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Introduction: Antitussive and expectorant drugs such as aminophylline (APL), doxofylline (DXL), bromhexine hydrochloride (BXH), and ambroxol hydrochloride (AXH), either individually or in combination, are widely used in the prevention and treatment of respiratory diseases. The study aimed to establish a high-performance liquid chromatography (HPLC) method for the simultaneous determination of these four drugs and to investigate their stability in 0.9% sodium chloride injection or 5% glucose injection over 48 hours. Methods: An InertSustain C 18 column (150 mm × 4.6 mm, 5 μm) was used. The mobile phase consisted of acetonitrile and 50 mmol·L -1 potassium dihydrogen phosphate solution (pH 4.0) with gradient elution. The flow rate was 0.8 mL·min -1 , and the column temperature was maintained at 30°C. The stability of APL, DXL, BXH, and AXH in 0.9% sodium chloride and 5% glucose injections over 48 h was determined using HPLC. Results: APL, DXL, BXH, and AXH showed good linearity within the ranges of 0.01 to 0.20, 0.003-0.06, 0.015-0.30, and 0.016-0.16 mg·mL -1 , respectively (r > 0.999). The intraday and interday relative standard deviations were <2%, with recovery rates between 98.4% and 102.2%. The four drugs remained colorless and clear in infusion mixtures. The pH value fluctuated within ±0.3 over 48 hours, and the relative percentage content of the drugs ranged from 95.0% to 105.0%. Conclusion: The established HPLC method is simple, reliable, and stable, allowing for the simultaneous determination of the four antitussive and expectorant drugs. APL, DXL, BXH, and AXH were stable within 48 hours when mixed with 0.9% sodium chloride and 5% glucose injections., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

New validated Spectroscopic methods were developed to assay Bromhexine Hydrochloride and its active metabolite Ambroxol Hydrochloride separately in pure form and pharmaceutical formulations. The spectrophotometric assay (method I) shows complex formation between each of the drugs and Eosin Y at 540nm at pH 3.6 and 3.4mL of 4×10 -4 M Eosin for Bromhexine and Ambroxol. The Spectrofluorimetric assay (method II) depends on quenching eosin native fluorescence by the studied drugs, which measured at 540nm after excitation at 302nm. The spectrophotometric absorbance-concentration plot is rectilinear over the ranges (1.0-5.0) and (1.0-10.0) μg/mL for bromhexine and ambroxol with LOD of 0.31 and 0.14μg/mL and LOQ of 0.94 and 0.42μg/mL for the two drugs respectively. The fluorometric-concentration plot is linear along the range (1.0-5.0) μg/mL and (1-10) μg/mL for the two drugs respectively with LOD of 0.13μg/mL and 0.22μg/mL and LOQ of 0.4μg/mL and 0.65μg/mL for the two drugs, respectively. Developed assays have been validated in agreement with ICH recommendations and they were used in the analysis of commercial drug formulations containing the two mucolytic drugs and the results were matching with those obtained by the comparison method., (Copyright © 2021 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

A gradient elution high-performance liquid chromatographic method with a diode array detector is introduced for the first time for the simultaneous estimation of three drugs, namely, oxytetracycline hydrochloride (OXT), lidocaine (LDC), and bromhexine hydrochloride (BRH), in a veterinary formulation (OxyClear® solution) that contains many interfering additives. The method used a C-8 column. The chromatographic eluting solution included acidified water (0.1% trifluoroacetic acid in water) and acetonitrile at a 1-ml/min flow rate and 254 nm as a nominated detection wavelength. The chromatographic process was assessed in terms of linearity, precision, accuracy, LOD, and LOQ. OXT, LDC, and BRH were linear in the range of 1-60, 5-100, and 1-60 μg/ml, respectively. The three drugs were determined successfully without the interference of three excipients having UV absorbances. Furthermore, the purities of the peaks of the three drugs were confirmed by comparing the UV spectra of investigated peaks to the UV reference spectra in Clarke's Analysis of Drugs and Poisons. The greenness value of the method was 0.69 with a faint green-colored pictogram using the AGREE tool. These merits recommend the application of the planned method in QC laboratories for purity testing and concentration assays for the pure drugs and commercial formulations., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Spectrophotometric-assisted chemometric techniques are beneficial for resolving spectral overlapping and are considered comparable to traditional chromatographic methods. In this work, different chemometric approaches were applied for simultaneous determination of Bromhexine HCl (BRHX), Guaifenesin (GUA) and Salbutamol sulphate (SALB) in the presence of Guaiacol (GUAIA), without any prior separation. Two-way and three-way techniques were applied. The resolving power of genetic algorithm (GA-PLS), trilinear partial least square (N-PLS) and multivariate curve resolution (MCR-ALS) were investigated. A set of 17 synthetic samples in the concentration range 10.0-30.0 μg/mL of BRHX, GUA and SALB and 6.0-10.0 μg/mL of GUAIA were used in the construction of the calibration models. Commercially available syrup dosage form was successfully analyzed by the developed methods without interference from formulation additives. The developed models were evaluated through calculation of root mean squared error of prediction (RMSEP), the obtained values were 0.263, 0.419 and 0.342 for BRHX, 0.254, 0.318 and 0.503 for GUA and 0.298, 0.268 and 0.302 for SALB using N-PLS, MCR-ALS and GA-PLS, respectively. The resolving power of the developed models was emphasized through comparison with a reported HPLC method, where no significant difference was found regarding both accuracy and precision., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: The objective of the present work was to develop and validate a simple, sensitive, rapid and stable reverse-phase high performance liquid chromatography (RP-HPLC) method for a combination of Terbutaline sulphate (TSL), Ambroxol hydrochloride (AML) and Guaifenesin (GFN)., Method: The combination of these drugs was analyzed by using Shimadzu LC 2010 CHT high performance liquid chromatography (HPLC). Successful separation was achieved by isocratic elution on a reverse-phase C 18 column (sun fire) (250mm, 4.6mm, 5μ), using a mobile phase consisting of buffer: acetonitrile in the ratio 80: 20 (buffer - 0.1% v/v triethyleamine pH-3.0) followed by 1.0mL/min flow rate. The wavelength of detection was at 220nm., Result: The chromatographic retention times were consistent at 3.0, 10.5 and 13.8minutes for TSL, AML and GFN respectively. For these three compounds, the lower limit of detection was 1.0, 1.25, and 1.5μg/mL and lower limit of quantification was 3.3, 4.1 and 5.0μg/mL respectively. The linearity concentrations established for TSL, AML and GFN were 1.0-7.0, 1.5-7.5 and 4.0-14.0μg/mL respectively. The correlation coefficients for all the drugs were found to be greater than 0.999. The relative standard deviation of inter- and intra-day were less than 2.0%., Conclusion: This method provides a necessary tool for quantification of the selected drugs for their assay. The proposed method is simple, accurate, reproducible and applied successfully to analyze three compounds in pure as well dosage form., (Copyright © 2019 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Three advanced chemmometric-assisted spectrophotometric methods namely; Concentration Residuals Augmented Classical Least Squares (CRACLS), Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) and Principal Component Analysis-Artificial Neural Networks (PCA-ANN) were developed, validated and benchmarked to PLS calibration; to resolve the severely overlapped spectra and simultaneously determine; Paracetamol (PAR), Guaifenesin (GUA) and Phenylephrine (PHE) in their ternary mixture and in presence of p-aminophenol (AP) the main degradation product and synthesis impurity of Paracetamol. The analytical performance of the proposed methods was described by percentage recoveries, root mean square error of calibration and standard error of prediction. The four multivariate calibration methods could be directly used without any preliminary separation step and successfully applied for pharmaceutical formulation analysis, showing no excipients' interference., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A stability-indicating method for the determination of S-carboxymethyl-L-cysteine and related degradation impurities in Exputex® 250mg/5mL syrup was developed in anion-exchange liquid chromatography mode. A forced degradation study supported the method development to ensure stability indicating conditions. Aqueous solutions of the active pharmaceutical ingredient and syrup samples at different pH-values were stress-tested in different thermal, light exposure and headspace conditions. One degradation product was detected in thermal stress studies at 60°C and 80°C in the pH range 5.0-7.0 and was identified by mass spectrometry as 5-oxo-thiomorpholine-3-carboxylic acid (lactam of carbocysteine). A second degradation product was only generated in moderately strong oxidizing conditions (0.5% H2O2 aqueous solution) and was identified as S-carboxymethyl-L-cysteine-(R/S)-sulphoxide (carbocysteine sulphoxide). The method was developed on a Zorbax SAX column, in isocratic mode. The mobile phase consisted of 200mM phosphate solution at pH 4.0 and acetonitrile (50:50 v/v) and UV detection was performed at a wavelength of 205nm. The method was linear for carbocysteine (R>0.9982) over a concentration range of 2.5-50μg/mL and 0.4-0.6mg/mL. Linearity for the impurities was shown from the LOQ to 50μg/mL. Specificity was verified and accuracy demonstrated for the active ingredient and its degradation products in syrup samples at 3 levels around their respective specification limits. Repeatability, intermediate precision and inter-laboratory reproducibility were assessed on three commercial batches, analyzed in triplicate by two operators at both the transferring and the receiving site and demonstrated a successful method transfer to the manufacturing quality control laboratory., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: The root of Aster tataricus L. f., recorded in all versions of Chinese Pharmacopoeia, is a traditional Chinese medicine with the function of dispelling phlegm and relieving cough for more than 2000 years. This study was designed to evaluate the expectorant, antitussive, and anti-inflammatory activities of the root of A. tataricus and to explore the chemical substances responsible for these activities., Materials and Methods: The 70% ethanol extract of the root of A. tataricus (RA-70) was divided into three fractions, Fr-0, Fr-50 and Fr-95. They were all orally administrated to the mice to investigate their potential expectorant activities by a tracheal phenol red secretion method. The most effective fraction, together with shionone, was evaluated the expectorant, antitussive and anti-inflammatory activities by the mouse models of phenol red secretion, ammonia-induced cough, and xylene-induced ear swelling. Furthermore, the chemical components of the effective fraction were analyzed and identified by an HPLC-Q-TOF/MS method., Results: Treatment with RA-70, Fr-0 and Fr-50 increased the amount of phenol red secretion by 65.3%, 56.5%, and 76.9%, respectively. Fr-50 was chosen for the further investigation and the results showed that Fr-50 at 40, 80 mg/kg significantly enhanced the phenol red secretion of tracheas, increased the latent period and decreased the frequency of cough and inhibited the ear edema in mice. Shionone at 80 mg/kg showed the trend of enhancing sputum secreting, but had no effect on ammonia-induced cough and xylene-induced ear edema. HPLC-Q-TOF/MS analysis indicated that Fr-50 was mainly composed of 12 caffeoylquinic acids (40.8%, in relative peak area), 7 astersaponins (12.0%) and 13 astins/asterinins (pentapeptides, 26.5%)., Conclusions: The root of A. tataricus has significant expectorant, antitussive and anti-inflammatory effects. Caffeoylquinic acids, astersaponins, and aster peptides, rather than shionone, may be the main constituents responsible for the expectorant and antitussive activities of A. tataricus and act in a synergistic way., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Therapeutic (or non-toxic) postmortem guaifenesin blood and liver concentrations have not been previously described. Peripheral blood guaifenesin concentrations were compared to central blood and liver concentrations in eight medical examiner cases. Specimens were initially screened for alcohol and simple volatiles, drugs of abuse, alkaline, and acid/neutral drugs. Guaifenesin, when detected by the acid/neutral drug screen, was subsequently confirmed and quantified by a high performance liquid chromatography procedure. Data suggest that postmortem guaifenesin peripheral blood concentrations may be considered non-toxic to at least 5.4mg/L with liver concentrations to at least 7.0mg/kg. Overall, guaifenesin concentrations ranged from 1.9 to 40mg/L in peripheral blood, 2.2-150mg/L in central blood, and 2.6-36mg/kg in liver. The median guaifenesin central blood to peripheral blood ratio was 1.1 (N=8). Similarly, liver to peripheral blood ratios showed a median value of 0.9L/kg (N=5). Given that a liver to peripheral blood ratio less than 5L/kg is consistent with little to no propensity for postmortem redistribution, these data suggest that guaifenesin is not prone to substantial postmortem redistribution., (Published by Elsevier Ireland Ltd.)

Liquid chromatographic assays were developed using a mixed-mode column coupled in sequence with a hydrophilic interaction liquid chromatography column to allow the simultaneous comprehensive analysis of inorganic/organic anions and cations, active pharmaceutical ingredients, and excipients (carbohydrates). The approach utilized dual sample injection and valve-mediated column switching and was based upon a single high-performance liquid chromatography gradient pump. The separation consisted of three distinct sequential separation mechanisms, namely, (i) ion-exchange, (ii) mixed-mode interactions under an applied dual gradient (reversed-phase/ion-exchange), and (iii) hydrophilic interaction chromatography. Upon first injection, the Scherzo SS C18 column (Imtakt) provided resolution of inorganic anions and cations under isocratic conditions, followed by a dual organic/salt gradient to elute active pharmaceutical ingredients and their respective organic counterions and potential degradants. At the top of the mixed-mode gradient (high acetonitrile content), the mobile phase flow was switched to a preconditioned hydrophilic interaction liquid chromatography column, and the standard/sample was reinjected for the separation of hydrophilic carbohydrates, some of which are commonly known excipients in drug formulations. The approach afforded reproducible separation and resolution of up to 23 chemically diverse solutes in a single run. The method was applied to investigate the composition of commercial cough syrups (Robitussin®), allowing resolution and determination of inorganic ions, active pharmaceutical ingredients, excipients, and numerous well-resolved unknown peaks., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigated whether aqueous extract of the root of Platycodon grandiflorum A. de Candolle (APG), platycodinD(3) and deapi-platycodin significantly affect the production and secretion of airway mucin using in vivo and in vitro experimental models. Effect of APG was checked on hypersecretion of pulmonary mucin in sulfur dioxide-induced bronchitis in rats. Confluent NCI-H292 cells were pretreated with platycodinD(3) or deapi-platycodin for 30min and then stimulated with PMA (phorbol 12-myristate 13-acetate) for 24h. The MUC5AC mucin production and secretion were measured by ELISA. The results were as follows: (1) APG stimulated the secretion of airway mucin in sulfur dioxide-induced bronchitis rat model; (2) platycodinD(3) and deapi-platycodin inhibited the production of MUC5AC mucin induced by PMA from NCI-H292 cells, respectively; (3) however, platycodinD(3) and deapi-platycodin did not inhibit but stimulated the secretion of MUC5AC mucin induced by PMA from NCI-H292 cells, respectively. This result suggests that aqueous extract of P. grandiflorum A. de Candolle and the two natural products derived from it, platycodinD(3) and deapi-platycodin, can regulate the production and secretion of airway mucin and, at least in part, explains the traditional use of aqueous extract of P. grandiflorum A. de Candolle as expectorants in diverse inflammatory pulmonary diseases., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Guaifenesin is an over-the-counter expectorant used for chest congestion and is available both in single-ingredient formulations and in combination with antihistamines, cough suppressants and decongestants. The documented side-effects of guaifenesin are generally mild. We present the case of a 23-year-old female who committed suicide by ingestion of guaifenesin along with small amounts of cetirizine, ethanol and sertraline. Approximately 2 h after ingestion, the patient experienced central nervous system depression followed by asystole. No anatomic cause of death could be determined at autopsy. The initial toxicology detected only ethanol, which was found at a concentration insufficient to cause death. Upon further analysis, guaifenesin was detected in femoral blood at 25.0 μg/mL, urine at >50.0 μg/mL, vitreous fluid at 9.2 μg/mL, brain at 17.0 μg/g and liver at 25.0 μg/g. This is the first reported human case that can be considered a death to which guaifenesin was the significant pharmacologic contributor. Guaifenesin is not detected by the primary screening methods employed by some labs and may be missed in toxicological analyses of overdoses unless specifically suspected.

This study aims to find metabolites responsible for antitussive and expectorant activities of Tussilago farfara L. by metabolomic approach. Different parts (roots, flower buds, and leaves) of the title plant were analyzed systematically. The in vivo study revealed that the leaves and flower buds had strong antitussive and expectorant effects. Then ¹H NMR spectrometry together with principal component analysis (PCA) and partial least squares discriminant (PLS-DA) analysis were used to investigate the compounds responsible for the bioactivities. PCA was used to find the differential metabolites, while PLS-DA confirmed a strong correlation between the observed effects and the metabolic profiles of the plant. The result revealed that chlorogenic acid, 3,5-dicaffeoylquinic acid, and rutin may be closely related with the antitussive and expectorant activities. The overall results of this study confirm the benefits of using metabolic profiling for screening active principles in medicinal plants., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Determination of ternary mixtures of ambroxol hydrochloride, guaifenesin, and theophylline with minimum sample pretreatment and without analyte separation has been successfully achieved by using chemometric and RP-HPLC methods. The developed chemometric models are partial least squares (PLS) and genetic algorithm coupled with PLS. Data of the analyses were obtained from UV-Vis spectra of the studied drugs in different concentration ranges. These models have been successfully updated to be applied for determination of the proposed drugs in Farcosolvin syrup and in the presence of a syrup excipient (methyl paraben). In the developed RP-HPLC method, chromatographic runs were performed on an RP-C18 analytical column with the isocratic mobile phase 0.05 M phosphate buffer-methanol-acetonitrile-triethylamine (63.5 + 27.5 + 9 + 0.25, v/v/v/v, pH 5.5 adjusted with orthophosphoric acid) at a flow rate of 1.2 mL/min. The analytes were detected and quantified at 220 nm. The method was optimized in order to obtain good resolution between the studied components and to prevent interference from methyl paraben. Method validation was performed with respect to International Conference on Harmonization guidelines and the validation acceptance criteria were met in all cases. The proposed methods can be considered acceptable for QC of the studied drugs in pharmaceutical capsules and syrup. The results obtained by the suggested chemometric methods for determination of the studied mixture in different pharmaceutical preparations were statistically compared to those obtained by applying the developed RP-HPLC method, and no significant difference was found.

A field-amplified sample stacking (FASS) and capillary zone electrophoresis (CZE) method is described for the quantification of ambroxol hydrochloride in human plasma, following liquid-liquid extraction in the 96-well format. The separation was carried out at 25 °C in a 31.2 cm × 75 μm fused-silica capillary with an applied voltage of 15 kV. The background electrolyte (BGE) was composed of 6.25 mM borate-25 mM phosphate (pH 3.0) and 1mM β-cyclodextrin. The detection wavelength was 210 nm. Clean-up and preconcentration of plasma biosamples were developed by 96-well format liquid-liquid extraction (LLE). In this study, FASS in combination with β-cyclodextrin enhanced the sensitivity about 60-70 fold in total. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision, extraction recovery and robustness. The calibration graph was linear for ambroxol hydrochloride from 2 to 500 ng/ml. The lower limit of quantification was 2 ng/ml. The intra- and inter-day precisions of lowest limit of quantification (LLOQ) were 9.61 and 11.80%, respectively. The method developed was successfully applied to the evaluation of clinical pharmacokinetic study of ambroxol hydrochloride tablet after oral administration to 12 healthy volunteers., (Copyright © 2012. Published by Elsevier B.V.)

Accurate and sensitive methods were developed for simultaneous determination of methocarbamol and ibuprofen or diclofenac potassium in their binary mixtures, and in the presence of a methocarbamol related substance (guaifenesin) using mean centering of the ratio spectra method. The results obtained were statistically compared with the reported HPLC methods; no significant difference between the proposed methods and the reported methods was found regarding either accuracy or precision.

A sensitive and efficient on-line clean up and pre-concentration method has been developed using column-switching technique and protein-coated µ-Bondapak CN silica pre-column for quantification of ambroxol (AM) in human serum. The method is performed by direct injection of serum sample onto a protein-coated µ-Bondapak CN silica pre-column, where AM is pre-concentrated and retained, while proteins and very polar constituents are washed to waste using a phosphate buffer saline (pH 7.4). The retained analyte on the pre-column is directed onto a C(18) analytical column for separation, with a mobile phase consisting of a mixture of methanol and distilled deionized water (containing 1% triethylamine adjusted to pH 3.5 with ortho-phosphoric acid) in the ratio of 50:50 (v/v). Detection is performed at 254 nm. The calibration curve is linear over the concentration range of 12-120 ng/mL (r(2) = 0.9995). The recovery, selectivity, linearity, precision, and accuracy of the method are convenient for pharmacokinetic studies or routine assays.

The accuracy in predicting different chemometric methods was compared when applied on ordinary UV spectra and first order derivative spectra. Principal component regression (PCR) and partial least squares with one dependent variable (PLS1) and two dependent variables (PLS2) were applied on spectral data of pharmaceutical formula containing pseudoephedrine (PDP) and guaifenesin (GFN). The ability to derivative in resolved overlapping spectra chloropheniramine maleate was evaluated when multivariate methods are adopted for analysis of two component mixtures without using any chemical pretreatment. The chemometrics models were tested on an external validation dataset and finally applied to the analysis of pharmaceuticals. Significant advantages were found in analysis of the real samples when the calibration models from derivative spectra were used. It should also be mentioned that the proposed method is a simple and rapid way requiring no preliminary separation steps and can be used easily for the analysis of these compounds, especially in quality control laboratories., (Copyright © 2011 John Wiley & Sons, Ltd.)

A simple and rapid analytical procedure was proposed for the determination of chromatographic peaks by means of partial least squares multivariate calibration (PLS) of high-performance liquid chromatography with diode array detection (HPLC-DAD). The method is exemplified with analysis of quaternary mixtures of potassium guaiacolsulfonate (PG), guaifenesin (GU), diphenhydramine HCI (DP) and carbetapentane citrate (CP) in syrup preparations. In this method, the area does not need to be directly measured and predictions are more accurate. Though the chromatographic and spectral peaks of the analytes were heavily overlapped and interferents coeluted with the compounds studied, good recoveries of analytes could be obtained with HPLC-DAD coupled with PLS calibration. This method was tested by analyzing the synthetic mixture of PG, GU, DP and CP. As a comparison method, a classsical HPLC method was used. The proposed methods were applied to syrups samples containing four drugs and the obtained results were statistically compared with each other. Finally, the main advantage of HPLC-PLS method over the classical HPLC method tried to emphasized as the using of simple mobile phase, shorter analysis time and no use of internal standard and gradient elution., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry method for the identification and quantification of pentoxyverine citrate and guaifenesin in human plasma has been developed. After extraction from plasma samples by ethyl acetate, the internal standard and analytes were separated by high-performance liquid chromatographic on a Shim-pack VP-ODS C(18) column (150 x 2.0 mm) using a mobile phase consisting of A (methanol) and B (0.4% glacial acetic acid and 4 mmol/L ammonium acetate) (A:B, 43 : 57). Analysis was performed on a Shimadzu LC/MS-2010A in selected ion monitoring mode with a positive electrospray ionization interface. The method was linear in the concentration range of 1.0-640.0 ng/mL for pentoxyverine citrate and 0.025-6.4 microg/mL for guaifenesin. The inter- and intra- precision were all within 12% and accuracy ranged from 85 to 115%.The lower limits of quantification were 1.0 ng/mL for pentoxyverine citrate and 25.0 ng/mL for guaifenesin. The extraction recovery was on average 81.95% for pentoxyverine citrate and 89.03% for guaifenesin. This is the first assay method reported for the simultaneous determination of pentoxyverine citrate and guaifenesin in plasma using one chromatographic run., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

This study was carried out to develop and optimize oral sustained-release formulations for Ambroxol hydrochloride matrix pellets using a combination of wax and water-insoluble polymer, glyceryl behenate (Compritol 888 ATO) and Ethylcellulose (EC(7 FP)). It involved three factors: the content of Compritol 888 ATO (X(1)), EC(7 FP) (X(2)), and the matrix formation methods (X(3)), as independent variables. The drug release percentages at 1, 2 and 4 h were the target responses and were restricted to 15-45% (Y(1)), 45-80% (Y(2)) and 80-100% (Y(3)), respectively. The final blend formulation prepared by extrusion spheronization, was achieved with 27.00% (w/w) Ambroxol hydrochloride, 48.70% (w/w) Compritol 888 ATO, and 24.30% (w/w) EC(7 Fp) with 40 degrees C for 12 h. Comparing the single matrix materials consisting of just the wax or water-insoluble in the complex matrix system containing wax and water-insoluble polymer, the release of the drug can be far more retarded, when the formulations have undergone the process of heat treatment. Furthermore, the combination of the two polymers, with flexible matrix formation methods, will offer a very promising way of producing matrix pellets instead of coated controlled-release pellets to meet various demands of drug release.

A simple, selective, precise, and stability-indicating high-performance thin-layer chromatographic (HPTLC) method for the analysis of ambroxol hydrochloride both as a bulk drug and in formulations was developed and validated. The method employed HPTLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of methanol-triethylamine (4:6 v/v). The system was found to give a compact spot for ambroxol hydrochloride (R(f) value of 0.53 +/- 0.02). Densitometric analysis of ambroxol hydrochloride was carried out in the absorbance mode at 254 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r(2) = 0.9966 +/- 0.0013 with respect to peak area in the concentration range 100-1000 ng/spot. The mean value +/- standard deviation of slope and intercept were 164.85 +/- 0.72 and 1168.3 +/- 8.26 with respect to peak area. The method was validated for precision, recovery, and robustness. The limits of detection and quantitation were 10 and 30 ng/spot, respectively. Ambroxol hydrochloride was subjected to oxidation and thermal degradation. The drug undergoes degradation under oxidation and heat conditions. This indicates that the drug is susceptible to oxidation and heat. Statistical analysis proves that the method is repeatable, selective, and accurate for the estimation of said drug. Stability indicating of new chemical entities is an important part for the drug development of ambroxol hydrochloride and for its estimation in plasma and other biological fluids; the novel Statistical analysis proves that the method is repeatable and selective for the analysis of ambroxol hydrochloride as bulk drug and in pharmaceutical formulations. The proposed developed HPTLC method can be applied for identification and quantitative determination of ambroxol hydrochloride in bulk drug and dosage forms. This work is to determine the purity of the drug available from the various sources by detecting the related impurities.

Purpose: To achieve efficient antibiotic delivery to the cystic fibrosis (CF) airway using a single inhalable powder co-encapsulating a mucolytic and an antibiotic., Methods: Inhalable dry powders containing deoxyribonuclease and/or ciprofloxacin (DNase, Cipro, and DNase/Cipro powders) were produced by spray-drying with dipalmitylphosphatidylcholine, albumin, and lactose as excipients, and their antibacterial effects were evaluated using the artificial sputum model., Results: All powders showed mass median aerodynamic diameters below 5 microm. Both drugs were loaded in the dry powders without loss in quantity and activity. Dry powders containing DNase significantly decreased the storage modulus of the artificial sputum medium in less than 30 min. When applied to artificial sputum laden with Pseudomonas aeruginosa, Cipro/DNase powder showed better antibacterial activity than Cipro powder. The higher activity of the Cipro/DNase powder is attributable to the mucolytic activity of DNase, which promotes penetration of the dry powder into the artificial sputum and efficient dissolution and diffusion of ciprofloxacin., Conclusions: Inhalational delivery of antibiotics to the CF airway can be optimized when the sputum barrier is concomitantly addressed. Co-delivery of antibiotics and DNase using an inhalable particle system may be a promising strategy for local antipseudomonal therapy in the CF airway.

The case of a 13-month-old boy with a diagnosis of unclear unconsciousness is reported on. As the physical examination did not lead to any explanation of his condition, the administration of drugs in the context of Munchausen syndrome by proxy was suspected. Complex forensic-toxicological analyses using HPLC/UV, LC/MS/MS, and GC/MS identified ambroxol and clobutinol, two drugs that are indicated for acute respiratory diseases. No other central active compounds were detected. The accusation of intentional bodily injury raised against the parents could be rebutted, since the boy's unconsciousness could be explained with a rare but harmful side effect of the antitussive clobutinol.

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.

Two accurate, precise, rapid and economical methods viz. Absorption correction method and Dual wavelength method were developed for the estimation of Cefixime (CEF) and Erdosteine (ERDO) in capsule dosage form. In both the methods linearity was observed in the concentration range of 2-25 microg/ml for Cefixime and 3-37.5 microg/ml for Erdosteine. The results of the analysis have been validated statistically and by recovery studies. The percentage assay was found to be 100.03 +/- 0.68 for Cefixime and 99.5 +/- 1.0 for Erdosteine (Mean +/- S.D) by method A and 99.54 +/- 0.84 for Cefixime and 100.54 +/- 1.3 for Erdosteine (Mean +/- S.D) by method B respectively.

A simple, precise and accurate reversed-phase liquid chromatographic method has been developed for the simultaneous estimation of ambroxol hydrochloride and azithromycin in tablet formulations. The chromatographic separation was achieved on a Xterra RP18 (250 mm x 4.6 mm, 5 microm) analytical column. A Mixture of acetonitrile-dipotassium phosphate (30 mM) (50:50, v/v) (pH 9.0) was used as the mobile phase, at a flow rate of 1.7 ml/min and detector wavelength at 215 nm. The retention time of ambroxol and azithromycin was found to be 5.0 and 11.5 min, respectively. The validation of the proposed method was carried out for specificity, linearity, accuracy, precision, limit of detection, limit of quantitation and robustness. The linear dynamic ranges were from 30-180 to 250-1500 microg/ml for ambroxol hydrochloride and azithromycin, respectively. The percentage recovery obtained for ambroxol hydrochloride and azithromycin were 99.40 and 99.90%, respectively. Limit of detection and quantification for azithromycin were 0.8 and 2.3 microg/ml, for ambroxol hydrochloride 0.004 and 0.01 microg/ml, respectively. The developed method can be used for routine quality control analysis of titled drugs in combination in tablet formulation.

A rapid, simple and sensitive LC-MS/MS method was developed for simultaneous determination of amoxicillin and ambroxol in human plasma using clenbuterol as internal standard (IS). The plasma samples were subjected to a simple protein precipitation with methanol. Separation was achieved on a Lichrospher C(18) column (150 mm x 4.6mm ID, dp 5 microm) using methanol (containing 0.2% of formic acid) and water (containing 0.2% of formic acid) as a mobile phase by gradient elution at a flow rate of 1.0 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 365.9-->348.9 (amoxicillin), m/z 378.9-->263.6 (ambroxol) and m/z 277.0-->203.0 (IS). Calibration curves were linear in the concentration range of 5-20,000 ng/mL for amoxicillin, and 1-200 ng/mL for ambroxol, with the intra- and inter-run precisions of <9% and the accuracies of 100+/-7%. The method has been validated and applied to pharmacokinetic studies of compound amoxicillin and ambroxol hydrochloride tablets in healthy Chinese volunteers.

A simple and rapid micellar electrokinetic capillary chromatographic method is described for the separation and quantification of five expectorant drugs, including ambroxol (AMB), bromhexine (BRM), carbocysteine, guaiacol and guaifenesin. The drugs were separated in a mixed solution of phosphate buffer (35 mM; pH 3.90) and acetonitrile (75:25, v/v) with sodium dodecylsulfate (120 mM) as the micellar source, and the separated drugs were directly monitored with UV detector (200 nm). Several key parameters affecting the separation and analysis of the drugs were studied and optimized. Based on the corrected peak-area ratios of the drugs to an internal standard (7-hydroxy-4-methyl-coumarin) versus the concentration of the drugs, the established method is applicable to quantify AMB and BRM each over 20-150 microM, carbocysteine over 100-1500 microM, guaiacol and guaifenesin each over 10-150 microM. The detection limits (S/N=3; 0.5 psi, 5 s injection) of the method for the analytes are in the range of 3.0-5.0 microM (except that of carbocysteine at 30 microM). The precision (relative standard deviation) and accuracy (relative error) of the method for the intra-day (n=3) and inter-day (n=5) analyses of the analytes at three levels are all below 4%. The method is speedy with a run time of about 6 min for the analysis of the five analytes. Application of this method to the analysis of AMB and BRM in pharmaceutical preparations or AMB in the urine of a dosed subject proved simple and effective.

The active pharmaceutical ingredient (ambroxol) in an intact capsule formulation has been non-destructively quantified using Raman spectroscopy. To improve the problem of insufficient representative sampling inherent in Raman measurements, we have employed a wide area illumination (WAI) scheme that enables much improved sample coverage through a circular excitation laser spot with a 6 mm diameter. One of the anticipated sources of variation for this measurement was variation in the capsule shells. However, the WAI scheme significantly decreased the spectral variation among empty capsules compared to a measurement with a traditional small-spot excitation. Therefore, measurement variations emanating from the capsule shell did not significantly influence the accuracy of the determination of ambroxol concentrations. The resulting standard error of prediction (SEP) using the WAI scheme was comparable to that from previous Raman measurements which used a conventional small-spot excitation and employed a sampling scheme that involved rotation of an ambroxol pellet. It is further noteworthy that the SEP was also similar to that obtained from the use of transmission NIR spectroscopy, which was achieved by collection of spectra of the powdered capsule contents removed from the shell. The proposed Raman measurement using the WAI scheme in this case was sufficient to achieve the quantitative measurement of the active pharmaceutical ingredient (API) content of capsules non-destructively.

Four simple, rapid, accurate, precise, reliable and economical spectrophotometric methods have been proposed for simultaneous determination of salbutamol sulphate (SS), bromhexine hydrochloride (BH) and etofylline (ET) in pure and commercial formulations without any prior separation or purification. They were first derivative zero crossing spectrophotometry (method 1), simultaneous equation method (method 2), derivative ratio spectra zero crossing method (method 3) and double divisor ratio spectra derivative method (method 4). The ranges for SS, BH and ET were found to be 1-35 microg mL(-1), 4-40 microg mL(-1) and 5-80 microg mL(-1). For methods 1 and 2, the values of limit of detection (LOD) were 0.2314 microg mL(-1), 0.4865 microg mL(-1) and 0.2766 microg mL(-1) and the values of limit of quantitation (LOQ) were 0.7712 microg mL(-1), 1.6217 microg mL(-1) and 0.9221 microg mL(-1) for SS, BH and ET, respectively. For method 3, LOD values were 0.3297 microg mL(-1), 0.2784 microg mL(-1) and 0.7906 microg mL(-1) and LOQ values were 0.9325 microg mL(-1), 0.9282 microg mL(-1) and 2.6352 microg mL(-1) for SS, BH and ET, respectively. For method 4, LOD values were 0.3161 microg mL(-1), 0.2495 microg mL(-1) and 0.2064 microg mL(-1) and LOQ values were 0.9869 microg mL(-1), 0.8317 microg mL(-1) and 0.6879 microg mL(-1) for SS, BH and ET. The precision values were less then 2% R.S.D. for all four methods. The common excipients and additives did not interfere in their determinations. The results obtained by the proposed methods have been statistically compared by means of Student t-test and by the variance ratio F-test.

Background: Although roxithromycin and ambroxol HCl were often administered concomitantly for the treatment of respiratory infections, the pharmacokinetic interactions between them have not been reported. We investigated the interactions between these drugs in health male Chinese volunteers by LC-MS/MS in human plasma., Methods: The pharmacokinetics were studied in 12 healthy male Chinese volunteers after an overnight fast by a single oral dose, 4-way crossover design with a period of 7-day washout. Each subjects was randomized to receive a single oral dose of 1 compound roxithromycin (150 mg) and ambroxol HCl (30 mg) dispersible tablet (test formulation, treatment A), one 150 mg roxithromycin dispersible tablet together with one 30 mg ambroxol HCl tablet (combined reference formulations, treatment B), one 150 mg roxithromycin dispersible tablet (reference formulation I, treatment C), or one 30 mg ambroxol HCl tablet (reference formulation II, treatment D) with 250 ml of water. Venous blood was collected at pre-dose (0 h) and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 h after dosing. The plasma concentrations of roxithromycin and ambroxol HCl were simultaneously determined by using a validated internal standard LC-MS/MS method., Results: No significant differences were observed for the major pharmacokinetic parameters such as C(max), T(max), t(1/2) and AUC of both roxithromycin and ambroxol HCl between different treatments., Conclusion: The pharmacokinetics of both roxithromycin and ambroxol HCl are not affected by their concomitant oral administration. Therefore, there are no obvious pharmacokinetic interactions between roxithromycin and ambroxol HCl after oral administration. Roxithromycin and ambroxol HCl dispersible tablets were bioequivalent with reference to the roxithromycin dispersible tablets and ambroxol HCl tablets in combination usage.

Fixed dose combination tablets containing ambroxol HCl and cetirizine HCl are clinically used as mucolytic and antiallergic. Several spectrophotometric and HPLC methods have been reported for simultaneous estimation of these drugs with other drugs. The drugs individually and in mixture obeys Beer's law over conc. range 1.2-4.4 microg/mL for cetirizine HCL and for ambroxol HCL 15-52 microg/mL at all five sampling wavelengths (correlation coeff. well above 0.995). The mean recoveries from tablet by standard addition method were 100.18% (+/-2.4) and 100.66 % (+/-2.31). The present work reports simple, accurate and precise spectrophotometric methods for their simultaneous estimation from tablet dosage form.

Ambroxol and clenbuterol were extracted from human plasma samples by liquid-liquid extraction, ambroxol was separated on a Zorbax XDB-C18 column and detected by tandem mass spectrometry with an atmospheric pressure chemical ionization interface after oral administration of a compound preparation. Clenbuterol was separated on a Zorbax XDB-C8 column and detected by tandem mass spectrometry with an electrospray ionization interface. Diphenhydramine is used as the internal standard. The linear concentration ranges of the calibration curves for ambroxol and clenbuterol were 0.080 - 400 microg x L(-1) and 5.0 - 5 000 ng x L(-1), respectively. The lower limits of quantification were 0.080 microg x L(-1) for ambroxol and 5.0 ng x L(-1) for clenbuterol, individually. The inter-day and intra-day precision (RSD) across three validation run over the entire concentration range was below 7.5%, and the accuracy (RE) was within +/- 2.5% for both ambroxol and clenbuterol. The methods were used to determine the pharmacokinetic parameters of ambroxol and clenbuterol in human plasma after oral administration of a compound preparation containing 60 mg ambroxol hydrochloride and 40 microg clenbuterol hydrochloride. The method was proved to be highly sensitive, selective and suitable for the pharmacokinetic study of different compound preparations containing ambroxol and clenbuterol.

Three methods are developed for the determination of two multicomponent mixtures containing guaiphenesine (GU) with salbutamol sulfate (SL), methylparaben (MP) and propylparaben (PP) [mixture 1]; and acephylline piperazine (AC) with bromhexine hydrochloride (BX), methylparaben (MP) and propylparaben (PP) [mixture 2]. The resolution of the two multicomponent mixtures has been accomplished by using numerical spectrophotometric methods such as partial least squares (PLS-1) and principal component regression (PCR) applied to UV absorption spectra of the two mixtures. In addition HPLC method was developed using a RP 18 column at ambient temperature with mobile phase consisting of acetonitrile-0.05 M potassium dihydrogen phosphate, pH 4.3 (60:40, v/v), with UV detection at 243 nm for mixture 1, and mobile phase consisting of acetonitrile-0.05 M potassium dihydrogen phosphate, pH 3 (50:50, v/v), with UV detection at 245 nm for mixture 2. The methods were validated in terms of accuracy, specificity, precision and linearity in the range of 20-60 microg ml(-1) for GU, 1-3 microg ml(-1) for SL, 20-80 microg ml(-1) for AC, 0.2-1.8 microgml(-1) for PP and 1-5 microg ml(-1) for BX and MP. The proposed methods were successfully applied for the determination of the two multicomponent combinations in laboratory prepared mixtures and commercial syrups.

Three methods are developed for the simultaneous determination of theophylline anhydrous (TH), guaiphenesin (GP), diphenhydramine hydrochloride (DP), methylparaben (MP), propylparaben (PP) and sodium benzoate (BZ) in pharmaceutical syrup. The chromatographic method depends on a high performance liquid chromatographic separation on a reversed-phase C(18) column at ambient temperature with mobile phase consisting of 25 mM KH2PO4, pH 3.2-acetonitrile (60:40, v/v). Quantitation was achieved with UV detection at 222 nm based on peak area. The other two chemometric methods applied were partial least squares (PLS-1) and principal component regression (PCR). These approaches were successfully applied to quantify the six components in the studied mixture using information included in the UV absorption spectra of appropriate solutions in the wavelength range of 220-270 nm with Deltalambda=0.4 nm. The calibration PLS-1 and PCR models were evaluated by internal validation (prediction of compounds in its own designed training set of calibration), by cross-validation (obtaining statistical parameters that show the efficiency for a calibration fit model) and by external validation over synthetic and pharmaceutical preparation. The results of PLS-1 and PCR methods were compared with the HPLC method and a good agreement was found.

The porous monolithic columns show high performance at relatively low pressure. The coupling of short monoliths with sequential injection technique (SIA) results in a new approach to implementation of separation step to non-separation low-pressure method. In this contribution, a new separation method for simultaneous determination of ambroxol, methylparaben and benzoic acid was developed based on a novel reversed-phase sequential injection chromatography (SIC) technique with UV detection. A Chromolith SpeedROD RP-18e, 50-4.6 mm column with 10 mm precolumn and a FIAlab 3000 system with a six-port selection valve and 5 ml syringe were used for sequential injection chromatographic separations in our study. The mobile phase used was acetonitrile-tetrahydrofuran-0.05M acetic acid (10:10:90, v/v/v), pH 3.75 adjusted with triethylamine, flow rate 0.48 mlmin(-1), UV-detection was at 245 nm. The analysis time was <11 min. A new SIC method was validated and compared with HPLC. The method was found to be useful for the routine analysis of the active compounds ambroxol and preservatives (methylparaben or benzoic acid) in various pharmaceutical syrups and drops.

A liquid chromatography-mass spectrometry (LC-MS) method for the determination of roxithromycin in rat lung tissue is described. Liquid-liquid extraction was adopted for sample preparation with recoveries from 72.5 to 76.9% at levels of 0.1, 5.0 and 20.0 microg/ml. Chromatographic separation was performed on a C18 column using a mixture of methanol, water and formic acid (80:20:1, v/v/v) as mobile phase delivered at a flow rate of 0.5 ml/min. Positive selected ion monitoring (SIM) mode was used for the quantification of roxithromycin at m/z 837.7 and clarithromycin (internal standard) at m/z 748.7. The linearity was obtained over the concentration range of 0.05-20.0 microg/ml and the lower limit of quantification was 0.05 microg/ml. For each QC level of roxithromycin, the intra- and inter-day precisions relative standard deviation (R.S.D.) were less than 4.1 and 7.5%, respectively, and accuracy (RE) was +/-10.0%. The proposed LC-MS method has been successfully used for the determination of roxithromycin in rat lung tissue after oral administration of roxithromycin formulations to 44 SD rats. The present study demonstrates that the concentration of roxithromycin in rat lung tissues can be significantly increased by ambroxol when they are formulated in combination.

A simple and rapid gas chromatographic (GC) method has been developed for the simultaneous determination of combinations of acetaminophen, phenylpropanolamine hydrochloride, guaifenesin, pseudoephedrine hydrochloride, caffeine, chlorpheniramine maleate, and dextromethorphan hydrobromide in cough and cold tablets and syrups. After extraction of the analyte with alkaline ethyl acetate, 2 microL extract was injected (splitting ratio of 50:1) into a gas chromatograph equipped with a CBP1-M25-025 fused silica capillary column (25 m x 0.22 mm; film thickness, 0.25 microm). The column temperature was held at 150 degrees C for 5 min, increased to 175 degrees C at 3 degrees C/min, and increased to 270 degreesC at 10 degrees C/min. The temperatures of the flame ionization detector and injector were maintained at 300 degrees C. The GC method is inexpensive, rapid, accurate, and precise, and thus it can be used for routine analysis of tablet and syrup preparations in quality control laboratories of pharmaceutical companies.

A new flow methodology exploiting the multi-pumping approach was developed for the spectrophotometric determination of ambroxol hydrochloride in pharmaceutical preparations. The flow manifold was implemented by using, exclusively, multiple solenoid-actuated micro-pumps, which acted simultaneously as sample insertion, solutions propelling and reagents commutation units. Linear calibration plots were obtained over an ambroxol concentration ranging from 10 to 200 mg l(-1) (r.s.d. < 0.5%, n = 15) and a sampling rate of about 60 samples per hour (flow rate = 1.92 ml min(-1), sample volume = 80 microl).

An electrochemical procedure for the determination of ambroxol in mucolytics was described. The method was based on adsorptive accumulation of the species at the hanging mercury drop electrode (HMDE), followed by one of different modes of stripping sweep, viz. direct current tast (DCT), differential pulse (DP), square wave (SW) and first harmonic alternating current (AC1). The behaviour of adsorptive stripping response was studied under various experimental conditions, e.g. type of supporting electrolyte, pH, accumulation time, pulse amplitude, scan rate and mode of sweep. In Britton-Robinson buffer solution, an irreversible reduction process involving transfer of one electron and one proton was took place. The response was linear over the 0.2-6 microg/ml concentration range. Determination of the compound in oral dosage forms was achieved using the standard addition method. The average of determinations obtained by the squarewave adsorptive voltammetric method with its relative standard deviation was 99.8 +/- 2.40%.

An on-line liquid chromatography/tandem mass spectrometry (LC-MS/MS) procedure, using the Prospekt- 2 system, was developed and used for the determination of the levels of the active ingredients of cough/cold medications in human plasma matrix. The experimental configuration allows direct plasma injection by performing on- line solid phase extraction (SPE) on small cartridge columns prior to elution of the analyte(s) onto the analytical column and subsequent MS/MS detection. The quantitative analysis of three analytes with differing polarities, dextromethorphan (DEX), dextrorphan (DET) and guaifenesin (GG) in human plasma presented a significant challenge. Using stable-isotope-labeled internal standards for each analyte, the Prospekt-2 on-line methodology was evaluated for sensitivity, suppression, accuracy, precision, linearity, analyst time, analysis time, cost, carryover and ease of use. The lower limit of quantitation for the on-line SPE procedure for DEX, DET and GG was 0.05, 0.05 and 5.0 ng mL(-1), respectively, using a 0.1 mL sample volume. The linear range for DEX and DET was 0.05-50 ng mL(-1) and was 5-5,000 ng mL(-1) for GG. Accuracy and precision data for five different levels of QC samples were collected over three separate days. Accuracy ranged from 90% to 112% for all three analytes, while the precision, as measured by the %RSD, ranged from 1.5% to 16.0%

A rapid and accurate liquid chromatographic method is described for the simultaneous determination of roxithromycin and ambroxol hydrochloride in a new tablet formulation. Chromatographic separation of the two drugs was achieved on a Diamonsil C(18) column (200 mm x 4.6 mm, 5 microm). The mobile phase consisting of a mixture of acetonitrile, methanol and 0.5% ammonium acetate (39:11:50 (v/v), pH 5.5) was delivered at a flow rate of 1.0 ml/min. Detection was performed at 220 nm. Linearity, accuracy and precision were found to be acceptable over the concentration range of 201.2-2012.0 microg/ml for roxithromycin and 42.7-427.0 microg/ml for ambroxol hydrochloride, respectively. Separation was complete in less than 10 min. The proposed method can be used for the quality control of formulation products.

Aim: To develop a near-infrared diffuse reflectance analysis (NIRDRA) method for rapid noninvasive quantitative determination of ambroxol hydrochloride in half-finished product particles and non-blister-packed, blistered tablets., Methods: All spectra were measured with a Fourier transform spectrometer equipped with a PbS and a InGaAs detector, an external integrating sphere, a rotating sample cup, and a fibre-optic probe for reflectance measurements. All samples were scanned from 12,000 cm-1 to 4,000 cm-1, and each sample spectrum was obtained as an automatic mean of 64 scans. No spectrum pre-processing method was used, and spectral regions, 4,602-4,247, 12,000-7,498 and 6,102-5,446, 12,000-5,446 cm-1 were selected to develope mathematical models by partial least square method for half-finished product particles and non-blister-packed, blistered tablets samples, respectively., Results: The optimal rank and mean square error determined for half-finished product particles and non-blister-packed, blistered tablets samples by cross validation method all was 6 and 0.306, 0.972 and 1.492, respectively, the average recovery was 100%, 100% and 102% respectively; and the RSD was 1.17%, 1.70% and 1.78% respectively., Conclusion: Results showed that the NIRDRA method was rapid, simple, noninvasive and sensitive, and it can be applied to assay the content of ambroxol hydrochloride in half-finished product particles non-blister-packed and blistered tablets.

Capillary electrophoresis (CE) is a powerful separation technique that is peculiarly able to determine the fingerprints of traditional Chinese medicine. The Capillary Electrophoresis Fingerprints (CEFP) of compound liquorice tablets (CLTs) was established to evaluate the quality of CLTs. The background electrolyte was a 50 mM sodium borate solution. The detection wavelength was 228 nm and a 14 kV voltage was applied. Hydrochlorothiazide served as an internal standard and temperature was 24-25 degrees C. The CLTs were extracted by a 50 mM borate solution containing 10% (v/v) methanol. The results showed that CE was a powerful tool for detecting of the fingerprints of traditional Chinese medicine and their constituents. The quality assessments were performed to compare the correlation coefficients (R) and cos theta (C) between each batch vector of CLTs and the total standard profile vector (TSPV), which was the mean vector of all the batch vectors of CLTs with 1.0. The nearer to 1.0 was the R or C, the higher was the similarity. The values of R and C between the TSPV and each batch vector of CLTs produced at different factories were all above 0.9150. The values of R and C between every two standard profile vectors (SPV) from different factories were all above 0.9420. A good stability and reproducibility of the CEFP of CLTs were obtained in the study. Further, we first put forward a new parameter Q to evaluate both the quantification accuracy and the qualitative accuracy for a CEFP, which was verified by determinations of GHIA, GHEA, MP and SB in CLTs. The CEFP was successfully employed to assess the quality of CLTs produced at Kunming Pharmaceutical Factory to be good.

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of (14)C-telmesteine in the Sprague-Dawley rat. 2. (14)C-telmesteine was rapidly absorbed after oral dosing (20 and 50 mg kg(-1)) with an oral bioavailability of >90% both in male and female rats. The C(max) and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats. 3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30 min after dosing was relatively low with a range of 0.1-0.8 except for excretory organs. 4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma. 5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.

A derivative UV spectrophotometric method for the determination of ambroxol in tablets was developed. Determination of ambroxol in tablets was conducted by using first-order derivative UV spectrophotometric method at 255 nm (n = 5). Standards for the calibration graph ranging from 5.0 to 35.0 microg/ml were prepared from stock solution. The proposed method was accurate with 98.6+/-0.4% recovery value and precise with coefficient of variation (CV) of 1.22. These results were compared with those obtained by reference methods, zero-order UV spectrophotometric method and reversed-phase high-performance liquid chromatography (HPLC) method. A reversed-phase C(18) column with aqueous phosphate (0.01 M)-acetonitrile-glacial acetic acid (59:40:1, v/v/v) (pH 3.12) mobile phase was used and UV detector was set to 252 nm. Calibration solutions used in HPLC were ranging from 5.0 to 20.0 microg/ml. Results obtained by derivative UV spectrophotometric method was comparable to those obtained by reference methods, zero-order UV spectrophotometric method and HPLC, as far as ANOVA test, F(calculated) = 0.762 and F(theoretical) = 3.89, was concerned., (Copyright 2003 Elsevier Science B.V.)

The separation of basic nitrogenous compounds commonly used as active ingredients in cold medicine formulations by micellar electrokinetic capillary chromatography and capillary zone electrophoresis with direct absorptiometric detection was investigated. The type and composition of the background electrolyte (BGE) were investigated with respect to separation selectivity and BGE stability. BGE of 10 mM sodium dihydrogenphosphate-sodium tetraborate buffer containing 10 mM SDS and 10% acetonitrile, pH 9.0 was found to be optimal. Dextromethorphan hydrobhromide, diphenhydramine hydrochloride and phenylephrine hydrochloride were baseline-separated in less than 11 min, giving separation efficiencies of up to 494,000 theoretical plates, reproducibility of corrected peaks areas below 3% relative standard deviation and concentration detection limits from 2.5 to 5.5 microg ml(-1). Detection was performed at 196 and 214 nm., (Copyright 2002 Elsevier Science B.V.)

"Neoceader smoking" is widely marketed in drug stores as an over the counter expectorant for cigarette smokers in Japan. Using high-pressure liquid chromatography, we determined that one piece of Neoceader (3 cm) contains 0.79 mg of nicotine, which is equivalent to one-sixth of the amount of nicotine in one Japanese cigarette (Mildseven extra-light, Mildseven super-light, or Sevenstar). Two patients who had switched from cigarette smoking to Neoceader smoking, subsequently became addicted to nicotine. The continine concentration in their urine were 937 ng/ml and 2,724 ng/ml, respectively. These findings demonstrate that Neoceader contains nicotine and that its use can lead to nicotine addiction.