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A chemometric approach based on the combined use of the principal component analysis (PCA) and artificial neural network (ANN) was developed for the multicomponent determination of caffeine (CAF), mepyramine (MEP), phenylpropanolamine (PPA) and pheniramine (PNA) in their pharmaceutical preparations without any chemical separation. The predictive ability of the ANN method was compared with the classical linear regression method Partial Least Squares 2 (PLS2). The UV spectral data between 220 and 300 nm of a training set of sixteen quaternary mixtures were processed by PCA to reduce the dimensions of input data and eliminate the noise coming from instrumentation. Several spectral ranges and different numbers of principal components (PCs) were tested to find the PCA-ANN and PLS2 models reaching the best determination results. A two layer ANN, using the first four PCs, was used with log-sigmoid transfer function in first hidden layer and linear transfer function in output layer. Standard error of prediction (SEP) was adopted to assess the predictive accuracy of the models when subjected to external validation. PCA-ANN showed better prediction ability in the determination of PPA and PNA in synthetic samples with added excipients and pharmaceutical formulations. Since both components are characterized by low absorptivity, the better performance of PCA-ANN was ascribed to the ability in considering all non-linear information from noise or interfering excipients.

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A new simple, rapid and sensitive liquid chromatographic method has been developed and validated for the simultaneous determination of pseudoephdrine, pheniramine, guaifenisin, pyrilamine, chlorpheniramine and dextromethorphan in cough and cold pharmaceuticals. The separation of these compounds was achieved within 13 min on a Kromasil C18 column using an isocratic mobile phase consisting of methanol-dihydrogenphosphate buffer at pH 3 (45:55, v/v). The analysis was performed at a flow rate of 1 mL min(-1) and at a detection wavelength of 220 nm. The selectivity, linearity of calibration, accuracy, within and between-days precision and recovery were examined as parts of the method validation. The concentration-response relationship was linear over a concentration range of 5-50 microg mL(-1) for pseudoephdrine, pheniramine, chlorpheniramine and 50-600 microg mL(-1) for guaifenisin, pyrilamine, dextromethorphan, methylparaben and sodium benzoate with correlation coefficients better than 0.998. The standard deviations of the intraday and interday were all less than 2%. The proposed liquid chromatographic method was successfully applied for the routine analysis of these compounds in different cough and cold pharmaceutical preparations such as syrups, capsules, tablets and sachets. The presence of preservatives (sodium benzoate and methylparaben) and other excipients did not show any significant interference on the determination of these compounds.

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The present work illustrated possibilities of column coupling electrophoresis combined with ionizable chiral selector and diode array detection (DAD) for the enantioselective analysis of trace drugs (pheniramine and its analogs) in pharmaceutical and clinical samples. Isotachophoresis (ITP), on-line coupled with capillary zone electrophoresis (CZE), served as an ideal injection technique (high sample load capacity, narrow and sharp drugs zones) of on-line pretreated samples (preseparation, purification and preconcentration of drugs) for the CZE stage. Enhanced (enantio)separation selectivity of CZE with ionizable chiral selector (carboxyethyl-beta-cyclodextrin recognized between drugs enantiomers on one hand as well as between drugs and sample matrix constituents on the other hand) enabled to obtain pure zones of the drugs enantiomers, suitable for their detection and quantitation. DAD in comparison with single wavelength UV detection enhanced value of analytical information verifying purity of drugs enantiomers zones (indicating interferents with different spectra to those of drugs). Obtained results indicated pure zones of interest confirming effective ITP-CZE (enantio)separation process. Distinguishing the trace analytes signals superposed on the baseline noise was provided with sufficient reliability (for this purpose the background correction and smoothing procedure had to be applied to the raw DAD spectra). The proposed ITP-CZE-DAD methods were characterized by favorable performance parameters (sensitivity, linearity, precision, recovery, accuracy, robustness, selectivity) and successfully applied for (i) enantiomeric purity testing of dexbrompheniramine in commercial pharmaceutical tablets and (ii) enantioselective metabolic study of pheniramine in human urine.

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Cyclodextrin (CD)-mediated capillary zone electrophoresis (CZE) in hydrodynamically closed separation system was developed for the separation and quantitation of pheniramine (PHM) enantiomers. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, carrier cation and counterion, and the pH of the buffer. A high effectivity of oppositely migrating carboxyethyl-beta-cyclodextrin (CE-beta-CD) to separate the PHM enantiomers was demonstrated in detail. The optimized chiral analysis of the antihistamine drug was performed in a buffer consisted of 20 mmol/l epsilon-aminocaproic acid adjusted to pH 4.5 with acetic acid, containing negatively charged CE-beta-CD (2.5 mg/ml) as chiral selector and 0.2% (w/v) methylhydroxyethylcellulose (m-HEC) as an electro-osmotic flow (EOF) suppressor. Acceptable validation criteria for sensitivity, linearity, precision, accuracy/recovery were included. The proposed CZE method was successfully applied to the assay of PHM in pharmaceutical formulations using dioxopromethazine as an internal standard.

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The method of capillary isotachophoresis was used to assay pheniramine in granulated powders. Several electrolyte systems of different composition and different pH were tested. Two electrolyte systems were selected for the validation of the method and pheniramine determination in real samples. Precision, accuracy, linearity, robustness, and selectivity of the ITP method for both electrolyte systems were evaluated. The pre-treatment of samples prior to analysis consisted in dissolving pheniramine-containing granulated powder in demineralized water and subsequent diluting with demineralized water to required concentration.

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Thin-layer chromatography (TLC)-densitometry was used to separate, identify, and quantitate chlorpheniramine maleate (CPM) and pheniramine maleate (PM) when present in combination with other drugs in pharmaceutical preparations of tablets, syrups, eye and ear drops, etc. CPM or PM was extracted (tablets, capsules, etc.) or diluted (liquid preparations, if needed) with 80% ethanol and isolated from other ingredients by TLC on silica gel G using cyclohexane-chloroform-methanol-diethylamine (4.5 + 4.0 + 0.5 + 1.0, v/v) as the mobile phase. Separated CPM and PM were detected under shortwave ultraviolet light and quantitated by scanning densitometry at 260 nm. Recoveries of CPM and PM were 100.09+/-0.77% and 100.09+/-0.87%, respectively.

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The separation and detection of five antihistamine drugs commonly found within over-the-counter allergy and cold pharmaceutical products was performed by HPLC with chemiluminescence (CL) detection. Comparable detection limits at 5-10 pmol were found for the antihistamines by both UV at 214 nm and tris(2,2'-bipyridine) ruthenium(III) CL. However, urine samples were found not to generate as large an unretained peak by CL detection as compared to those peaks by UV detection at 214 and 254 nm. For example, the pheniramine peak representing 0.15 microgram/ml was almost totally obscured at 214 nm. Quantitative results received for three antihistamine commercial samples ranged from 4 to 8% error in accuracy when an internal standard was used to compensate for short term detector drift.

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The quantitative determinations of codeine phosphate, guaifenesin, pheniramine maleate, phenylpropanolamine hydrochloride, and pyrilamine maleate in a liquid dosage form are described. All active and inactive ingredients (sodium benzoate and FD&C Yellow No. 5 dye) can be separated with high-pressure liquid chromatography except the two antihistamines, pheniramine maleate and pyrilamine maleate. Pheniramine maleate is determined colorimetrically, and pyrilamine maleate is determined either by difference or spectrophotometrically. The methods are simple short, accurate, and precise. The standard deviations are reported.

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