A Review of Different Analytical Techniques for Fexofenadine Hydrochloride and Montelukast Sodium in Different Matrices.

Fexofenadine hydrochloride is an antihistamine agent used for the treatment of allergic disorders like rhinitis. It is a second generation antihistamine. Montelukast sodium is an anti-asthmatic agent and leukotriene receptor antagonist used in the treatment of respiratory disorders. This article exemplifies the reported analytical methods like electrometric methods, ultraviolet spectroscopy, mass spectroscopy, thin layer chromatography, high performance liquid chromatography, high performance thin layer chromatography and tandem spectroscopy for determination of fexofenadine HCl and montelukast sodium in dosage form and in biological matrices. This review covers almost all the analytical methods for fexofenadine hydrochloride and montelukast sodium form 1968-2018 years. Complete analytical validation parameters reported are discussed in this review for both analytes. Among various analytical methods, HPLC and UV-visible spectrophotometry were found to be the most extensively used methods by the researchers.

Development of an enantioselective capillary electrophoretic method for the simultaneous determination of montelukast enantiomeric and diastereoisomeric forms and its main degradation product.

A stereoselective CD-MEKC system has been developed for the quality control of Montelukast (MK), commercialized as a pure enantiomer. The proposed method is the first one that allows the simultaneous determination of MK, its enantiomeric form, diasteroisomers and its main degradation compound (MK sulphoxide). CD-MEKC system is composed of 10 mM SDS, 10 mM sulfobutylether-ß-CD, 10 mM TM-ß-CD, and 20 mM borate buffer at pH 9.0. Combination of these two CDs allows high baseline enantioresolution between MK and its enantiomeric impurity, but also, between the diasteroisomeric forms. Moreover, a multivariate design was applied to optimize operational parameters. The method was designed to meet with requirements of the official pharmacopoeias and fully validated according to international guidelines. Linearity of MK was demonstrated in the range from 10.0 to 100.0 µg/mL (r(2) = 0.9908) with a LOD and LOQ of 0.30 and 0.90 µg/mL, respectively. Intra and interday precision were evaluated and RSD values were below 2%, and also, accuracy expressed as percentage of recovery was in a range from 99.0 to 101.9 for the three assayed levels. The method allows determining 0.02% w/w of the enantiomeric and diasteroisomeric impurities, and 0.01% w/w of MK sulphoxide. Robustness was evaluated by a Plackett and Burman design. Finally, the CD-MEKC system was successfully applied to the determination of related substances in MK bulk drug and its quantification in two pediatric pharmaceutical dosage forms.

Determination of the impurities in drug products containing montelukast and in silico/in vitro genotoxicological assessments of sulfoxide impurity.

Impurities affecting safety, efficacy, and quality of pharmaceuticals are of increasing concern for regulatory agencies and pharmaceutical industries, since genotoxic impurities are understood to play important role in carcinogenesis. The study aimed to analyse impurities of montelukast chronically used in asthma theraphy and perform genotoxicological assessment considering regulatory approaches. Impurities (sulfoxide, cis-isomer, Michael adducts-I&II, methylketone, methylstyrene) were quantified using RP-HPLC analysis on commercial products available in Turkish market. For sulfoxide impurity, having no toxicity data and found to be above the qualification limit, in silico mutagenicity prediction analysis, miniaturized bacterial gene mutation test, mitotic index determination and in vitro chromosomal aberration test w/wo metabolic activation system were conducted. In the analysis of different batches of 20 commercial drug products from 11 companies, only sulfoxide impurity exceeded qualification limit in pediatric tablets from 2 companies and in adult tablets from 7 companies. Leadscope and ToxTree programs predicted sulfoxide impurity as nonmutagenic. It was also found to be nonmutagenic in Ames MPF Penta I assay. Sulfoxide impurity was dose-dependent cytotoxic in human peripheral lymphocytes, however, it was found to be nongenotoxic. It was concluded that sulfoxide impurity should be considered as nonmutagenic and can be classified as ordinary impurity according to guidelines.

Stability indicating method for sodium montelukast in pharmaceutical preparations by micellar electrokinetic capillary chromatography.

A simple, reliable micellar electrokinetic chromatography method (MEKC) for the determination of sodium montelukast in coated tablets was developed and validated. Successful results were obtained with 10 mmol L(-1) borate buffer and 30 mmol L-(1) sodium dodecyl sulfate at pH 9.4, injection time of 5.0 s, an applied voltage of 25 kV and a column temperature of 25 degrees C. The detector response for sodium montelukast was linear over the concentration range from 20 to 100 microg mL(-1) (r = 0.9995). The intra and inter-day precision showed suitable results (RSD < 1.46%). The analytical method accuracy was 99.67% (RSD = 1.11%). The limits of detection and quantitation were 0.75 and 2.00 microg mL(-1) respectively. The method demonstrated robustness and showed to be viable for the sodium montelukast determination in pharmaceutical dosage form.

Montelukast treatment (cysteinyl leukotriene receptor antagonist) in a model of food allergy: modifications in lymphatic cell population from rectal mucosa

Objective: the aim is to determine immunopathological modifications in rectal mucosa from rabbits after local challenge in ovalbumin (OVA) sensitized animals previously treated with montelukast. Material and methods: experimental design: thirty two rabbits divided into four groups: G1: normal; G2: subcutaneously OVA sensitized; G3: sensitized, locally OVA challenged and sampled 4 hours after challenge; and G4: sensitized, locally OVA challenged and treated 4 hours before challenge with montelukast (0.15 mg/kg). Specific anti-OVA IgE levels were evaluated by passive cutaneous anaphylaxis test (PCA). In each group 200 high microscopical power fields (HPF) were counted. Results were expressed as arithmetic mean and SE. Anti -CD4, CD5, micro chain monoclonal antibodies were used. Avidin biotin horseradish peroxidase system was used. Results: CD 4: G1: 8.3 ± 0.06; G2: 13.4 ± 0.08, G3: 8.25 ± 0.06, G4: 11.8 ± 0.02. CD 5: G1: 7.3 ± 0.05; G2: 9.4 ± 0.05, G3: 11.3 ± 0.06, G4: 8.1 ± 0.06. ì chain: G1: 10.4 ± 0.06; G2: 3.8 ± 0.02, G3: 6.0 ± 0.10, G4: 2.2 ± 0.10. In all cases, experimental groups (G3 vs. G4) presented statistical significant differences (p < 0.05). CD4+, CD5+ cells and micro chain+ decrease in experimental group (G4), probably due to lymphocyte migration inhibition to challenged mucosa. micro chain+ cell decrease could be based on B cell activation and expression of different surface immunoglobulins. Cells expressing micro chain decreased in G2 and G3 likely due to activation of B cells and subsequent expression of other immunoglobulin chains in cell surface. Conclusions: we conclude that obtained data are important to elucidate immunopathology of local anaphylactic reaction in rectal mucosa from systemic sensitized animals after treatment with montelukast(AU)

Identification, synthesis, isolation and spectral characterization of potential impurities of montelukast sodium.

During the process development of montelukast sodium, three polar impurities and one non-polar impurity with respect to montelukast sodium were detected by simple reverse phase high-performance liquid chromatography (HPLC). Initially, all the four impurities were identified by the liquid chromatography-mass spectrometry (LC-MS) data and out of four impurities, three have been prepared by the synthetic method and remaining one is isolated by preparative HPLC. Based on the spectral data (IR, (1)H NMR, (13)C NMR and MS), the structure of these impurities 1-4 were characterised as 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetamide (impurity-1), {1-[1-{3-[2-(7-chloro-quinolin-2-yl)-vinyl]-phenyl}-3-(2-isopropenyl-phenyl)-propylsulfanylmethyl]-cyclopropyl}-acetic acid (impurity-2), 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethyl]phenyl-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (impurity-3) and 1-[[[(1R)-1-[3-[(1E)-2-(2-quinolinyl)ethenyl]phenyl-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (impurity-4).

Optimisation, validation and application of a capillary electrophoretic method for the determination of zafirlukast in pharmaceutical formulations.

Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes and currently indicated for the prophylaxis and treatment chronic asthma. A simple, rapid, reliable capillary zone electrophoresis method for the determination of ZAF in pharmaceutical formulations was developed and validated. The influence of buffer concentration, buffer pH, organic modifier, capillary temperature, applied voltage and injection time was systemically investigated in a fused silica capillary (i.d. 50 microm, total length 80.5 cm and effective length 72.0 cm). Optimum results were obtained with 50mM borate buffer at pH 8.50, capillary temperature 25 degrees C and applied voltage 30 kV. The samples were injected hydrodynamically for 3s at 50 mbar. Detection wavelength was set at 240 nm. Meloxicam was used as internal standard. The method was suitably validated with respect to linearity, limit of detection and quantification, accuracy, precision, selectivity, robustness and ruggedness. The linear calibration range was 2.00-80.00 microg mL(-1) and the limits of detection and quantification were 0.75 and 2.00 microg mL(-1) with R.S.D. of 3.88 and 2.75%, respectively. The proposed method was applied for the determination of ZAF in its pharmaceutical formulations. The results obtained from developed method were compared with a HPLC method reported in the literature and no significant difference was found statistically.

Electrochemical characteristics of zafirlukast and its determination in pharmaceutical formulations by voltammetric methods.

Simple, rapid, reliable and fully validated voltammetric methods were developed for the determination of zafirlukast in pharmaceutical formulations, based on its electrochemical reduction at a hanging mercury drop electrode. Its electrochemical behavior in borate buffer (pH 8.0) was investigated using cyclic voltammetry, linear sweep voltammetry and chronoamperometry. The linear sweep voltammetric study of zafirlukast was carried out using glassy carbon electrode. A well-defined cathodic peak at -1326 mV without the adsorptive accumulation time and at -1312 mV with 20 s of accumulation time versus Ag/AgCl reference electrode in square-wave and square-wave adsorptive stripping voltammetric methods, respectively, was observed. The experimental and instrumental parameters affecting the peak current of zafirlukast were investigated and optimized for the zafirlukast determination. The detection limits of square-wave and square-wave adsorptive stripping voltammetric methods were 50 and 5 ngmL(-1) with R.S.D. of 6.79 and 5.72%, respectively. The methods showed good sensitivity, accuracy, precision, selectivity, robustness and ruggedness. The proposed methods were applied for the determination of zafirlukast in its pharmaceutical formulations. The results obtained from developed methods were compared with a spectrophotometric method reported in the literature and no significant difference was found statistically.

Determination of Pranlukast and its metabolites in human plasma by LC/MS/MS with PROSPEKT on-line solid-phase extraction.

A highly sensitive and selective liquid chromatography/ionspray tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of Pranlukast and its oxidative metabolites (SB 240103, SB 241484 and SB 218663) in human plasma in order to support pharmacokinetic studies. The method employed direct injection of human plasma into an on-line solid phase extraction (SPE) PROSPEKT instrument for isolation of the analytes followed by column switching to the LC/MS/MS. The use of on-line SPE resulted in reduced sample preparation time and cleaner extracts, therefore minimizing ion suppression and HPLC back-pressures issues. The use of a 20 mM ammonium acetate-methanol system and a step gradient yielded intense ion species, excellent separation between the polar metabolites and the parent drug and sufficient selectivity for baseline resolution of the two positional isomers, SB 240103 and SB 218663. Pranlukast, its metabolites and the internal standard (SK&F 108566) were quantified using a turbo-ionspray interface by negative ion selected reaction monitoring (SRM). The lower limit of quantification (LLQ) for the assay was 10.0 ng ml-1 for Pranlukast and 1.00 ng ml-1 for its metabolites based on a 100 microliters plasma aliquot. The calibration curves were linear for analyte concentrations ranging from 10.0 to 2000 ng ml-1 for Pranlukast and 1.00 to 200 ng ml-1 for the metabolites. The calculated intra- and inter-assay precision from quality control (QC) samples resulted in mean variability values of less than 12% for all analytes. Pranlukast and its metabolites were shown to be stable under routine analysis conditions for clinical trial samples. The method provides automated sample analysis in a total cycle time of 5 min with improved robustness, sensitivity, selectivity, accuracy and reproducibility compared to the existing methodology.