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Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso -substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure., Competing Interests: The authors declare no conflicts of interest.

In respiratory and genetic disorders such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and cystic fibrosis (CF), the lungs produce excess mucus, resulting in a thickened mass, which clogs up the airways and reduces airflow. Consequently, breathing becomes more difficult. Medications that break down the structure of mucus will be especially useful in managing the early symptoms of these diseases and preventing their progression into the more severe forms. This work therefore seeks to develop an inhaled mucoactive dry powder formulation that is efficacious on multiple fronts. As an innovative step, sodium chloride was used to tailor the surface architecture of ambroxol hydrochloride particles, such that the resulting angular features on the surfaces contributed to the creation of corrugated particles with enhanced aerodynamicity. The optimized spray-dried powder particles were of respirable-size (d 50 of 2.85 ± 0.15 μm) and moderately corrugated. When the crystalline powder was dispersed via an Aerolizer® inhaler at 60 L/min, it gave a fine particle fraction (FPF) of ~31%, which was a ten-fold improvement over the unmodified species (i.e. ambroxol hydrochloride alone). Tests on artificial sputum medium (ASM) showed that the optimized formulation was potentially useful in liquefying the mucus, which favorably pointed towards the effectiveness of the formulation. In addition, the formulation was also stable to moisture ingress (up to ~60% RH) and had good flowability. Hence, the advent of angular adjuvant sodium chloride particles in a mucoactive formulation conferred a three-fold benefit to the product: (1) Improved aerodynamicity and flowability, (2) Enhanced moisture stability and (3) Synergistic mucolytic properties., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Ambroxol relieves cough symptoms based on its secretagogue, anti-inflammatory, anti-oxidant, anti-bacterial, anti-viral, immunomodulatory and local anesthetic effects. The present study was designed to explore differential patient profiles and efficacy against acute respiratory symptoms of four formulations registered as over-the-counter medicines., Methods: Nine hundred sixty-five pharmacy customers purchasing one of four branded ambroxol formulations (extended release capsules, adult syrup, pediatric syrup and soft pastilles) filled a questionnaire including a patient-adapted version of the Bronchitis Severity Scale, several questions on degree of impairment by acute cough, time to onset of symptom relief and duration of treatment. Data on pediatric syrup users were entered by their parents. Based on the exploratory character of the study, no hypothesis-testing statistical analysis was applied., Results: Users of the pediatric syrup and the pastilles reported somewhat less severe baseline symptoms. The patient-adapted Bronchitis Severity Scale proved feasible as a self-administered tool. Among BSS items, ambroxol formulations improved chest pain while coughing to the largest and sputum to smallest degree (- 75% vs. -40%). Reported efficacy was comparable among formulations with minor differences in favor of the pediatric syrup. Time to onset of symptom relief was less than 60 min in more than 90% of patients and occurred prior to known systemic t max . Time to onset was the parameter with the greatest differences between formulations, being reported fastest with pastilles and pediatric syrup and, as expected, slowest with extended release capsules. All ambroxol formulations were well tolerated., Conclusions: We conclude that over-the-counter formulations of ambroxol exhibit comparable user profiles and efficacy. Differences in speed of onset of symptom relief may involve not only those in systemic pharmacokinetics but also local anesthetic effects of immediate release formulations. Differences between pediatric and adult syrup may in part reflect reporting bias.

The bitterness of 10 different products with ambroxol as active ingredient, the original and nine generics, were evaluated by human gustatory sensation tests in which the tablets were kept in the mouth, with water, at 20 and 37°C. The products all showed different bitterness intensities. The original and some of the generic products had comparatively low bitterness intensities but some of the generic products had comparatively high bitterness intensities. The bitterness intensities of these 10 was found to be significantly correlated with both the disintegration time, as evaluated using the ODT-101 (a recently developed apparatus), and the drug concentration in dissolved medium, as measured in a conventional dissolution test. The bitterness threshold of ambroxol solution was found to increase when the temperature of the water with which the tablets were taken, was raised from 20 to 37°C. The equation was calculated to predict the bitterness intensity of ambroxol, a function based on temperature and the ambroxol concentration using data from a standard ambroxol solution at 4, 20 and 37°C. The bitterness intensities obtained for the 10 ambroxol formulations with water at 20 and 37°C, coincided with the bitterness values predicted by the equation.

The aim of the present study is to perform stability study of ambroxol hydrochloride sustained release pellets stored in different storage conditions. The drug loaded beads were prepared by extrusion-spheronization technology then coated with ammonio methacrylate copolymer type A (Eudragit RL 30 D) and ammonio methacrylate copolymer type B (Eudragit RS 30 D) at a ratio of 2:3 (8% polymer by weight on dry basis) in fluid bed coater (Wurster column). Stability study of pellets was performed as capsule dosage form in aluminium-PVDC packaging mode at room temperature, 40 degrees C, 40 degrees C/75%RH & 30 degrees C/70%RH for three months. After one month the shape & size of the pellets was changed in all conditions. The color of the pellets remains unchanged up to the 2nd month in all conditions except at 40 degrees C/75%RH and in this case some pellets become brown. But after 3rd month, pellets become brownish in all conditions except at room temperature. At RT the color of pellets remains unchanged during the stability study. The mean drug content decreased gradually in all conditions. In acid media the initial drug release was 23% but after 1st month it was decreased to 13-15% in all conditions. In the buffer media (pH 6.8) the drug release was increased a little bit in all conditions except at 30 degrees C/70%RH with the passes of storage time. Stability studies at 30 degrees C/70%RH revealed consistent drug release (f(2)>50) throughout the stability period. The physical properties of pellets as well as the in vitro release profile of the drug was found to be a function of the different storage conditions as well as the physico-chemical nature of the polymers.

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.

Ambroxol is an expectoration improver and mucolytic agent that has been used to treat acute and chronic disorders. However, ambroxol needs to be administered percutaneously in order to avoid systemic adverse effects, such as headache, drowsiness, dizziness, and insomnia, which can occur after oral administration. The aim of this study was to develop a gel preparation containing a permeation enhancer to enhance the delivery of ambroxol. The ambroxol gels were prepared using hydroxypropyl methylcellulose (HPMC) and poloxamer 407. The release characteristics of the drug from the gels were examined according to the receptor medium, drug concentration, and temperature. The rate of drug permeation into the skin was enhanced by incorporating various enhancers such as the ethylene glycols, the propylene glycols, the glycerides, the non-ionic surfactants, and the fatty acids into the gels. The permeation study through mouse skin was examined at 37 C. The rate of drug release increased with increasing drug concentration and temperature. Among the enhancers used, propylene glycol mono caprylate showed the best enhancing effects. The estimated activation energy of release (Ea), which was calculated from the slope of a log P versus 1000/T plot, was 14.80, 14.22, 13.91, and 12.46 kcal/mol for ambroxol loading doses of 2, 3, 4, and 5%, respectively. The results of this study show that the gel preparation of ambroxol containing a permeation enhancer could be developed for the enhanced transdermal delivery of ambroxol.

Gels formed in situ following oral administration of dilute aqueous solutions of pectin (1.0 and 1.5%, w/v) to rats were evaluated as vehicles for the sustained release of the expectorant drug ambroxol hydrochloride. The solutions contained calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion-controlled release of ambroxol from the gels over a period of 6 h. A bioavailability of ambroxol of approximately 64% of that of a commercially available formulation could be achieved from gels containing an identical dose of ambroxol formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h. The influence of added sorbitol (17%, w/v) on the rheological and drug release properties of the formulations has been examined.

Ambroxol and bromhexine are shown to be scavengers of both superoxide and hydroxyl radicals as determined by pulse radiolysis experiments. The dismutation of superoxide was accelerated 3-fold by bromhexine and 2.5-fold by ambroxol over the rate of spontaneous dismutation. The reaction constants of hydroxyl radicals with bromhexine and ambroxol were determined by competition kinetics to be 1.58 +/- 0.15 x 10(10) M-1S-1 and 1.04 +/- 0.1 x 10(10) M-1S-1, respectively. N-acetyl-L-cysteine also reacted with hydroxyl radicals (1.28 +/- 0.14 x 10(10) M-1S-1) but not with superoxide radical. These effects may be clinically relevant in the treatment of oxidant-associated lung damage induced by inflammatory agents and/or environmental pollutants.