CN101865891A - Ambroxol hydrochloride detection method - Google Patents
Ambroxol hydrochloride detection method Download PDFInfo
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- CN101865891A CN101865891A CN 201010195713 CN201010195713A CN101865891A CN 101865891 A CN101865891 A CN 101865891A CN 201010195713 CN201010195713 CN 201010195713 CN 201010195713 A CN201010195713 A CN 201010195713A CN 101865891 A CN101865891 A CN 101865891A
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Abstract
The invention provides a method for measuring ambroxol and related substances trans-4-[6,8-dibromo-1,4-orexin-3(H)] cyclohexanol (impurity B) and 2-amino-3,5-dibromo-benzaldehyde (impurity A) in a preparation of the ambroxol, which is characterized in that: in the measurement of the trans-4-[6,8-dibromo-1,4-orexin-3(H)] cyclohexanol, an adopted detection wavelength is 258 nm and a chromatogram is recorded for a time that is 3 times the retention time of the main component; and the method for measuring the 2-amino-3,5-dibromo-benzaldehyde is characterized in that: the adopted detection wavelength is 238 nm and the chromatogram is recorded for the time that is 3 times the retention time of the main component.
Description
Technical field
The present invention relates to a kind of detection method of ambroxol hydrochloride, particularly a kind of method that adopts high effective liquid chromatography for measuring ambroxol hydrochloride content and related substance.
Background technology
Respiratory disease is a kind of common disease, frequently-occurring disease, and worldwide its incidence of disease is all higher, and the trend of increase is arranged, and it is China human mortality's a second largest factor.World population is just being stepped into astogeny at present, and the over-65s old man accounts for sizable ratio because of respiratory disease death.Breathe heavily, cough, phlegm, scorching four diseases is respiratory disease common symptons, reciprocal causation simultaneously.Phlegm is the product of respiratory inflammation, can stimulate respiratory mucosa, causes cough and asthma, and can increase the weight of to infect.When acute/chronic bronchitis or chronic lung diseases respiratory failure, too high or form the phlegm bolt as patient's sputum stickiness, can block respiratory tract and cause suffocating.Therefore, use glutinous phlegm correctives, make the glutinous phlegm dissolving of patient, thinning, viscosity reduces, and quickens the respiratory mucosa ciliary movement, improves transport function, has crucial meaning.
Ambroxol is the expectorant of present wide clinical application, is applicable to sticky, the expiratory dyspnea of sputum that acute and chronic respiratory disease (as acute and chronic bronchitis, bronchial astehma, bronchiectasis, chronic obstructive pneumonia, pulmonary tuberculosis, pulmonary emphysema, pneumoconiosis etc.) causes.Ambroxol also can be used for the perform the operation prophylactic treatment of back pulmonary complication and the treatment of the poverty-stricken disease of infant breathes simultaneously.
Ambroxol hydrochloride (ambroxol) is the metabolic product of bromhexine in human body, chemical name is anti--4[(2-amino-3,5-dibromobenzene methyl) amino] the cyclohexanol hydrochloride, be a kind of new glutinous phlegm dissolving medicine, be curative effect is affirmed and most widely used expelling phlegm drugs clinically at present.Early 1980s, ambroxol hydrochloride went on the market in Germany first.This medicine has pharmacological action more widely, comprising: can stimulate the secretion of bronchus mucus, make the sputum dilution, vicidity reduces; Increase the generation and the secretion of pulmonary surfactant, reduce the adhesive force of mucus and cilium; Can activate the mucus fibre function; Because the stickiness of sputum reduces, make antibacterials be easy to infiltrate, improve antibacterial effect.This product half life period is 7.5h.Its main combination with two kinds of glucosiduronates generates metabolic product, discharges through urine.
The important pathophysiological feature one that the high secretion of mucus is a chronic inflammatory airway disease can increase the weight of respiratory tract air flow and block, the acceleration pulmonary function descends, the mucus that air flue stores also becomes the good nutrient culture media of bacterial growth, cause the generation of infecting in the air flue and increase the weight of, and infection and follow-up inflammatory products further cause the high secretion of mucus, thereby the formation vicious cycle, the admission rate and the mortality ratio of increase disease.The viscoelasticity of air flue mucus is mainly by wherein glutinous albumen (mucin, MUC) determine that ambroxol hydrochloride can decompose polysaccharide part wherein, and increase the secretion of respiratory mucosa slurries body of gland, reduce the mucous gland secretion, thereby reduce the sputum viscosity, promote the effect that mucus is got rid of, the synthetic and secretion of alveolar surfactant, remarkable facilitation is arranged, increase the bronchus ciliary movement, play remarkable expectoration, improve the effect of breath state.
In addition, ambroxol hydrochloride can increase the penetrability of many microbiotic such as Amoxicillin, Cefixime, erythromycin, fortimicin to lung tissue, improves the concentration of this microbiotic at infection site.Therefore, when ambroxol hydrochloride and these microbiotic (Amoxicillin, cefuroxime, erythromycin, fortimicin) Synergistic treatment, can raise microbiotic at lung tissue concentration, raising germicidal efficiency.The security of ambroxol hydrochloride is very high.The poison exponent of ambroxol hydrochloride is very low in the acute toxicity test.Ambroxol hydrochloride does not have mutagenesis (Ames and micronucleus test).Carcinogenicity for mouse and rat studies show that, the ambroxol hydrochloride non-carcinogenesis.Still the report that does not have at present the clinical related reactions of share with other medicines.
The former producer of grinding of ambroxol hydrochloride is German Boehringer Ingelheim, and the said firm released the ambroxol hydrochloride parenteral solution first in 1979, and in import China in 2000, commodity were called Mucosolvin.Ambroxol hydrochloride parenteral solution (Mucosolvin, Yi Nuoshu) has been widely used in various acute and chronic pulmonary disease, the poverty-stricken syndrome of respiratory tract at present, has the effect that reduces the sputum viscosity, improves patient's expectoration function and pulmonary function, determined curative effect is suitable for the age broadness, and patient usually can fine tolerance.
At present, as follows to the condition determination of ambroxol hydrochloride related substance regulation in the Chinese Pharmacopoeia: it is an amount of to get test sample, add the moving phase dissolving and make the need testing solution that contains 1mg among every 1ml and every 1ml in contain the contrast solution of 10 μ g.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, make the major component peak height reach the 20%-25% of full scale, precision measures need testing solution and each 20 μ l of contrast solution inject liquid chromatograph, and the record chromatogram is to 2 times of major component peak retention time.In the need testing solution chromatogram if any impurity peaks, each impurity peak area and must not be greater than contrast solution main peak area, promptly total impurities must not surpass 1% of major component, wherein the chromatographic condition of Cai Yonging is a filling agent for the employing octadecylsilane chemically bonded silica; (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50) is a moving phase with the 0.01mol/L ammonium dibasic phosphate solution; The detection wavelength is 248nm.Yet, this method is to the mensuration insufficient sensitivity of ambroxol hydrochloride related substance, to the main composition in the impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol (impurity B) and 2-amino-3, the assay of 5-dibromo benzaldehyde (impurity A) is inaccurate, and the content of the related substance that records makes the quality controllability of ambroxol be affected than actual little.
Therefore, prior art still needs the method for its related substances in a kind of accurate and effective mensuration ambroxol.
Summary of the invention
The present inventor is through a large amount of creative works, by screening, find to detect wavelength by adjusting, and the retention time that will show in the technology extends to more than 3 times or 3 times of major component retention time, quantitative measurement goes out main composition in the impurity exactly trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol-(impurity B) and 2-amino-3, the content of 5-dibromo benzaldehyde (impurity A), thus the present invention finished.
The invention provides in a kind of mensuration ambroxol hydrochloride and the preparation thereof related substance trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] method of cyclohexanol (being related substance B), it is characterized in that the detection wavelength that adopts is 258nm, the record chromatogram is to 3 times of main composition retention time.
The present invention also provides related substance 2-amino-3 in a kind of mensuration ambroxol hydrochloride and the preparation thereof, and the method for 5-dibromo benzaldehyde (being related substance A) is characterized in that the detection wavelength that adopts is 238nm, and the record chromatogram is to 3 times of main composition retention time.
In mensuration ambroxol hydrochloride provided by the invention and the preparation thereof related substance trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] method of cyclohexanol (impurity B) comprises the steps:
1, it is an amount of to get test sample, adds moving phase and is diluted to debita spissitudo, as need testing solution;
2, it is an amount of to measure above need testing solution, adds 100 times of moving phase dilutions, in contrast solution;
3, precision is measured contrast solution injection liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).
4, negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density solution, as trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution;
5, precision measure need testing solution and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution is an amount of, injects liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.
Wherein, the chromatographic condition of employing is as follows, detects wavelength 258nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).
In the method for the present invention, the concentration of need testing solution is 100-2000 μ g/ml; Preferred 500-1000 μ g/ml; 750 μ g/ml most preferably.Trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] concentration of cyclohexanol reference substance is 0.3-6.0 μ g/ml; Preferred 1.5-3.0 μ g/ml; 2.25 μ g/ml most preferably.Inject the need testing solution of liquid chromatograph and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] volume of cyclohexanol reference substance solution is 5-200 μ l; Preferred 10-50 μ l; 20 μ l most preferably.
Related substance 2-amino-3 in mensuration ambroxol hydrochloride provided by the invention and the preparation thereof, the method for 5-dibromo benzaldehyde (impurity A) comprises the steps:
1, it is an amount of to get test sample, adds moving phase and is diluted to debita spissitudo, as need testing solution;
2, it is an amount of to get above need testing solution, adds 100 times of moving phase dilutions, in contrast solution;
3, precision is measured contrast solution injection liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).
4, get 2-amino-3,5-dibromo benzaldehyde reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density solution, as 2-amino-3,5-dibromo benzaldehyde reference substance solution;
5, precision is measured need testing solution and 2-amino-3, and 5-dibromo benzaldehyde reference substance solution is an amount of, injects liquid chromatograph respectively, and the record chromatogram is to 3 times of main composition retention time;
Wherein, the chromatographic condition of employing is as follows, detects wavelength 238nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).
In the method for the present invention, the concentration of need testing solution is 100-2000 μ g/ml; Preferred 500-1000 μ g/ml; 750 μ g/ml most preferably.2-amino-3, the concentration of 5-dibromo benzaldehyde reference substance are 0.2-4.0 μ g/ml; Preferred 1.0-2.0 μ g/ml; 1.5 μ g/ml most preferably.Inject the need testing solution and the impurity 2-amino-3 of liquid chromatograph, the volume of 5-dibromo benzaldehyde reference substance solution is 5-200 μ l; Preferred 10-50 μ l; 20 μ l most preferably.
Further, the invention provides a kind of method of measuring related substance in ambroxol hydrochloride and the preparation thereof, may further comprise the steps: it is an amount of that precision is measured test sample, adds moving phase and be diluted to scale, shakes up, as need testing solution.It is an amount of that precision is measured need testing solution, adds 100 times of moving phase dilutions, in contrast solution; Other gets impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol (impurity B) reference substance solution; Get impurity 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, accurate claims surely, and with the moving phase dissolving and be diluted to certain density 2-amino-3,5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3, and 5-dibromo benzaldehyde (impurity A) reference substance solution.Precision is measured contrast solution and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).(1) adopting octadecylsilane chemically bonded silica is filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50), detect wavelength 258nm, precision is measured need testing solution and impurity B reference substance solution, injects liquid chromatograph respectively, and the record chromatogram is to 3 times of main composition retention time.(2) adopting octadecylsilane chemically bonded silica is filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50), detect wavelength 238nm, precision is measured need testing solution and impurity A contrast solution, injects liquid chromatograph respectively, and the record chromatogram is to 3 times of main composition retention time.
In the above method, the concentration of need testing solution is 100-2000 μ g/ml; Preferred 500-1000 μ g/ml; 750 μ g/ml most preferably.The concentration of impurity B reference substance is 0.3-6.0 μ g/ml; Preferred 1.5-3.0 μ g/ml; 2.25 μ g/ml most preferably.The concentration of impurity A reference substance is 0.2-4.0 μ g/ml; Preferred 1.0-2.0 μ g/ml; 1.5 μ g/ml most preferably.Injecting the need testing solution of liquid chromatograph and the volume of impurity B and impurity A reference substance solution is 5-200 μ l; Preferred 10-50 μ l; 20 μ l most preferably.
Description of drawings
Fig. 1 adopts the inventive method to measure the need testing solution high-efficient liquid phase chromatogram of impurity B in the ambroxol hydrochloride raw material
Fig. 2 adopts the inventive method to measure the high-efficient liquid phase chromatogram of the reference substance solution of impurity B in the ambroxol hydrochloride raw material
Fig. 3 adopts the inventive method to measure the need testing solution high-efficient liquid phase chromatogram of impurity A in the ambroxol hydrochloride raw material
Fig. 4 adopts the inventive method to measure the high-efficient liquid phase chromatogram of the reference substance solution of impurity A in the ambroxol hydrochloride raw material
Fig. 5 adopts the inventive method to measure the need testing solution high-efficient liquid phase chromatogram of impurity B in the ambroxol hydrochloride parenteral solution
Fig. 6 adopts the inventive method to measure the high-efficient liquid phase chromatogram of the reference substance solution of impurity B in the ambroxol hydrochloride parenteral solution
Fig. 7 adopts the inventive method to measure the need testing solution high-efficient liquid phase chromatogram of impurity A in the ambroxol hydrochloride parenteral solution
Fig. 8 adopts the inventive method to measure the high-efficient liquid phase chromatogram of the reference substance solution of impurity A in the ambroxol hydrochloride parenteral solution
Fig. 9 adopts official method to measure the need testing solution high-efficient liquid phase chromatogram of related substance in the ambroxol hydrochloride raw material
Figure 10 adopts official method to measure the reference substance solution high-efficient liquid phase chromatogram of related substance in the ambroxol hydrochloride raw material
Figure 11 adopts official method to measure the need testing solution high-efficient liquid phase chromatogram of related substance in the ambroxol hydrochloride parenteral solution
Figure 12 adopts official method to measure the reference substance solution high-efficient liquid phase chromatogram of related substance in the ambroxol hydrochloride parenteral solution
Embodiment
Following examples of the present invention only are used for illustrating and realize technical scheme of the present invention that these embodiments do not constitute further qualification to the present invention.Those skilled in the art according to existing knowledge the present invention are equal to replacement or corresponding logic is improved, and all belong to scope of the present invention.
The related substance of embodiment 1 high effective liquid chromatography for measuring ambroxol hydrochloride raw material
Precision is measured the about 37.5mg of ambroxol hydrochloride, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, as need testing solution.Precision is measured need testing solution 1ml and is put in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Other is negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to every ml contain the impurity of 2.25 μ g trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol (impurity B) reference substance solution; Get 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, and accurate the title decides, with moving phase dissolving and be diluted to the impurity 2-amino-3 that every ml contains 1.5 μ g, 5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3,5-dibromo benzaldehyde (impurity A) reference substance solution.
Adopt high performance liquid chromatography, chromatographic condition is: octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are moving phase, wavelength 248nm.Precision is measured contrast solution 20 μ l and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale.
(1) adopting octadecylsilane chemically bonded silica is filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 258nm, precision is measured need testing solution and each 20 μ l of impurity B reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.Specifically see Fig. 1 and Fig. 2.
(2) precision is measured need testing solution 20 μ l, adopts following chromatographic condition, and octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 238nm, precision is measured need testing solution and each 20 μ l of impurity A reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.Specifically see Fig. 3 and Fig. 4.
Precision is measured ambroxol hydrochloride parenteral solution (15mg/2ml) 5ml, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, as need testing solution.Precision is measured need testing solution 1ml and is put in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Other is negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to every ml contain the impurity of 2.25 μ g trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution; Get 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, and accurate the title decides, with moving phase dissolving and be diluted to the impurity 2-amino-3 that every ml contains 1.5 μ g, 5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3,5-dibromo benzaldehyde (impurity A) reference substance solution.
Adopt high performance liquid chromatography, chromatographic condition is: octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are moving phase, wavelength 248nm.Precision is measured contrast solution 20 μ l and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale.
(1) adopting octadecylsilane chemically bonded silica is filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 258nm, precision is measured need testing solution and each 20 μ l of impurity B reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.Specifically see Fig. 5 and Fig. 6.
(2) precision is measured need testing solution 20 μ l, adopts following chromatographic condition, and octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 238nm, precision is measured need testing solution and each 20 μ l of impurity A reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.Specifically see Fig. 7 and Fig. 8.
Comparative example 1 adopts official method to measure the related substance of ambroxol hydrochloride raw material
It is an amount of to get among the embodiment 1 the ambroxol hydrochloride raw material that adopts, add the moving phase dissolving and make the need testing solution that contains 0.75mg among every 1ml and every 1ml in contain the contrast solution of 7.5 μ g.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, make the major component peak height reach the 20%-25% of full scale, precision measures need testing solution and each 20 μ l of contrast solution inject liquid chromatograph, and the record chromatogram is to 2 times of major component peak retention time.In the need testing solution chromatogram if any impurity peaks, each impurity peak area and must not be greater than contrast solution main peak area, promptly total impurities must not surpass 1% of major component, wherein the chromatographic condition of Cai Yonging is a filling agent for the employing octadecylsilane chemically bonded silica; (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50) is a moving phase with the 0.01mol/L ammonium dibasic phosphate solution; The detection wavelength is 248nm.Its chromatogram is seen Fig. 9 and Figure 10.
Comparative example 2 adopts official method to measure the related substance of ambroxol hydrochloride parenteral solution
It is an amount of to get among the embodiment 2 the ambroxol hydrochloride parenteral solution that adopts, add the moving phase dissolving and make the need testing solution that contains 0.75mg among every 1ml and every 1ml in contain the contrast solution of 7.5 μ g.Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, make the major component peak height reach the 20%-25% of full scale, precision measures need testing solution and each 20 μ l of contrast solution inject liquid chromatograph, and the record chromatogram is to 2 times of major component peak retention time.In the need testing solution chromatogram if any impurity peaks, each impurity peak area and must not be greater than contrast solution main peak area, promptly total impurities must not surpass 1% of major component, wherein the chromatographic condition of Cai Yonging is a filling agent for the employing octadecylsilane chemically bonded silica; (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50) is a moving phase with the 0.01mol/L ammonium dibasic phosphate solution; The detection wavelength is 248nm.Its chromatogram is seen Figure 11 and Figure 12.
Experimental example 1 adopts the inventive method and official method quantitative measurement ambroxol related substance relatively
From measurement result as can be seen, adopt method of the present invention, the content of the related substance of measuring is higher than the content that adopts the related substance that official method determines far away, can control the quality of ambroxol better.
Claims (9)
1. measure in ambroxol hydrochloride and the preparation thereof related substance trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] method of cyclohexanol comprises the steps:
1) it is an amount of to get test sample, adds moving phase and is diluted to debita spissitudo, as need testing solution;
2) measure above need testing solution, add 100 times of moving phase dilutions, in contrast solution;
3) precision is measured contrast solution injection liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50);
4) negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density solution, as trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution;
5) precision measure need testing solution and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution is an amount of, injects liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time; The chromatographic condition that adopts is as follows, detects wavelength 258nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50).
2. according to the process of claim 1 wherein, the concentration of need testing solution is 750 μ g/ml; Trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] concentration of cyclohexanol reference substance is 2.25 μ g/ml; Inject the need testing solution of liquid chromatograph and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] volume of cyclohexanol reference substance solution is 20 μ l.
3. measure related substance 2-amino-3 in ambroxol hydrochloride and the preparation thereof for one kind, the method for 5-dibromo benzaldehyde comprises the steps:
1) test sample is an amount of, adds moving phase and is diluted to debita spissitudo, as need testing solution;
2) measure above need testing solution 1ml and put in the 100ml measuring bottle, add moving phase and be diluted to scale, in contrast solution;
3) precision is measured contrast solution injection liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50);
4) get 2-amino-3,5-dibromo benzaldehyde reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density solution, as 2-amino-3,5-dibromo benzaldehyde reference substance solution;
5) precision is measured need testing solution and 2-amino-3, and 5-dibromo benzaldehyde reference substance solution is an amount of, injects liquid chromatograph respectively, and the record chromatogram is to 3 times of main composition retention time; The chromatographic condition that adopts is as follows, detects wavelength 238nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (50: 50).
4. according to the method for claim 3, wherein, the concentration of need testing solution is 750 μ g/ml; 2-amino-3, the concentration of 5-dibromo benzaldehyde reference substance are 1.5 μ g/ml; Inject the need testing solution and the impurity 2-amino-3 of liquid chromatograph, the volume of 5-dibromo benzaldehyde reference substance solution is 20 μ l.
5. a method of measuring related substance in ambroxol hydrochloride and the preparation thereof comprises the steps:
It is an amount of that precision is measured test sample, adds moving phase and be diluted to scale, shakes up, as need testing solution.It is an amount of that precision is measured need testing solution, adds 100 times of moving phase dilutions, in contrast solution; Other gets impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to certain density trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution; Get impurity 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, accurate claims surely, and with the moving phase dissolving and be diluted to certain density 2-amino-3,5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3, and 5-dibromo benzaldehyde reference substance solution.According to following chromatographic condition, precision is measured contrast solution and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale, and chromatographic condition is for detecting wavelength 248nm, and octadecylsilane chemically bonded silica is a filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50).(1) adopting octadecylsilane chemically bonded silica is filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50), detect wavelength 258nm, precision measure need testing solution and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.(2) adopting octadecylsilane chemically bonded silica is filling agent; Moving phase is 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50), detect wavelength 238nm, precision is measured need testing solution and impurity 2-amino-3,5-dibromo benzaldehyde reference substance solution, according to the chromatographic condition under the assay item, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.
6. according to the method for claim 5, wherein, the concentration of need testing solution is 750 μ g/ml; Impurity is trans-4-[6, and 8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol and impurity 2-amino-3, the concentration of 5-dibromo benzaldehyde reference substance is respectively 2.25 μ g/ml and 1.5 μ g/ml; Need testing solution, contrast solution, the impurity that injects liquid chromatograph is trans-4-[6, and 8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol and impurity 2-amino-3, the volume of 5-dibromo benzaldehyde reference substance solution is 20 μ l.
7. method of measuring related substance in the ambroxol parenteral solution, may further comprise the steps: precision is measured ambroxol hydrochloride parenteral solution 5ml, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, as need testing solution.Precision is measured need testing solution 1ml and is put in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Other is negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to every ml contain the impurity of 2.25 μ g trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution; Get 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, accurate claims surely, and with the moving phase dissolving and be diluted to the impurity 2-amino-3 that every ml contains 1.5 μ g, 5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3, and 5-dibromo benzaldehyde reference substance solution;
Adopt high performance liquid chromatography, chromatographic condition is: octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are moving phase, wavelength 248nm.Precision is measured contrast solution 20 μ l and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale;
(1) adopting octadecylsilane chemically bonded silica is filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 258nm, precision measure need testing solution and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] each 20 μ l of cyclohexanol reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time;
(2) precision is measured need testing solution 20 μ l, adopts following chromatographic condition, and octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 238nm, precision is measured need testing solution and impurity 2-amino-3, each 20 μ l of 5-dibromo benzaldehyde reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.
8. according to the method for claim 7, wherein the specification of parenteral solution is 2ml, contains the 15mg ambroxol hydrochloride; Perhaps specification is 4ml, contains the 30mg ambroxol hydrochloride.
9. method of measuring ambroxol hydrochloride, may further comprise the steps: precision is measured the about 37.5mg of ambroxol hydrochloride, puts in the 50ml measuring bottle, adds moving phase and is diluted to scale, shakes up, as need testing solution.Precision is measured need testing solution 1ml and is put in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, in contrast solution; Other is negate formula-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance is an amount of, accurate claim fixed, with the moving phase dissolving and be diluted to every ml contain the impurity of 2.25 μ g trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] cyclohexanol solution, shake up, as impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] the cyclohexanol reference substance solution; Get 2-amino-3 again, 5-dibromo benzaldehyde reference substance is an amount of, accurate claims surely, and with the moving phase dissolving and be diluted to the impurity 2-amino-3 that every ml contains 1.5 μ g, 5-dibromo benzaldehyde solution shakes up, as impurity 2-amino-3, and 5-dibromo benzaldehyde reference substance solution;
Adopt high performance liquid chromatography, chromatographic condition is: octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are moving phase, wavelength 248nm.Precision is measured contrast solution 20 μ l and is injected liquid chromatograph, regulates instrumental sensitivity, makes the peak height of major component chromatographic peak be about 20% of registering instrument full scale;
(1) adopting octadecylsilane chemically bonded silica is filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 258nm, precision measure need testing solution and impurity trans-4-[6,8-two bromo-1,4-dihydroquinazoline-3 (H)] each 20 μ l of cyclohexanol reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time;
(2) precision is measured need testing solution 20 μ l, adopts following chromatographic condition, and octadecylsilane chemically bonded silica is a filling agent; Get 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH value to 7.0): acetonitrile=(50: 50) are the moving phase chromatographic condition, detect wavelength 238nm, precision is measured need testing solution and 2-amino-3, each 20 μ l of 5-dibromo benzaldehyde reference substance solution, inject liquid chromatograph respectively, the record chromatogram is to 3 times of main composition retention time.
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| CN102262135A (en) * | 2011-06-17 | 2011-11-30 | 成都金典药物科技开发有限公司 | Method for detecting impurities in ambroxol hydrochloride injection and content determination method |
| CN104316482A (en) * | 2014-08-15 | 2015-01-28 | 河北菲尼斯生物技术有限公司 | A quality control method for ambroxol hydrochloride particles |
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| CN104316482A (en) * | 2014-08-15 | 2015-01-28 | 河北菲尼斯生物技术有限公司 | A quality control method for ambroxol hydrochloride particles |
| CN104597025A (en) * | 2014-09-01 | 2015-05-06 | 浙江康恩贝制药股份有限公司 | Content and impurity detection method for ambroxol hydrochloride injection |
| CN107764905A (en) * | 2016-08-19 | 2018-03-06 | 江苏康缘药业股份有限公司 | A kind of ether compound of quinazoline 7 and its detection method about material |
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| CN106478524A (en) * | 2016-10-11 | 2017-03-08 | 合肥久诺医药科技有限公司 | A kind of preparation method of ambroxol hydrochloride impurity standard substance |
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| CN110229111A (en) * | 2019-05-08 | 2019-09-13 | 梯尔希（南京）药物研发有限公司 | Ambroxol impurity and the preparation method and application thereof |
| CN110229111B (en) * | 2019-05-08 | 2022-03-15 | 梯尔希（南京）药物研发有限公司 | Ambroxol impurity and preparation method and application thereof |
| CN112540137A (en) * | 2020-12-08 | 2021-03-23 | 合肥远志医药科技开发有限公司 | Method for detecting organic impurities in ambroxol hydrochloride oral solution |
| CN114137093A (en) * | 2021-09-03 | 2022-03-04 | 山东齐都药业有限公司 | Method for detecting trans-4-aminocyclohexanol in ambroxol hydrochloride injection |
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