quality control:
The term "quality" has a relative meaning. This is expressed by the ISO definition: "The totality of features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs". In simpler words, one can say that a product has good quality when it "complies with the requirements specified by the client". When projected on analytical work, quality can be defined as "delivery of reliable information within an agreed span of time under agreed conditions, at agreed costs, and with necessary aftercare". The "agreed conditions" should include a specification as to the precision and accuracy of the data which is directly related to "fitness of use" and which may differ for different applications. Yet, in many cases the reliability of data is not questioned and the request for specifications omitted. Many laboratories work according to established methods and procedures which are not readily changed and have inherent default specifications. Moreover, not all future uses of the data and reports can be foreseen so that specifications about required precision and accuracy cannot even be given. Consequently, this aspect of quality is usually left to the discretion of the laboratory. However, all too often the embarrassing situation exists that a laboratory cannot evaluate and account for its quality simply because the necessary documentation is lacking.
In the ensuing discussions numerous activities aimed at maintaining the production of quality are dealt with. In principle, three levels of organization of these activities can be distinguished. From the top down these levels are:
Quality Control
A major part of the quality assurance is the Quality Control defined by ISO as "the operational techniques and activities that are used to satisfy quality requirements. " An important part of the quality control is the Quality Assessment: the system of activities to verify if the quality control activities are effective, in other words: an evaluation of the products themselves.
Quality control is primarily aimed at the prevention of errors. Yet, despite all efforts, it remains inevitable that errors are be made. Therefore, the control system should have checks to detect them. When errors or mistakes are suspected or discovered it is essential that the "Five Ws" are trailed:
1.2 Bromohexine :
Synonyms: 2-Amino-3,5-dibromo-N-cyclohexyl-N-methylbenzylamine hydrochloride; N-(2-Amino-3,5-dibromobenzyl)-N-methylcyclohexylamine hydrochloride
Molecular Formula : C14H20Br2N2.HCl Molecular Weight 412.59 CAS Registry Number 611-75-6 EINECS 210-280-8 Bromhexine hydrochloride, 2-Amino-3,5-dibromo-N-cyclohexyl-N-methylbenzylamine hydrochloride, N-(2-Amino-3,5-dibromobenzyl)-N-methylcyclohexylamine hydrochloride, CAS #: 611-75-6
1.2.1 properties :
Appearance : White or almost white, crystalline powder.
Solubility : Very slightly soluble in water, slightly soluble in alcohol and in methylene chloride.
It shows polymorphism.
roperties : Melting point 240-244 °C
1.2.2 pharmacology :
Generic name: Bisolvon, Barkacin
Description :Bromhexine is a mucolytic agent. It is used to treat respiratory disorders linked with viscid or excessive mucus. It is secretolytic. This means that it increases the production of serous mucus in the respiratory tract and makes the phlegm less sticky and thinner. This lead to secretomotoric effect. This helps the cilia transport the phlegm out of the lungs. Cilia represents the tiny hairs that line the respiratory tract. For this reason, bromhexine is added to some anti tussive (cough) syrups.
Available as syrup, drops and tablets.
Uses :
To treat cough with phlegm.
To treat acute and chronic diseases bronchus and lung violation othozdenia patients.
The medicine should not be used for any other uses other than those mentioned in the product information section. However, Bisolvon® (bromhexine) is at times recommended to treat respiratory disease in animals.
Dosage
Always take the medicine as directed by your physician or as mentioned in the packet. Usually the recommended doses are stated below:
Children 2-6 years: ¼ tablet 2 times daily.
Children 6-12 years: ½ tablet 3 times daily.
Adult and children over 12 years: 1 tablet 3 times daily.
Bromhexine Side Effects
Bromhexine is used to treat respiratory disorders that are caused by excessive or overly sticky mucus. Bromhexine, which is sold under the brand names Bisolvon or Barkacin, acts as a mucolytic agent that increases the water content of mucus, making the mucus thinner and less sticky. This thinner phlegm is more easily expelled out of the lungs. Bromhexine can be administered by itself, or it is sometimes included in cough syrups. The side effects caused by bromhexine are generally mild, although rare cases of severe allergic reactions have been reported.
Diarrhea and Upset Stomach
Bromhexine is known to cause a variety of gastrointestinal effects. Some people experience diarrhea, while other people may develop nausea and indigestion. Some users of bromhexine also report feeling bloated after taking the medicine.
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Allergic Reactions
In rare cases, more severe allergic reactions to bromhexine may develop. Some users have reported itchy skin or skin rashes after taking bromhexine. Instances of shortness of breath and difficult or painful breathing have also been reported.
Swelling
Another allergic reaction that rarely occurs is swelling of the face, which may include the mouth, lips, tongue or throat.
Drug Interactions
A doctor should always be consulted before taking bromhexine, which may cause complications due to interactions with other medications. Bromhexine has been known to increases the activity of antibiotics, which can have adverse health effects.
Headaches
Some people may experience headaches after taking taking bromhexine. Additionally, some users complain of vertigo or dizziness. These effects are usually mild.
Sweating
Instances of increased sweating have also been reported after taking bromhexine.
(2.0) analytical view
2.1 )Volumetric methods for analysis of Bromhexine
Microcomputer-aided titrimetric determination of bromine-containing active ingredients in some drug formulations
Several microcomputer-aided titrimetric procedures were developed to determine active components with bromide or covalently bound bromine in their molecules in some pharmaceutical preparations of different formulations. Titrations were carried out either with a standard silver nitrate solution (indirect determination), employing catalytic spectrophotometric, potentiometric and controlled-current potentiometric methods to monitor the course of the titration, or with a standard solution of perchloric acid in acetic acid (direct determination) in catalytic thermometric titration. The indicator reaction used in catalytic spectrophotometric titrations was the peroxodisulfate-sulfanilic acid reaction in the presence of 2,2′-bipyridine as activator and acetate buffer (pH 4.35), whereas in catalytic thermometry it was the hydroquinone-acetic anhydride reaction. In the controlled-current potentiometric procedure, use was made of the peroxodisulfate decomposition reaction in the presence of 2,2′-bipyridine as the indicator. Amounts of 10-20 µmol of the investigated active ingredients per titration were determined with a relative standard deviation that, depending on the procedure and mode of sample preparation, was in the range 0-2.6%. The results are comparable to those obtained by official methods. The microcomputer-aided titrimetric procedures developed are relatively fast and economical and can be applied to the analysis of large numbers of pharmaceutical products. {1}
2.2) Spectrophotometric determination of bromhexine
1- Spectrophotometric determination of bromhexine hydrochloride in pharmaceutical preparations.
Abstract
The presence of an aromatic primary amino group in bromhexine HCl enables the use of diazotization-coupling, according to the classic Bratton-Marshall method, for its analysis in pharmaceutical preparations. Spectrophotometric parameters were established for standardization of the method, including statistical analysis of data. Substances such as potassium
guaiacolsulfonate, ampicillin, cephalexin, oxytetracycline HCl, amoxycillin, and erythromycin ethylsuccinate do not interfere with the determination. The precision of the method is about 2.0%.
2-Determination of bromhexine in cough-cold syrups by absorption spectrophotometry and multivariate calibration using partial least-squares and hybrid linear analyses. Application of a novel method of wavelength selection
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Abstract
The mucolitic bromhexine [N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine] has been determined in cough suppressant syrups by multivariate spectrophotometric calibration, together with partial least-squares (PLS-1) and hybrid linear analysis (HLA). Notwithstanding the spectral overlapping between bromhexine and syrup excipients, as well as the intrinsic variability of the latter in unknown samples, the recoveries are excellent. A novel method of wavelength selection was also applied, based on the concept of net analyte signal regression, as adapted to the HLA methodology. This method allows one to improve the performance of both PLS-1 and HLA in samples containing nonmodeled interferences.
3- Chemiluminescence determination of bromhexine hydrochloride with morin as chemiluminescent reagent.
Abstract
A new chemiluminescence (CL) reaction was observed when cerium(IV) solution was injected into bromhexine hydrochloride-morin solution. Based on this, a flow-injection CL method for the determination of bromhexine hydrochloride was established. A possible mechanism of the CL reaction was proposed via the investigation of the CL kinetic characteristics, the CL spectrum and the fluorescence spectra of some related substances. Under optimum conditions, the CL signal was correlated linearly with concentration of bromhexine hydrochloride over the range 2.0 x 10(-9)-2.0 x 10(-7) g/mL, with a linear correlation of 0.9995. The detection limit was 9 x 10(-10) g/mL bromhexine hydrochloride and the relative standard deviation was 1.0% (c = 2.0 x 10(-8) g/mL bromhexine hydrochloride, n = 11). The method was applied to the determination of bromhexine hydrochloride in pharmaceutical preparations and human urine samples with satisfactory results.
4-multaneous Determination of Salbutamol Sulphate and Bromhexine Hydrochloride in Tablets by Reverse Phase Liquid Chromatography
Abstract
A simple reverse phase liquid chromatographic method has been developed and subsequently validated for simultaneous determination of salbutamol sulphate and bromhexine hydrochloride. The separation was carried out using a mobile phase consisting of acetonitrile, methanol and phosphate buffer, pH 4 in the ratio 60:20:20 v/v. The column used was SS Wakosil-II C-18 with a flow rate of 1 ml/min and UV detection at 224 nm. The described method was linear over a concentration range of 10-110 μg/ml and 20-140 μg/ml for the assay of salbutamol sulphate and bromhexine hydrochloride, respectively. The mean recovery was found to be 95-105% for salbutamol sulphate and 96.2-102.1% for bromhexine hydrochloride when determined at five different levels.
2.3) Electrochemical methods for analysis of Bromhexine
1-Potentiometric Flow Injection Analysis of Bromhexine Hydrochloride and its Pharmaceutical Preparation Using Conventional and Coated Wire IonSelective Electrodes
Abstract
Bromhexine hydrochloride ion-selective electrodes (conventional type) based on bromhexinium tetraphenyl borate (I) and bromhexinium-phosphotungstate (II) were prepared. The electrodes exhibited mean slopes of calibration graphs of 59.4 mV and 59.8 mV per decade of bromhexine concentration at 25ô€±C for electrode (I) and (II), respectively. Both electrodes could be used within the concentration range 3.16x10-5-1.00x10-2 M bromhexine within the pH range 2.0-4.5. The standard electrodes potentials were determined at different temperatures and used to calculate the isothermal coefficients of the electrodes, which were 0.00065 and 0.00050 Vô€±C-1 for (I) and (II), respectively. The electrodes showed a very good selectivity for bromhexine with respect to a number of inorganic cations, amino acids and sugars. The electrodes were applied to the potentiometric determination of bromhexine hydrochloride and its pharmaceutical preparation under batch and flow injection conditions. Graphite, copper and silver coated wires were prepared, characterized and successfully applied as sensors for the drug under investigation.
2-Determination of ambroxol or bromhexine in pharmaceuticals by capillary isotachophoresis
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Abstract
Expectorant drugs ambroxol (AX) and bromhexine (BX) were determined by capillary isotachophoresis (ITP) with conductimetric detection. The leading electrolyte (LE) was a buffer solution that contained 5 mM picolinic acid and 5 mM potassium picolinate (pH 5.2). The terminating electrolyte (TE) was 10 mM formic acid. The driving current was 80 μA (for≈200 s) or 50 μA (for≈350 s) and the detection current was 20 μA (a single analysis took about 8 min). The effective mobilities of AX and BX (evaluated with tetraethylammonium as the mobility standard) were 18.8Ã-10−9 m2 V−1 s−1 and 14.3Ã-10−9 m2 V−1 s−1 respectively. The calibration graphs relating the ITP zone length to the concentration of the analytes were rectilinear (r=0.9993-0.9999) in the range 10 mg l−1 (20 mg l−1 for BX) to 200 mg l−1 of the drug standard. The relative standard deviations (RSD) were 1.2-1.6% (n=6) when determining 100 mg l−1 of the analytes in pure test solutions. The method has been applied to the assay of AX or BX in seven commercial mass-produced pharmaceutical preparations. According to the validation procedure based on the standard addition technique the recoveries were 97.5-102.7% of the drug and the RSD values were 0.11-2.20% (n=6).
2.4 )chromatography methods for analysis of Bromhexine
1-LIQUID CHROMATOGRAPHIC METHOD FOR DETERMINATION OF
AMOXICILLIN TRIHYDRATE AND BROMHEXINE HYDROCHLORIDE IN ORAL DOSAGE FORMS
ABSTRACT
A simple highâ€performance liquid chromatographic method is reported for the simultaneous determination of Amoxicillin Trihydrate and Bromhexine Hydrochloride in oral dosage forms. Investigated drugs were resolved on HiQ Sil C18 (4.6 Ã- 250mm, 5μm) reverseâ€phase column, utilizing a mobile phase of Methanol: 0.02M Ammonium acetate, pH5 (adjusted with orthophosphoric acid 10% aqueous) 90:10v/v. Mobile phase was delivered at the flow rate of 1.0
ml/minute. Ultra violet Detection was carried out at 254nm. Separation was completed within 10 minutes. Calibration curves were linear with correlation coefficient 0.993 and 0.995 over a concentration range of 100â€300 μg/ml for Amoxicillin Trihydrate and 2â€10 μg/ml for Bromhexine Hydrochloride respectively. Recovery was between 99.5†101.32 percent and 98.93â€101.18 percent for Amoxicillin Trihydrate and Bromhexine Hydrochloride respectively.
Method was found to be reproducible with relative standard deviation (R.S.D) for intra and interday precision to be <1.5% over the said concentration range.
2-TLC Densitometric Determination of Bromhexine Hydrochloride in Pharmaceuticals, and Its Validation Journal of Liquid Chromatography & Related Technologies
Abstract
A simple and rapid densitometric method has been developed for determination of bromhexine hydrochloride in pharmaceutical preparations. After dilution or extraction of the analyte using a mixture of acetone-water (2:1), the extracts were spotted on pre-coated silica gel plates, which were then developed with a mixture of n-butanol-glacial acetic acid-water (26:7.5:7.5). Quantitative evaluation was performed by measuring the absorbance-reflectance of the analyte spots at 325 nm. The densitometric method is selective, precise, and accurate and can be used for routine analysis of pharmaceutical preparations in pharmaceutical industry quality control laboratories.
3-Simultaneous high-throughput determination of clenbuterol, ambroxol and bromhexinenext term in pharmaceutical formulations by HPLC with potentiometric detection
Abstract
Potentiometric detection of clenbuterol, ambroxol and previous termbromhexinenext term in marketed
pharmaceuticals was described in six isocratic HPLC systems. The podant- and macrocyclic-type neutral ionophores, N,N,N′,N′-tetracyclohexyl-oxybis(o-phenyleneoxy)diacetamide (TOPA) and hexakis(2,3,6-tri-O-octyl)-α-cyclodextrin (OCD), were applied in poly(vinyl)chloride (PVC)-based liquid membrane electrodes. Both types of neutral ionophores improve the sensitivity for all mentioned drugs when compared with a tetrakis(p-chlorophenyl)borate (BOR)-based electrode as well as with single wavelength UV detection. Detection limits (S/N=3) of 2.6Ã-10−10 mol l−1 (injected concentration) for the highly hydrophobic previous termbromhexinenext term were achieved with the TOPA-based electrode and a cyano reversed-phase (RP)-HPLC with Uptisphere® UP5CN-25QS silica column (250Ã-4.6 mm i.d.) eluted with acetonitrile (AcN)-ethanol-perchloric acid (1.66 mM) (60:2:38, v/v/v) (pH* 2.45). Comparable result was obtained with OCD-based electrodes and an XTerraâ„¢ RP18 hybrid silica-polymer column eluted with AcN-phosphoric acid (20 mM) (25:75, v/v) (pH* 2.60). In the mobile phases containing 60-75% v/v AcN or methanol, stable and reproducible response of both types of neutral ionophore-based electrodes was observed for at least 3 days. The results of the validated procedure for reliable simultaneous determination of the drugs in fortified representative samples of pharmaceuticals were also presented.
4-Simultaneous high-throughput determination of clenbuterol, ambroxol and bromhexinenext term in pharmaceutical formulations by HPLC with potentiometric detection
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Abstract
Potentiometric detection of clenbuterol, ambroxol and previous termbromhexinenext term in marketed
pharmaceuticals was described in six isocratic HPLC systems. The podant- and macrocyclic- type neutral ionophores, N,N,N′,N′-tetracyclohexyl-oxybis(o-phenyleneoxy)diacetamide (TOPA) and hexakis(2,3,6-tri-O-octyl)-α-cyclodextrin (OCD), were applied in poly(vinyl)chloride (PVC)-based liquid membrane electrodes. Both types of neutral ionophores improve the sensitivity for all mentioned drugs when compared with a tetrakis(p-chlorophenyl)borate (BOR)-based electrode as well as with single wavelength UV detection. Detection limits (S/N=3) of 2.6Ã-10−10 mol l−1 (injected concentration) for the highly hydrophobic previous termbromhexinenext term were achieved with the TOPA-based electrode and a cyano reversed-phase (RP)-HPLC with Uptisphere® UP5CN-25QS silica column (250Ã-4.6 mm i.d.) eluted with acetonitrile (AcN)-ethanol-perchloric acid (1.66 mM) (60:2:38, v/v/v) (pH* 2.45). Comparable result was obtained with OCD-based electrodes and an XTerraâ„¢ RP18 hybrid silica-polymer column eluted with AcN-phosphoric acid (20 mM) (25:75, v/v) (pH* 2.60). In the mobile phases containing 60-75% v/v AcN or methanol, stable and reproducible response of both types of neutral ionophore-based electrodes was observed for at least 3 days. The results of the validated procedure for reliable simultaneous determination of the drugs in fortified representative samples of pharmaceuticals were also presented.
(3) Discussion:
3.1 ) comparison between Spectrophotometric determination of bromhexine hydrochloride in pharmaceutical preparations & chromatography LIQUID CHROMATOGRAPHIC METHOD
1- Spectrophotometric determination of bromhexine hydrochloride in pharmaceutical preparations.
use of diazotization-coupling in classic Bratton-Marshall method . Spectrophotometric parameters were established for standardization of the method
use statistical analysis of data. Substances such as potassium guaiacolsulfonate, ampicillin, cephalexin, oxytetracycline HCl, amoxycillin, and
erythromycin ethylsuccinate do not interfere with the determination.
The precision of the method is about 2.0%.
2-LIQUID CHROMATOGRAPHIC METHOD FOR DETERMINATION OF
AMOXICILLIN TRIHYDRATE AND BROMHEXINE HYDROCHLORIDE IN ORAL DOSAGE FORMS
is reported for the simultaneous determination of Amoxicillin Trihydrate and Bromhexine Hydrochloride in oral dosage forms.
Investigated drugs were resolved on HiQ Sil C18 (4.6 Ã- 250mm, 5μm) reverseâ€phase column, utilizing a mobile phase of Methanol: 0.02M Ammonium acetate, pH5 (adjusted with orthophosphoric acid 10% aqueous) 90:10v/v.
Mobile phase was delivered at the flow rate of 1.0 ml/minute.
Ultra violet Detection was carried out at 254nm.
Separation was completed within 10 minutes.
Calibration curves were linear with correlation coefficient 0.993 and 0.995 over a concentration range of 100â€300 μg/ml for Amoxicillin Trihydrate and 2â€10 μg/ml for Bromhexine Hydrochloride respectively.
Recovery was between 99.5†101.32 percent for Bromhexine Hydrochloride
Method was found to be reproducible with relative standard deviation (R.S.D) for intra and interday precision to be <1.5% over the said concentration range.
conclusion
Quality Control is a major part of the quality assurance is the Quality Control defined by ISO as "the operational techniques and activities that are used to satisfy quality requirements. "
Bromhexine is a mucolytic drug that acts by diluting sticky secretion of cough and other related respiratory illness making phlegm easier to be taken out through expectoration.and there are several methods of analysis used for determination of Bromhexine as Microcomputer-aided titrimetric determination of bromine-containing active ingredients in some drug formulations and Spectrophotometric determination of bromhexine hydrochloride in pharmaceutical preparations.
And cough-cold syrups by absorption spectrophotometry and multivariate calibration using partial least-squares and hybrid linear analyses. Application of a novel method of wavelength selection and Chemiluminescence determination of bromhexine hydrochloride with morin as chemiluminescent reagent.,Determination of ambroxol or bromhexine in pharmaceuticals by capillary isotachophoresis, Simultaneous high-throughput determination of clenbuterol, ambroxol and bromhexinenext term in pharmaceutical formulations by HPLC with potentiometric detection, TLC Densitometric Determination of Bromhexine Hydrochloride in Pharmaceuticals, and Its Validation Journal of Liquid Chromatography and Related Technologies
