confirmed the mutagenicity and toxicity of NZ-NO. Experiments evidenced that ascorbic acid strongly suppresses the nitrosation of NZ suggesting their co-administration for protection from potential risks. In addition, the impacts of the HILIC method on safety, health, and environment were favorably evaluated by three green analytical chemistry metrics and it was proved that, unlike the popular impression, HILIC methods could be green to the environment.

Radioiodination and biological evaluation of nizatidine as a new highly selective radiotracer for peptic ulcer disorder detection.

Nizatidine has been labeled using [125 I] with chloramine-T as oxidizing agent. Factors such as the amount of oxidizing agent, amount of substrate, pH, reaction temperature, and reaction time have been systematically studied to optimize the iodination. Biodistribution studies indicate the suitability of radioiodinated nizatidine as a novel tracer to image stomach ulcer. Radioiodinated nizatidine may be considered a highly selective radiotracer for peptic ulcer imaging.

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.

Molecular mobility in the supercooled and glassy states of nizatidine and perphenazine.

The dielectric properties of two pharmaceuticals nizatidine and perphenazine were investigated in the supercooled liquid and glassy states by broadband dielectric spectroscopy. Two relaxation processes were observed in both the pharmaceuticals. The relaxation process observed above the glass transition temperature is the structural alpha relaxation and below the glass transition temperature is the gamma relaxation of intramolecular origin. The Johari-Goldstein beta relaxation coming from the motion of the entire molecule is found to be hidden under the structural relaxation peak in both the pharmaceuticals.

The Slow Relaxation Dynamics in the Amorphous Pharmaceutical Drugs Cimetidine, Nizatidine, and Famotidine.

The slow molecular mobility in the amorphous solid state of 3 active pharmaceutical drugs (cimetidine, nizatidine, and famotidine) has been studied using differential scanning calorimetry and the 2 dielectric-related techniques of dielectric relaxation spectroscopy and thermally stimulated depolarization currents. The glass-forming ability, the glass stability, and the tendency for crystallization from the equilibrium melt were investigated by differential scanning calorimetry, which also provided the characterization of the main relaxation of the 3 glass formers. The chemical instability of famotidine at the melting temperature and above it prevented the preparation of the amorphous for dielectric studies. In contrast, for cimetidine and nizatidine, the dielectric study yielded the main kinetic features of the α relaxation and of the secondary relaxations. According to the obtained results, nizatidine displays the higher fragility index of the 3 studied glass-forming drugs. The thermally stimulated depolarization current technique has proved useful to identify the Johari-Goldstein relaxation and to measure τßJG in the amorphous solid state, that is, in a frequency range which is not easily accessible by dielectric relaxation spectroscopy.

Molecular Encapsulation of Histamine H2-Receptor Antagonists by Cucurbit[7]Uril: An Experimental and Computational Study.

The histamine H2-receptor antagonists cimetidine, famotidine and nizatidine are individually encapsulated by macrocyclic cucurbit[7]uril (CB[7]), with binding affinities of 6.57 (±0.19) × 10³ M(-1), 1.30 (±0.27) × 104 M(-1) and 1.05 (±0.33) × 105 M(-1), respectively. These 1:1 host-guest inclusion complexes have been experimentally examined by ¹H-NMR, UV-visible spectroscopic titrations (including Job plots), electrospray ionization mass spectrometry (ESI-MS), and isothermal titration calorimetry (ITC), as well as theoretically by molecular dynamics (MD) computation. This study may provide important insights on the supramolecular formulation of H2-receptor antagonist drugs for potentially enhanced stability and controlled release based on different binding strengths of these host-guest complexes.

Effect of oxidation on nitro-based pharmaceutical degradation and trichloronitromethane formation.

Nitro-based compounds are the direct precursors of trichloronitromethane during chlorination disinfection. Two nitro-based pharmaceuticals ranitidine and nizatidine were selected as model compounds to assess the effect of oxidation on the removal of nitro-based pharmaceuticals, as well as the reduction of their trichloronitromethane formation potentials (TCNMFPs). The four oxidants were ozone (O3), chlorine (Cl2), chlorine dioxide (ClO2) and potassium permanganate (KMnO4). The changes in pharmaceuticals and their TCNMFPs during oxidation using various oxidants and dosages were quantified. The relationships between oxidation product structures and TCNMFP changes were also analyzed. The results showed that oxidation with Cl2 and KMnO4 were more effective than ClO2 and O3 in removing the nitro-based pharmaceuticals. Meanwhile, decreased TCNMFPs by KMnO4 oxidation but increased TCNMFPs by Cl2, ClO2 and O3 oxidation were observed. The results of product analysis indicated that chlorine transfer products had higher TCNMFPs, while oxygen transfer products made little contribution to TCNMFPs after oxidation. In addition, one possible reaction pathway leading TCNMFP increase was that chloro-nitromethane or nitromethane, which was a better TCNM precursor, formed when double bond was attacked by oxidants.

Formulation and characterization of floating microballoons of nizatidine for effective treatment of gastric ulcers in murine model.

BACKGROUND: The purpose of the present study was to formulate and characterize Nizatidine-encapsulated microballoons for enhancing bioavailability and increasing the residence time of drug in the gastrointestinal tract. METHODS: Microballoons were prepared using emulsion solvent diffusion method using Eudragit S-100 and HPMC as the polymer. The formulation process was optimized for polymer ratio, drug: polymer ratio, emulsifier concentration, stirring speed, stirring time. Optimized formulation was subjected to scanning electron microscopy, drug entrapment, buoyancy studies, in-vitro drug release and in-vivo floating efficiency (X-ray) study. In-vivo antiulcer activity was assessed by ethanol-induced ulcer in murine model. RESULTS: The microballoons were smooth and spherical in shape and were porous in nature due to hollow core. A sustained release of drug was observed for 12 h. Examination of the sequential X-ray images taken during the study clearly indicated that the optimized formulation remained buoyant and uniformly distributed in the gastric contents for a period of 12 h. In ethanol-induced ulcer model, drug-loaded Microballoon-treated group showed significant (p < 0.01) ulcer protection index as compared to free drug-treated group. CONCLUSION: Nizatidine-loaded floating microballoons may serve as a useful drug delivery system for prolonging the gastric residence time and effective treatment of gastric ulcers.

[Analytical application of phosphotungstic acid complexes. Fabrication and characterisation of membrane selective electrodes for some H2 antihistaminics]. / Complecsi ai acidului fosfowolframic cu aplicatii analitice. Constructia si caracterizarea unor electrozi membrana selectivi pentru unele antihistaminice H2.

PVC matrix membrane selective electrodes for ranitidine, nizatidine and famotidine, based on sparingly soluble complexes, were prepared and characterized. The optimum functional pH range, response time, selectivity and lifetime were determined for each of the built electrodes. The linear range, precision and accuracy of each method were obtained by statistical interpretation of experimental results, while the limit of detection and thelimit of quantification were determined by a graphical method. All these electrodes were applied for the direct quantitative potentiometric determination of ranitidine hydrochloride, nizatidine and famotidine in pharmaceutical formulations.

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.

[Analytical application of phosphotungstic acid complexes. Synthesis and characterisation]. / Complecsi ai acidului fosfowolframic cu aplicatii analitice. Sinteza si caracterizare.

UNLABELLED: Phosphotungstic acid forms salt type ionic association complexes with a large number of medicinal drugs that contain cation forming proton acceptor moieties. MATERIAL AND METHOD: Ranitidine, nizatidine and famotidine complexes with phosphotungstic acid were synthesized and subsequently characterized by their melting point, water solubility, specific absorbance, UV spectra and IR spectra. RESULTS: These sparingly soluble complexes were applied for the fabrication of membrane selective electrodes for quantitative potentiometric determination of ranitidine, nizatidine and famotidine. CONCLUSIONS: There have been synthesized phosphotungstic acid complexes with uses in fabrication of membrane selective electrodes for quantitative potentiometric determination of ranitidine, nizatidine and famotidine.

Adiabatic pulses in 1H-15N direct and long-range heteronuclear correlations.

The application of adiabatic inversion pulses to the detection of (1)H-(15)N heteronuclear correlations is described. The pulse sequences studied were gHSQC, CRISIS-gHSQC, gHMBC and CRISIS-gHMBC. The poor inversion quality of rectangular 180 degrees X pulses can lead to a loss of signal at the peripheries of the spectrum. Replacing these pulses with adiabatic sweeps significantly improves sensitivity across the potentially large (15)N spectral window. Satellite spectrum profiles are shown to demonstrate the increase in sensitivity when employing adiabatic pulses on wide spectral widths. Additionally, the active pharmaceutical nizatidine was used as a model compound to demonstrate the improvements in the long-range correlation data.

Nonisothermal stability tests of famotidine and nizatidine.

Nonisothermal stability tests have been proposed as an attractive and alternative method to the conventional isothermal stability tests. The stability and the degradation properties of famotidine and nizatidine were investigated using both isothermal and nonisothermal stability test techniques. Linear and logarithmic temperature programs were used and the degradation rate constant and activation energies were calculated using a computer program, which was written in BASIC. Also the advantages and disadvantages of these temperature programs are compared. The method to estimate parameters is based on nonlinear curve fitting the nonisothermal concentration-time-temperature curve equation. The nonisothermal stability test results were compared with the results of isothermal stability tests and similar results were obtained.

Spectrophotometric determination of three anti-ulcer drugs through charge-transfer complexation.

A simple charge-transfer complexation method is described for the spectrophotometric assay of nizatidine, ranitidine, and famotidine. This method is based on interaction of these drugs, as n-electron donors, with 7,7,8,8-tetracyanoquinodimethane, as the pi-acceptor, in acetonitrile to give highly colored green radical anions that are measured at 840 nm. Calibration graphs for the 3 compounds are linear over the concentration ranges of 1-6 microg/mL for nizatidine and ranitidine and 1-7 microg/mL for famotidine, with correlation coefficients (n = 6) of >0.999. The conditioned stability constants and the free energy changes were measured; the values obtained were generally high and negative, respectively, suggesting highly stable complexes. The proposed method was successfully applied to the determination of the drugs in pharmaceutical preparations. The assay results were in accordance with those obtained by using reference methods.

Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora.

The H(2)-receptor antagonist ranitidine has previously been shown to be a substrate for colonic bacterial metabolism. The objective of the present study was to assess the in vitro stability of the other H(2)-receptor antagonists, cimetidine, famotidine and nizatidine, to colonic bacteria. One hundred milligrams of each drug were introduced into individual batch culture fermenters (100 ml) consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments, equivalent drug quantities in buffer medium without the presence of faeces, were also run in parallel. Samples were removed at set time intervals over a 24 h period and were subsequently analysed by HPLC. A selection of the samples removed from the fermenters was also subjected to analysis by UV spectroscopy and mass spectrometry. Following an initial dissolution phase in the fermentation system, a marked decline in nizatidine concentration was noted over time with virtually no drug remaining after 12 h, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted for cimetidine or famotidine or for any of the drugs in the control buffer systems. The metabolic reaction pathway for nizatidine was complex, although UV and mass spectrometry analysis indicated that metabolism was initiated via cleavage of an N-oxide bond within the molecule. These results in combination with those obtained from a previous study indicate that of the four commercially available H(2)-receptor antagonists, nizatidine and ranitidine are susceptible to metabolism by colonic bacteria, which in turn has ramifications for drug delivery and absorption.

pH-Metric log K calculations of famotidine, naproxen, nizatidine, ranitidine and salicylic acid.

The octanol/water partition coefficient (log K) is one of the most commonly used parameters in structure-activity relationships in many areas such as drug design (including pesticides), pharmacokinetics, anesthesiology, environmental sciences, toxicology, bioaccumulation and predicting skin permeability as a predictive parameter. log K is generally determined using shake flask method, but the possibility of calculating log K using pH-metric titrations and half neutralization points is demonstrated in this study. The potentiometric pH titration technique has been developed as an automatic technique for log K determination but it can be achieved by manual titrations. This technique uses the pKa of the substance. The pKa of the substance shifts pK'a when the titration is repeated in the presence of octanol. log K value of the substance can be determined using pKa, pK'a values and relevant equation. The aim of the study was to determine the log K values of a series of compounds using pH-metric titrations and to compare pH-metric log K determination results with the other methods. The log K values of famotidine, naproxen, nizatidine, ranitidine and salicylic acid were determined using both shake flask method and potentiometric titrations. Their log K values were also calculated theoretically using computer program and all results were compared. The pH-metric log K values were found to be close to the shake flask method results. This method was found to be useful for the determination of log K values as it provides a high degree of accuracy even in the presence of titratable impurities in the solution.

Chitosan microspheres prepared by spray drying.

Non-crosslinked and crosslinked chitosan microspheres were prepared by a spray drying method. The microspheres so prepared had a good sphericity and a smooth but distorted surface morphology. They were positively charged. The particle size ranged from 2 to 10 micron. The size and seta potential of the particles were influenced by the crosslinking level. With decreasing amount of crosslinking agent (either glutaraldehyde or formaldehyde), both particle size and zeta potential were increased. Preparation conditions also had some influence on the particle size. DSC studies revealed that the H2 antagonist drug cimetidine, as well as famotidine was molecularly dispersed inside the microspheres, in the form of a solid solution. The release of model drugs (cimetidine, famotidine and nizatidine) from these microspheres was fast, and accompanied by a burst effect.

Sustained release chitosan microspheres prepared by novel spray drying methods.

Modified spray drying methods, especially a novel w/o/w emulsion-spray drying method, were developed to prepare chitosan microspheres with a sustained drug release pattern. Release of the model drugs cimetidine and famotidine, from the microspheres prepared by the emulsion-spray drying methods, was greatly retarded with release lasting for several hours, compared with drug loaded microspheres prepared by conventional-spray drying or emulsion methods where drug release was almost instant. The slow release of drug was partly due to the poor wetting ability of the microspheres which floated on the surface of the dissolution medium. The addition of a wetting agent increased the release rate significantly. The coating of the microspheres with gelatin decreased the rate of release of drug in the presence of wetting agents.