Excess Of N-bromosuccinimide Research Articles

On the Bromination of Diethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate: the True Structure of the Halbig’s Product

Pyrrole and its derivatives have attracted the attention of researchers as promising objects of practical importance in various areas of human life. Focusing on Knorr pyrrole as the most readily available pyrrole derivative, our objective was to obtain its bromo derivatives, containing an allyl bromine atom followed by phosphorylation reactions. The reaction involving bromination was carried out with 2 mol of N-bromosuccinimide per 1 mol of Knorr pyrrole 1 in carbon tetrachloride. This reaction was initiated with azobis(isobutyronitrile) and carried out at a boiling point. In acetic acid, the bromination reaction was carried out at a temperature of 38-45°C with a molar ratio of Knorr pyrrole to bromine of 1:4 and another reaction was carried out at 40-50°C with a molar ratio of Knorr pyrrole to bromine of 1:5. The bromination reaction was also performed in chloroform at 27-30°C in the presence of catalytic amounts of aluminum chloride. The same crystalline product was obtained in all cases. X-ray diffraction analysis revealed that the single crystal structure is diethyl 5-(dibromomethyl)-3-methyl-2-oxo-2,3-dihydro-1H-pyrrole-3,4-dicarboxylate 5 with two bromine atoms. This composition is identical to that of the Halbig product. It was found that the bromination of Knorr pyrrole 1 occurs stepwise with excess N-bromosuccinimide and bromine, resulting in the unsaturated lactam 5, commonly known as Halbig’s product. The true structure of product 5 was determined.

Utility of N-Bromosuccinimide-Water Combination as a Green Reagents for a Validated Indirect Spectrophotometric Determination of Some Antihypertensive Drugs: An Application to Their Monitoring in Marketed Tablets and Capsules.

Analytical tests were conducted to investigate the use of N-bromosuccinimide (NBS) as an important, safe analytical reagent for the spectrophotometric detection of therapeutically significant dihydropyridine-based calcium antagonists (DHP), namely nifedipine (NIF) and amlodipine (AML), which have been demonstrated to possess antioxidant activity in vivo and to reduce the intracellular production of reactive oxygen species (ROS). Following the reaction of DHP and NBS in acidic media, the excess NBS was evaluated for the first time by its interaction with P-aminophenol (PAP), which produced a violet-colored product that was detected at 556 nm. The analytical method was performed and validated since different variables disturbing the reaction (concentration of reagent, type and concentration of the selected acid, reaction time and the diluting solvents) were carefully studied and optimized. The stoichiometry of the applied reaction was determined by Job's method of continuous variation. Monitoring of these drug dosage forms' content uniformity is a first tool or evidence for their efficacy and safety after their administration. Beer's law was obeyed in the concentration range 1.25-11.0 µg/mL for NIF and 1.25-10.0 µg/mL for AML. The calculated limit of detection (LODs) and limit of quantification (LOQs) for NIF and AML were 0.220, 0.155 µg/mL and 0.519, 0.735 µg/mL, respectively. The precision of the applied method was satisfactory; the RSDs did not exceed 2%. Two greenness assessment tools, the Green Analytical Procedure Index (GAPI) and Analytical Greenness Metric for Sample Preparation (AGREEprep) were used for measuring the environmental friendliness of the recommended method. The micro-determinations of content uniformity for NIF and AML in their pharmaceutical dosage forms were extremely comparable with those from official and validated procedures. A validated indirect spectrophotometric method for accurate quantification of some 1,4-dihydropyridine drugs using NBS with the aid of PAP. Monitoring of NIF and AML dosage forms' content uniformity as a first tool or evidence for their efficacy and safety after their administration. Greenness evaluation tools, GAPI and AGREEprep, for measuring the environmental friendliness of the recommended method.

Spectrophotometric Determination of Catecholamine Containing Drugs Using Calcon Dye

Calcon dye has been used for spectrophotometric determination of catecholamine-containing drugs, namely, adrenaline, methyldopa and dopamine in their pure forms and pharmaceutical formulations. The method is based on the oxidation of the above drugs with an excess of Nbromosuccinimide (NBS) in an acidic medium. The residual oxidizing agent bleaches the blackish-brown color of calcon measured at 510 nm. The decolorization of the dye is proportional to the residual amount of NBS, which is proportional to the concentration of the drug. Linear calibration graphs were obtained in the concentration range 0.5-16.0, 2.0-40.0 and 1.036.0 μgmL -1 with molar absorptivity values 1.10×104 , 3.2×103 and 4.3×103 Lmol-1 cm-1 for above drugs, respectively. The method is simple, sensitive, accurate, precise and free from excipients. The developed method was successfully applied to determine the drugs in their pharmaceutical formulations.

Spectrophotometric determination of atenolol via oxidation and bleaching color reaction for methyl red dye

A selective and sensitive spectrophotometric method has been suggested for the quantitative assay of atenolol (ATNL) as pure and in its manufactural formulation(Tablet). The suggested procedure included oxidation of ATNL with an excess quantity of the oxidant N-bromosuccinimide (NBS), and then the excess of NBS was occupied in bleaching the color of methyl red dye(MRD), then measuring the absorbance of remaining MRD at 518 nm. The absorbance of the unbleached color of MRD corresponds to the ATNL concentration in the sample solution. Beer’s law was followed in the range of 0.1-2.0 μg.ml−1with molar absorptivity value equal to 8.8864x104 l.mol−1. cm−1. The suggested method was applied to the assay of ATNL in commercial tablets, with satisfactory results.

Utilization of N-bromosuccinimide for the sensitive spectrophotometric determination of pipazethate HCl as antitussive drug in pure and dosage forms

Three simple, sensitive, precise, reproducible and validated spectrophotometric methods have been developed for the quantification of pipazethate HCl as antitussive drug in pure and dosage forms. The methods are based on utilization of N-bromosuccinimide as an oxidant and three dyes, amaranth, methylene blue, and indigo carmine, as auxiliary reagents. The proposed methods are based on oxidation reaction of pipazethate HCl with a known excess of N-bromosuccinimide in acid medium, followed by determination of unreacted N-bromosuccinimide by the reaction with a fixed amount of dyes, amaranth, methylene blue, and indigo carmine followed by the measurement of the absorbance at 520, 663 and 610nm, respectively. The optimization of the reaction conditions was investigated. Under the optimum conditions, linear relationships with good correlation coefficients (0.9998-0.9999) were found over the concentration ranges of 0.3-9.0, 0.5-12 and 0.5-10μgmL-1 with a limit of detection (LOD) of 0.1, 0.15 and 0.15μgmL-1 using amaranth, methylene blue, and indigo carmine methods, respectively. Intra-day and inter-day accuracy and precision of the methods have been evaluated. No interference was observed from the common tablet excipients. The developed methods were validated in accordance with ICH guidelines and successfully applied to the analysis of pipazethate HCl in dosage forms with good accuracy and precision. The reliability of the methods was further ascertained by performing recovery studies via the standard addition method. Statistical comparison of the results obtained by applying the proposed methods with those of the reported method by applying Student's t-test and variance ratio F-test at the 95% confidence level revealed good agreement and indicates no significant difference in accuracy and precision.

Spectrophotometric Indirect Determination of Captopril through Redox Reaction with n-bromosuccinimide and RB dye in Pharmaceutical Products

A simple, accurate, and sensitive method for the spectrophotometric determination of captopril in bulk and dosage forms is reported. The method is based on the bromination of captopril with excess solution of n-bromosuccinimide (NBS) in HCl acid medium. The excess NBS is pursued by the assessment of the residual NBS based on its ability to bleach the rhodamine B dye and measuring the absorbance at 555 nm. The amount of NBS reacted coincides to the drug content. The different experimental parameters influencing the development and stability of the color are precisely studied and optimized. Beer’s law is valid within a concentration range of 0.3–1.0 μg/mL with a correlation coefficient R2 = 0.991. The limit of detection 0.169 μg/mL is attained and relative standard deviation values for five replicated measurements of 0.3, 0.7, and 1.0 μg/mL captopril were between 0.53% and 2.03%. No interference is detected from prevalent additives found in pharmaceutical preparations. The proposed method is profitably put on to the determination of captopril in the tablet formulations with mean recoveries 98.91–101.27% and the results were statistically confronted with those of a reference method by applying Student’s t-and F-test.

VALIDATED SPECTROPHOTOMETRIC METHODS FOR DETERMINATION OF MONTELUKAST SODIUM IN PURE AND DOSAGE FORMS USING N-BROMOSUCCINIMIDE AND DYES

Objective: Simple, sensitive, precise, reproducible and validated spectrophotometric methods have been developed for the quantification of montelukast sodium as leukotriene receptor antagonist drug, in pure and dosage forms (tablets).
 Methods: The methods use N-bromosuccinimide (NBS) as an oxidant and three dyes, amaranth, methylene blue, and indigo carmine, as auxiliary reagents. The three methods are based on oxidation reaction of montelukast sodium with a known excess of N-bromosuccinimide (NBS) in acid medium, followed by determination of unreacted NBS by the reaction with a fixed amount of dyes, amaranth, methylene blue, and indigo carmine followed by the measurement of the absorbance at 520, 664 and 610 nm, respectively.
 Results: Under the optimum conditions, linear relationships with good correlation coefficients (0.9993-0.9996) were found over the concentration ranges of 0.5-10, 1.0-12 and 0.5-8.0 µg/ml with a limit of detection (LOD) of 0.15, 0.3 and 0.14 µg/ml using amaranth, methylene blue, and indigo carmine methods, respectively. Intra-day and inter-day accuracy and precision of the methods have been evaluated. No interference was observed from the common tablet excipients.
 Conclusion: The proposed methods were validated in accordance with ICH guidelines and successfully applied to the analysis of montelukast sodium in dosage forms (tablets). The reliability of the methods was further ascertained by performing recovery studies using the standard addition method. Statistical comparison of the results obtained by applying the proposed methods with those of the reported method by applying student’s t-test and F-test revealed good agreement.

Spectrophotometric Method for Indirect Determination Of Antihypertensive Drugs in Pharmaceuticals

Abstract A spectrophotometric method is proposed for the determination of antihypertensive drugs namely Propranolol and Methyldopa in their pure forms and in pharmaceutical formulations, based on the oxidation of the drugs with an excess of N-Bromo succinimide and the residual oxidizing agent bleaches the red colored eriochrom black-T (EBT) which is measured at 530 nm at room temperature. Linear calibration graphs were obtained in the concentration range 0.1-10 and 0.1-9 μg ml-1 with molar absorptivity 6.06×104 and 4.60×104 L.mol-1.cm-1 for above drugs respectively. No interference was observed coexistent substance. The proposed method was applied successfully for the determination of the drugs in their pharmaceutical formulations.

Utility of N-Bromosuccinimide as a Green Chemical Reagent for Determination of H2-Receptor Antagonists in their Pharmaceutical Dosage Forms

Abstract An environmentally safe, simple and robust spectrophotometric method has been developed for determination of H2-receptor antagonists namely: cimetidine (CIM), famotidine (FAM), nizatidine (NIZ), and ranitidine hydrochloride (RAN). The method was depend on the reaction of the studied drugs with N-bromosuccinimide (NBS), environmentally friendly reagent, and the excess NBS was measured by its reaction with phloroglucinol to give a yellow chromogenic product (λmax at 435 nm). The absorption intensity decrease (ΔA) was correlated with drug concentrations in the sample solutions. By using of the optimum conditions, linear calibration curves with good correlation coefficients (0.9958–0.9998) were found between the measured ΔA values and the corresponding drugs concentrations in the range of 12-80 μg mL−1. Limits of detection were in the range 1.31-2.21 μg mL−1. The proposed method was validated and successfully applied for the analysis of the above mentioned drugs in their bulk and pharmaceutical dosage forms with good recoveries (98.5 ± 0.98 to 102.5 ± 0.79%). No interferences were obtained from the common excipients. The proposed method was successfully applied for the analysis of H2RAs in their dosage forms and the results were comparable with that obtained by the official methods.

Application of Box-Behnken design and desirability function in the optimization of spectrophotometric method for the quantification of WADA banned drug: Acetazolamide

Experimental design approach was used to optimize the experimental factors in developing a spectrophotometric method for quantification of acetazolamide using N-bromosuccinimide (NBS) as a reagent. In this method, a known excess of NBS was mixed with acetazolamide in acid medium and the unreacted NBS was treated with methyl orange which was monitored at 513 nm. The effects of critical factors such as volumes of 5.60 × 10−4 mol L−1 NBS, 0.5 mol L−1 HCl, 4.2 × 10−2 mol L−1 KBr and 1.53 × 10−4 mol L−1 methyl orange on the absorbance were analysed and these factors were optimized using Box-Behnken design (BBD) and desirability function. The calibration curve was linear in the range of 6–18 μg mL−1 with a correlation coefficient of 0.9999. The detection limit was 0.023 μg mL−1. The method was used to quantify the acetazolamide content in commercial tablets and urine samples. The percentage recoveries of acetazolamide in urine samples were found to vary from 96.22–96.39%.

Vortex-assisted liquid-liquid microextraction procedure for iodine speciation in water samples

A novel, sensitive and selective method for the spectrophotometric determination of the basic inorganic iodine species was developed based on the vortex-assisted liquid–liquid microextraction (VALLME) of an ion pair formed between colorless tetrabutylammonium cation (TBA) and triiodide anion (I3−). Molecular iodine was determined spectrophotometrically at 295nm by the measurement of the intrinsic triiodide absorbance after the addition of an excess of TBA iodide to the sample and following VALLME of the ion-pair TBA-I3 with amyl acetate. The procedure for iodate determination includes the formation of iodine as a result of iodate reduction with TBA-I in acid solution. The new approach was introduced in order to determine iodide or total inorganic iodine content. N-Bromosuccinimide (NBS) was used for the oxidation of iodide to iodate. The excess NBS was removed with oxalic acid. Afterwards, the analysis proceeded as for iodate. The experimental conditions were optimized and found to be: 0.04molL−1 HCl; 0.12mmolL−1 NBS (only for iodide, total iodine); 1mmolL−1 and 1.4mmolL−1 TBA-I for iodide and iodate determination, respectively; 150μL of amyl acetate as the extraction solvent; vortexing, 20s at 3000rpm; and centrifugation, 2min at 3000rpm. The calibration plot was linear in the range 3.8–63 (R2=0.994) and 5.2–88 (R2=0.998) μgL−1 of iodide (as I−) and iodate (as IO3−), respectively. The calibration curve for iodine determination (as I2) is satisfactorily described by the second-order equation (R2=0.999) in the concentration range 6.4–76.2μgL−1 (as I−). The limit of detection (LOD) was 1.1, 2.3 and 1.5μgL−1 of iodide, iodine (as I−) and iodate, respectively. The suggested procedure was successfully applied for the determination of iodide, iodate and iodine in salt, sea and mineral water samples. The accuracy of the method was assessed through comparison with reference methods and by recovery testing.

Development and validation of a rapid stability indicating HPLC-method using monolithic stationary phase and two spectrophotometric methods for determination of antihistaminic acrivastine in capsules

Simple, rapid and accurate high performance liquid chromatographic (HPLC) and spectrophotometric methods are described for determination of antihistaminic acrivastine in capsules. The first method (method A) is based on accurate, sensitive and stability indicating chromatographic separation method. Chromolith® Performance RP-18e column, a relatively new packing material consisting of monolithic rods of highly porous silica, was used as stationary phase applying isocratic binary mobile phase of ACN and 25mM NaH2PO4 pH 4.0 in the ratio of 22.5:77.5 at flow rate of 5.0mL/min and 40°C. A diode array detector was used at 254nm for detection. The elution time of acrivastine was found to be 2.080±0.032. The second and third methods (methods B and C) are based on the oxidation of acrivastine with excess N-bromosuccinimide (NBS) and determination of the unconsumed NBS with, metol–sulphanilic acid (λmax: 520nm) or amaranth dye (λmax: 530nm). The reacted oxidant corresponds to the drug content. Beer’s law is obeyed over the concentration range 1.563–50, 2.0–20 and 1.0–10μgmL−1 for methods A, B and C, respectively. The limits of detection and quantitation were 0.40, 0.292 and 0.113μgmL−1 and 0.782, 0.973 and 0.376μgmL−1 for methods A, B and C, respectively. The HPLC method was validated for system suitability, linearity, precision, limits of detection and quantitation, specificity, stability and robustness. Stability tests were done through exposure of the analyte solution for four different stress conditions and the results indicate no interference of degradants with HPLC-method. The proposed methods was favorably applied for determination of acrivastine in capsules formulation. Statistical comparison of the obtained results from the analysis of the studied drug to those of the reported method using t- and F-tests showed no significant difference between them.

Unveiling the chemistry behind bromination of quercetin: the ‘violet chromogen’

Bromination of quercetin with N-bromosuccinimide in neutral aqueous methanol occurs surprisingly in the electron-deficient A-ring only. Deprotonation of the acidic 7-OH is a major driver of this regioselective reaction. The increase of electron density makes in fact the quercetin anion suitable for an electrophilic attack by bromine at positions 8 and 6. Several pieces of evidence (NMR spectra and H/D exchange) are presented to substantiate the mechanism advanced. Bromoquinones/quinomethides produced in excess of N-bromosuccinimide are responsible for the formation of a stable ‘violet chromogen’.

Method for the preparation of 4-aryl-3-pyrrolin-2-ones and their 5-bromo derivatives

An effective method for the conversion of 1-acetyl-4-phenyl-2-pyrrolidone into 1-acetyl-4-phenyl-3-pyrrolin-2-one by bromination–dehydrobromination with N-bromosuccinimide, catalyzed by azo-bisisobutyronitrile or by UV irradiation is developed. The method was extended to the 1-acetyl-4-phenyl-3-pyrrolin-2-one structural analogs. An employment of an excess of N-bromosuccinimide under given reaction conditions leads to the bromination of 1-acetyl-4-phenyl-3-pyrrolin-2-one and its structural analogs at position 5.

Utility of Oxidation-Reduction Reaction for Determination of Gemifloxacin Mesylate and Moxifloxacin HCl in Pure Form and in Pharmaceutical Formulations using N-Bromosuccinimide

Three sensitive spectrophotometric methods are presented for the assay of gemifloxacin mesylate (GMF) and moxifloxacin HCl (MXF) in bulk drug and in pharmaceutical formulations using N-bromosuccinimide (NBS) and three dyes, methyl orange, amaranth and indigo carmine, as reagents. The methods involve the addition of a known excess of NBS to drug in acid medium, followed by determination of unreacted oxidant by reacting with a fixed amount of methyl orange and measuring the absorbance at 510 nm (method A), amaranth and measuring the absorbance at 528 nm (method B) or indigo carmine and measuring the absorbance at 610 nm (method C). In all methods, the amount of NBS reacted corresponds to the amount of drug and the measured absorbance is found to increase linearly with the concentration of drug which is corroborated by the correlation coefficients of 0.9992- 0.9998. The systems obey Beer’s law for 0.1-4.8 and 0.2-4.0 μg mL-1 for GMF and MXF, respectively. The limits of detection and quantification are also reported. Intra-day and inter-day precision and accuracy of the methods have been evaluated. The methods were successfully applied to the assay of GMF and MXF in tablet preparations and the results were statistically compared with those of the reference methods by applying Student’s t-test and F-test. No interference was observed from the common tablet excipients. The accuracy of the methods was further ascertained by performing recovery studies via standard-addition method.

HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC AND SPECTROPHOTOMETRIC DETERMINATIONS OF PIOGLITAZONE-HCl EITHER ALONE OR IN COMBINATION WITH METFORMIN-HCl

HPLC and spectrophotometric methods are described for pioglitazone-HCl determination in bulk powder and the dosage forms either alone or combined with metformin-HCl. The chromatographic method involves separation of pioglitazone-HCl and metformin-HCl on a monolithic column, using mobile phase of MeOH and 25 mM KH2PO4 at pH 4.9 in ratio of 75:25 (v/v) at flow rate of 2.7 mLmin−1, at 25°C, and at 210 nm. Total elution time is less than one minute. The method is validated for system suitability, linearity, precision, limits of detection and quantitation, specificity, and robustness. Robustness is studied for small changes in pH, flow rate, % of MeOH, and injection volume. Limits of detection are 0.5 and 0.25 µgmL−1 for them, respectively. Recovery values of this method are between 97% and 103% and reproducibility values are within 0.99 for pioglitazone-HCl and 1.5 for metformin-HCl. Spectrophotometric method is based on oxidation of pioglitazone-HCl with excess n-bromosuccinimide followed by oxidation of metol through unreacted amount of n-bromosuccinimide and then coupling between oxidation product of metol and sulphanilic acid. Metformin-HCl does not interfere with this method. The colored compound developed in acidic medium was measured at 520 nm. Beer's law is obeyed in the concentration range of 5–20 µgmL−1.

Epimerization, transacylation and bromination of dihydroquercetin acetates; synthesis of 8-bromodihydroquercetin

Abstract Dihydroquercetin (dhq) and its 3-acetate react with acetic anhydride in the absence of a base catalyst to yield mixtures of partially acetylated products. Three new esters were characterized by NMR spectroscopy as dhq 3,7,3′-triacetate, 3,7,4′-triacetate and 5,7,3′,4′-tetraacetate. At its melting point neat dhq 3,7,3′,4′-tetraacetate is partially converted to dhq 3,3′,4′-triacetate and dhq pentaacetate by intermolecular acetyl transfer. Dhq 7,3′,4′-triacetate yields exclusively dhq 3′,4′-di- and 3,7,3′,4′-tetraacetate under these conditions. The acetylation/deacetylation reactions are accompanied by partial epimerization: 3 new acetates with 2,3-cis stereochemistry (dhq 3-, 3,7,3′,4′-tetra- and penta-) were identified. Dhq and its 3,7,3′,4′-tetraacetate undergo regiospecific dibromination at C-6 and C-8 with excess N-bromosuccinimide in polar solvents, and 6,8-dibromo-dhq can be regioselectively debrominated to 8-bromo-dhq with sodium sulfite.

Biosorption of Malathion from Aqueous Solutions Using Herbal Leaves Powder

Commonly available herbal leaves powder namely Achyranthes aspera (uthareni) and Phyllanthus niruri (Nela usiri) are used as biosorbents for the removal of malathion in the present investigation. The efficiency of the biosorbents is tested for the determination of malathion using batch experiments under controlled conditions as a function of pH, contact time, initial malation concentration and the optimization amount of biosorbents. The quantification of malathion in aqueous samples, before and after equilibration with biosorbents is carried out by existing spectrophotometric method based on the oxidation of malathion with excess N-bromosuccinimide (NBS) and Rhodamine B at (?max = 550 nm) is used for the unconsumed NBS. The biosorption capacities are found to be pH dependent. The maximum adsorption is noticed at pH = 6 with a contact time of 120 minutes. Biosorption equilibrium isotherms are plotted for malathion uptake capacity (Qe) against residual malathion concentration (Ce) in solution. The Qe versus Ce sorption isotherms relationship is expressed mathematically by Langmuir and Freundlich models. The removal of malathion using biosorbents Achyranthes aspera (Uthareni) and Phyllanthus niruri (Nela usiri) from spiked river water samples are found to be 94% and 96% respectively. The developed eco-friendly potential biosorbents indicate that the present method can be successfully applied for the quantitative determination and removal of malathion from real water samples.

Validation of HPLC and FIA Spectrophotometric Methods for the Determination of Lansoprazole in Pharmaceutical Dosage Forms and Human Plasma

A chromatographic and aspectrophotometric methods for the quantitative determination of lansoprazole in pharmaceutical combinations and human plasma were developed. The analytical parameters were studied according to International Conference on Harmonization guidelines. The Flow Injection Analysis (FIA) method is based on the oxidation of lansoprazole by a known excess of N-bromosuccinimide (NBS) in an acidic medium, followed by a reaction of excess oxidant with chloranilic acid (CAA) to bleach its purple color. The separation was carried out using RP-C18 column with a mobile phase composed of ACN: TEA: phosphate buffer (60: 0.2: 39.8 v/v) adjusted to pH = 4.

Development of Simple Green Spectrophotometric and Conductometric Methods for Determination of Cephalosporins in Pure, Pharmaceutical Dosage forms and Human Urine

Five Simple, accurate and rapid spectrophotometric and conductometric methods were developed for the determination of four third generation cephalosporins, namely, cefotaxime sodium (I) , cefoperazone sodium (II), ceftazidime pentahydrate (III) and cefdinir (IV) in pure active ingredient, pharmaceutical dosage forms and human urine. Method A: is based on the reaction of the sulphide ions produced from the alkaline hydrolysis of the cited four drugs with P- aminophenol (PAP). This reaction results in a thionine dye (phenothiazine derivative) formation which exhibits maximum absorbance at 545 nm. Method B: is based on oxidation of drug (I and III) with a known excess of n-bromosuccinimide (NBS) in acidic medium followed by the determination of unreacted amount of n-bromosuccinimide with metol and sulphanilic acid. The purple-red reaction product exhibits maximum absorbance at 520 nm. Method C: is based on the formation of yellow chelate between drug (IV) and palladium (II) chloride in buffered medium (pH 3.5) with an absorption maximum at 314 nm. Method D: is based on the reaction of drug (IV) with aqueous ninhydrin to give yellow colored product in the presence of bicarbonate with an absorption maximum at 433 nm . Method E: A conductometric method is based on the reaction of the four cited drugs with phosphotungstic acid (PTA) forming an ion associate in aqueous medium. Validation of the proposed methods was carried out. All proposed methods were successfully applied for the commercial dosage forms of the cited drugs. Method C was successfully applied for the determination of cefdinir in human urine.