Determination of chloramphenicol and its monosuccinate ester in piglet plasma using HPLC

Summary A method for the determination of chloramphenicol and its monosuccinate ester in piglet plasma is described. It involves precipitation of plasma proteins by addition of methanol to the plasma sample, followed by injection of the supernate onto the column. Chloramphenicol and its ester are separated using a LiChrosorb RP-18 column and phosphate buffer pH 4.9 containing 30% methanol as eluent. Determination of chloramphenicol and its monosuccinate ester in pig plasma was made with a precision of 2.6% and 2.4% (relative standard deviation) at drug levels of 2 and 4 g·cm^–3, respectively. Stability data for the chloramphenicol monosuccinate ester are also presented.     

Preparation and evaluation of topical microemulsion system containing metronidazole for remission in rosacea

The aim of this study was to prepare a topical water-in-oil type microemulsion containing metronidazole and to compare its effectiveness with a commercial gel product in the treatment of rosacea. A pseudo-ternary phase diagram (K(m)=2:1) was constructed using lecithin/butanol/isopropyl myristate/water. The microemulsion was chosen from the microemulsion region in the phase diagram. The formulation was a water-in-oil type microemulsion (droplet size: 11.6 nm, viscosity: 457.3 mPa·s, conductivity: 1.5 μs/cm, turbidity: 6.89 NTU) and the addition of the metronidazole did not alter the properties of the system. The release experiment showed that the release rate of metronidazole from the commercial gel product was higher than that of the microemulsion. Stability experiments showed that the metronidazole microemulsion remained stable for at least 6 months; none of the characteristic properties of the microemulsion had changed, the system retained its clarity and there was no sign that crystallization of metronidazole has occurred. Microemulsion was compared to a gel product in a randomized, double-blind, baseline-controlled, split-face clinical trial for the treatment of patients. After the 6-week treatment period there was a statistically significant difference in reduction of the main symptoms of rosacea. Of the patients treated with the microemulsion, 17% experienced complete relief from inflammatory lesions, and 50% from erythema. The microemulsion resulted in complete relief in 38% of the patients with telangiectasia while the commercial product did not provide any relief of telangiectasia symptoms. In conclusion, the microemulsion containing metronidazole was found to be more effective in reducing the symptoms of rosacea compared to the commercial gel product.     

Development of thermogravimetric method for quantitative determination of metronidazole

The objective of this work was to develop and validate a fast and reproducible method to determine the concentration of metronidazole in drug substance and tablets. The samples were analyzed by dynamic thermogravimetry, using 10, 20, 40, 60 and 80°C min^–1 heating rates in nitrogen and in nitrogen with synthetic air. Obtained data were used in the Antoine and Langmuir equations in order to have the pressure curves. Vapor pressure curves of drug and tablet of metronidazole were evaluated using the mathematical indexes of difference factor, f ₁, and similarity factor, f ₂, to compare their profiles. The data showed that there is no significant difference between the vapor pressure profiles of drug and tablet of metronidazole in both environmental conditions, which confirms that the process is really vaporization. The concentration of metronidazole was determined in the raw material and tablets of the drug.     

Rapid ultraviolet spectrophotometric assay of benzoyl metronidazole in an oral suspension.

A procedure is described for the rapid determination of benzoyl metronidazole in an oral suspension which is based on measurement of the change in absorbance at 276 nm during alkaline hydrolysis of the compound in 2 mol dm-3 NaOH. The change in absorbance follows a linear relationship with concentration in the range 3-18 micrograms ml-1. Results of the determination of benzoyl metronidazole in an oral suspension and of the recovery experiments performed on this formulation, and also on various individual excipients and other additives, confirmed the applicability of the proposed method to complex formulations.     

Study on the determination of metronidazole in human serum by adsorptive stripping voltammetry

In Britton-Robinson buffer, metronidazole is preconcentrated on a HMDE at 0.0 V (vs. AgAgCl). An adsorptive stripping peak is observed at -0.62 V. The response is linear from 1 x 10(-8) to 1 x 10(-6)M with 1.5 min accumulation. The method has been successfully applied to the determination of metronidazole in human serum and formulations.     

Association of polyacrylic acids with metronidazole

Intermolecular interactions in mixtures of dilute solutions of poly acids with 1-(β-hydroxyethyl)-2-methyl-5-nitroimidazole were studied by viscometry, potentiometry, and IR spectroscopy. The rheological behavior of dilute aqueous solutions of polyacrylic and polymethacrylic acids and of metronidazole at a total concentration of the components of 0.1 wt % was examined. The composition dependences of the specific viscosity show positive deviations from the additivity with a maximum at approximately 50% relative content of the poly acid. In these mixtures, polyelectrolytic complexes stabilized by hydrogen bonds are formed. The strength of the associates increases with an increase in the temperature to 40°C. Hydrophobic groups in macromolecules of the poly acid play a significant role in stabilization of the complexes. In aqueous solutions metronidazole interacts with acrylic, methacrylic, and hydrochloric acids, and in the solid state it forms linear hydrogen-bonded associates.     

Thermal stability of metronidazole drug and tablets

TG and DSC data were used to determine the thermal parameters of metronidazole drug and tablets. Three tablets A, B and C were analysed. The TG curves of metronidazole drug and tablets A and B displayed five and C four thermal decomposition processes, respectively. Analysis of the DSC data pointed to chemical interactions between metronidazole drug and the excipients of tablets, suggested by alterations in the melting point of metronidazole. The rate constants obtained from the isothermal TG data presents following sequence of the thermal stability: tablet A>tablet C>metronidazole drug>tablet B. This revised version was published online in July 2006 with corrections to the Cover Date.     

The effect of methylcellulose on metronidazole release from polyacrylic acid hydrogels

Topical treatment of acne rosacea, a chronic condition characterized by recurrent course for many years, is primarily based on metronidazole preparations. The aim of this study was to evaluate the effect of various acrylic acid polymers, in composition with methylcellulose on metronidazole release rate from hydrogels proposed for the treatment of acne rosacea. Viscosity and release studies using "Paddle over Disk" system with semipermeable membrane of MWCO 3500 were performed. Compositions of Carbopol 971P and methylcellulose revealed an increase in viscosity with increasing concentration of methylcellulose in the range of 17200-26166 mPa.s. In all the examined formulations, the release process was characterized by a two-stage course. Among bipolymeric formulations, the highest first-stage release rate of 9.18 x 10(-3) min(-1) was determined for the gel consisting of 2.00% Carbopol 980NF with 1.00% methylcellulose. The second-stage release rates ranged between 2.88 x 10(-3) and 8.00 x 10(-3) min(-1). Two-stage release course can thus be attributed to metronidazole distribution into two compartments of hydrogel matrix. Proposed gels, with similar rheological properties, may be used for ex vivo and in vivo studies to obtain a suitable drug activity of metronidazole in the treatment of acne rosacea.     

Voltammetry and determination of metronidazole at a carbon fiber microdisk electrode

The electrochemistry of metronidazole, 1-(hydroxyethyl)-2-methyl-5-nitroimidazole, was investigated at a carbon fiber microdisk electrode in pH 9 Britton Robinson buffer. Under these conditions, the reduction of metronidazole is controlled by both mass transport to the microdisk and adsorption with an equilibrium constant of 4 × 10³ mol⁻¹ dm³ and a saturation coverage of 0.88 × 10⁻⁸ mol cm⁻². The adsorption and accumulation of metronidazole on the surface of the carbon fiber allows its determination at low concentrations by square wave adsorptive stripping voltammetry. A detection limit for metronidazole of 5 × 10⁻⁷ mol dm⁻³ and a R.S.D. of 3.7% at 1 × 10⁻⁶ mol dm⁻³ (n = 4) were obtained with a two electrode system with no stirring during the accumulation step. Based on this method, a simple procedure for the determination of metronidazole in urine is described which requires no pre-treatment of the sample before analysis.     

Determination of the dihedral angle of the monoanion of succinic acid in aprotic media

A value of 74(+/-4) degrees was determined from NMR-observed dipolar couplings for the rotational dihedral angle of the monosuccinate anion in an aprotic liquid-crystal solution of the gauche conformation of tetraoctylammonium monosuccinate. This value is in reasonable agreement with other, somewhat less definitive, evidence gleaned from isotropic vicinal proton-proton couplings of the essentially completely gauche preference of the monosuccinate anion in tert-butyl alcohol and aprotic solvents, such as DMSO and THF, and quantum computations for the monoanion in THF.     

高效液相色谱法同时测定祛痘产品中6种抗生素及甲硝唑

建立了一种高效液相色谱-二极管阵列检测器(HPLC-DAD)同时测定祛痘产品中6种抗生素(盐酸美满霉素、土霉素、盐酸四环素、盐酸金霉素、盐酸多西环素和氯霉素)及甲硝唑的分析方法。样品用甲醇提取,采用Agilent ZORBAX SB-C18色谱柱(250 mm×4.6 mm, 5 μm)分离;以甲醇、乙腈和0.002 mol/L草酸为流动相进行梯度洗脱,流速0.8 mL/min;柱温20 ℃,检测波长268 nm,进样量10 μL,外标法定量。结果表明,6种抗生素及甲硝唑在1～30 mg/L范围内呈良好的线性关系,相关系数(r)均不低于0.9970;方法检出限为1.1～1.2 μg/g;高、中、低(5、10、20 mg/L) 3个添加水平下的回收率为91.9%～107.7%,相对标准偏差(RSD)为0.13%～1.74%。应用该方法对祛痘产品进行检验,15%的样品中检出甲硝唑。该方法具有灵敏、准确、快速、分离效果好的优点,适用于祛痘产品中6种抗生素及甲硝唑的检测。     

Pharmacokinetics of metronidazole in rat blood,brain and bile studied by microdialysis coupled to microbore liquid chromatography

Metronidazole is a synthetic nitroimidazole-derived antibacterial and antiprotozoal agent used for the treatment of infections involving gram-negative anaerobes. The aim of this study is to develop an in vivo microdialysis with microbore high-performance liquid chromatographic system for the pharmacokinetic study of metronidazole in rat blood, brain and bile. In addition, to investigate the disposition mechanism of metronidazole, the P-glycoprotein modulator and cytochrome P450 inhibitor were concomitantly administered. Separation of metronidazole from various biological fluids was applied to a microbore reversed-phase ODS 5 microm (150 x 1 mm I.D.) column. Its mobile phase consists of an acetonitrile-50 mM monosodium phosphate buffer (pH 3.0) containing 0.1% triethylamine (10:90, v/v) with a flow-rate of 0.05 ml/min. The UV detector wavelength was set at 317 nm. The results suggest that metronidazole penetrates the blood-brain barrier (BBB) and goes through hepatobiliary excretion. However, these pathways of BBB penetration and hepatobiliary excretion of metronidazole may not be related to the P-glycoprotein.     

A novel high selective and sensitive metronidazole voltammetric sensor based on a molecularly imprinted polymer-carbon paste electrode

The design and construction of a highly selective voltammetric sensor for metronidazole by using a molecularly imprinted polymer (MIP) as recognition element were introduced. A metronidazole selective MIP and a nonimprinted polymer (NIP) were synthesized and then incorporated in the carbon paste electrodes (CPEs). The sensor was applied for metronidazole determination using cathodic stripping voltammetric method. The MIP-CP electrode showed very high recognition ability in comparison to NIP-CPE. Some parameters affecting the sensor response were optimized and then the calibration curve was plotted. Two dynamic linear ranges of 5.64 × 10⁻⁵ to 2.63 × 10⁻³ mg L⁻¹ and 2.63 × 10⁻³ to 7.69 × 10⁻² mg L⁻¹ were obtained. The detection limit of the sensor was calculated as 3.59 × 10⁻⁵ mg L⁻¹. This sensor was used successfully for metronidazole determination in biological fluids.     

Non-destructive determination of metronidazole powder by using artificial neural networks on short-wavelength NIR spectroscopy

The present study aimed at providing a new method in sight into short-wavelength near-infrared (NIR) spectroscopy of in pharmaceutical quantitative analysis. To do that, 124 experimental samples of metronidazole powder were analyzed using artificial neural networks (ANNs) in the 780-1100 nm region of short-wavelength NIR spectra. In this paper, metronidazole was as active component and other two components (magnesium stearate and starch) were as excipients. Different preprocessing spectral data (first-derivative, second-derivative, standard normal variate (SNV) and multiplicative scatter correction (MSC)) were applied to establish the ANNs models of metronidazole powder. The degree of approximation, a new evaluation criterion of the networks was employed to prove the accuracy of the predicted results. The results presented here demonstrate that the short-wavelength NIR region is promising for the fast and reliable determination of major component in pharmaceutical analysis.     

Application of DSC and NIRS to study the compatibility of metronidazole with different pharmaceutical excipients

The purpose of the present work was to study the compatibility of metronidazole with different pharmaceutical excipients (hydroxypropyl methylcellulose, poly(ethylene oxide), microcrystalline cellulose, dicalcium phosphate dihydrate, and anhydrous dicalcium phosphate) using differential scanning calorimetry and diffuse reflectance spectroscopy. Dicalcium phosphate dihydrate was the only excipient that showed interaction with metronidazole even before storage. Changes referring to a possible transition to dihydrate form were observed in the thermal curves of anhydrous dicalcium phosphate after four weeks of storage. Although dicalcium phosphate dihydrate can be replaced by the anhydrous form in pharmaceutical formulations, the observed transition might negatively influence the stability of dosage forms.     

Solid phase synthesis of a metronidazole oligonucleotide conjugate

Direct, solid phase synthesis of an oligonucleotide conjugate of the antibiotic drug metronidazole was accomplished by the phosphoramidite method. Removal of protecting groups and cleavage from the controlled pore glass (CPG) solid support was successful using mild conditions (20% Et(3)N in pyridine, then conc. NH(3) (aq) at rt for 30 min) whereas standard conditions (conc. NH(3) (aq) at 55 degrees C for 16 h) cleaved the drug.     

Efficient and selective separation of metronidazole from human serum by using molecularly imprinted magnetic nanoparticles

Magnetic molecularly imprinted nanoparticles were prepared through surface‐initiated reversible addition fragmentation chain transfer polymerization by using metronidazole as a template. The molecularly imprinted magnetic nanoparticles were characterized by attenuated total reflection Fourier transform infrared spectroscopy, X‐ray photoelectron spectroscopy, transmission electron microscopy, X‐ray diffraction, and vibrating sample magnetometry. The adsorption characteristics were also investigated and the kinetics of the adsorption of metronidazole on the imprinted nanoparticles were described by the second‐order kinetic model with the short equilibrium adsorption time (30 min). The adsorption isotherm was well matched with the Langmuir isotherm in which the maximum adsorption capacity was calculated to be 40.1 mg/g. Furthermore, the imprinted magnetic nanoparticles showed good selectivity as well as reusability even after six adsorption–desorption cycles. The imprinted magnetic nanoparticles were used as a sorbent for the selective separation of metronidazole from human serum. The recoveries of metronidazole from human serum changed between 97.5 and 99.8% and showed similar sensitivity as an enzyme‐linked immunoassay method. Therefore, the molecularly imprinted magnetic nanoparticles might have potential application for the selective and reliable separation of metronidazole from biological fluids in clinical applications.     

超高效液相色谱-串联质谱法分析化妆品中的常见抗生素及甲硝唑

建立了超高效液相色谱-串联质谱(UPLC-MS/MS)测定化妆品中常见的6种抗生素(美满霉素、土霉素、四环素、金霉素、多西环素、氯霉素)及甲硝唑的方法,并用于实际样品的分析。样品经甲醇-0.1 mol/L甲酸溶液(体积比为1∶1)超声提取后,以甲醇(含1%甲酸)-水(含1%甲酸)为流动相,经UPLC梯度洗脱分离后以多反应监测(MRM)模式质谱测定。方法的检出限为3～20 ng/g,回收率为87%～101%,工作曲线的线性相关系数大于0.995,线性范围为2～1000 μg/L (达3个数量级)。对11份市售化妆品进行分析检测,其中2份检出氯霉素,质量分数分别为0.37%和0.19%;1份检出甲硝唑,质量分数为1.02%;美满霉素、土霉素、四环素、金霉素、多西环素未检出。     

Study on metronidazole distribution in rectal cancer tissue using application method of administration in experiment in vivo

The distribution of metronidazole in rectal cancer tissue using application method of administration was studied. A comparative evaluation of pharmacokinetic parameters of metronidazole accumulation in the tissues depending on the concentration of the drug in the application mixture was carried out. The generalized actual data on metronidazole distribution in tissue samples (341 sample) obtained during 31 surgery are presented.     

Polarographic investigation of the metronidazole complex with polyvinylpyrrolidone*

Polarographic behavior of the metronidazole complex with polyvinylpyrrolidone in Britton-Robinson buffer solutions have been studied. This complex possesses prolonged antimicrobial action. Complexation with polyvinylpyrrolidone was shown to alter the mechanism of metronidazole reduction and increases its solubility in water. The temperature dependence of the limiting currents indicates the formation of additional hydrogen bonds in the complex, which restricts diffusion of the depolarizer to the cathode.