CN104267122A - Method for detecting related substances of azithromycin eye drops - Google Patents
Method for detecting related substances of azithromycin eye drops Download PDFInfo
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- CN104267122A CN104267122A CN201410499659.6A CN201410499659A CN104267122A CN 104267122 A CN104267122 A CN 104267122A CN 201410499659 A CN201410499659 A CN 201410499659A CN 104267122 A CN104267122 A CN 104267122A
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Abstract
The invention provides a method for detecting related substances of azithromycin eye drops. The method comprises the steps of preprocessing a test solution of the azithromycin eye drops by virtue of a cation exchange resin column, testing a processed to-be-tested solution by virtue of an HPLC, and calculating the contents of the related substances by virtue of an area normalization method or an external standard method. According to the method provided by the invention, the interference of ionic compounds, particularly cationic compounds such as benzalkonium chloride, on the detection of the related substances of the azithromycin eye drop can be effectively eliminated, and the contents of the related substances in the azithromycin eye drops are effectively and accurately measured.
Description
Technical field
The present invention relates to field of medicine and chemical technology, relate to a kind of detection method of related substance of Azithromycin eye-drops more specifically.
Background technology
Azithromycin is fifteen-membered ring macrolide antibiotics, has a broad antifungal spectrum, and except having antibacterial action to most of bacterium, chlamydia, mycoplasma also have good activity.Mechanism of action is identical with erythromycin, is mainly combined with the 50S subunit of bacterial ribosome, suppresses the albumen synthesis depending on RNA.Clinical acpuei pharyngitis, the acute tonsillitis being widely used in micrococcus scarlatinae and causing; The nasosinusitis that sensitive bacterial causes, tympanitis, acute bronchitis, AECB; Pneumonia caused by streptococcus pneumonia, haemophilus influenzae and mycoplasma pneumoniae; Chlamydia trachomatis and the urethritis caused by non-several drug resistance NEISSERIA GONORRHOEAE and cervicitis; The skin soft-tissue infection that sensitive bacterial causes.
At present, azithromycin can be made into various dosage form, and as tablet, dispersing tablet, injection, dry suspensoid agent, injection and eye drops etc., these formulations commercially all have sale.
Usually also have in Azithromycin eye-drops outside azithromycin, also can containing a series of auxiliary materials comprising antiseptic.Benzalkonium chloride is common antiseptic.As, containing the benzalkonium chloride of 0.003% in the AZASITE Azithromycin eye-drops that FDA ratifies for 2007 first.
Benzalkonium chloride as a kind of common medical antiseptic, its structural formula:
Wherein, n=8,10,12,14,16 or 18, the benzalkonium chloride composition that different manufacturers is produced is inconsistent, may be the benzalkonium chloride only having n=8, also may containing wherein several.Do not affect it containing multiple benzalkonium chloride to use in Azithromycin eye-drops as antiseptic.
Benzalkonium chloride is white waxy solid or yellow colloidal body, in the aobvious neutral or faintly alkaline reaction of aqueous solution, produces volume foam during jolting.Benzalkonium chloride very easily dissolves in water or ethanol, slightly soluble in ether, and belong to Cidex-7 class, it is dissociated into cationic reactive groups in aqueous, is a kind of cationic surfactant.
Benzalkonium chloride belongs to cationic antiseptic, and the solubleness in water is better, poor in the solubleness of organic phase.The retention of ionic compound in the reverse-phase chromatography being Stationary liquid with octadecylsilane Bonded Phase is all bad.In repeatedly analyte detection process, benzalkonium chloride retention time is unstable, and drift is very serious, and poor repeatability, therefore affects specificity and the accurate quantitative analysis of other impurity in Azithromycin eye-drops.In fact, all similar ionic compounds all can affect the accurate detection of other related substances of azithromycin because retention time is unstable.
In a kind of Azithromycin slow-release of prior art eye drops, the content assaying method (CN102590392B) of azithromycin discloses a kind of HPLC method getting rid of the potency of azithromycin of eye drops in polycarbophil interference Accurate Determining azithromycin.
The detection method (CN 103245744A) of prior art azithromycin injection related substance, it comprises: get azithromycin B reference substance, and be solution with sodium chloride injection dilution, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to injection rate IR, until when there is dead mouse result in the retrial of the test of a certain azithromycin B injection rate IR, injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of azithromycin B; According to same method, measure the injection rate IR limit of azithromycin Gx and Erythromycin A iminoether; The content C of above-mentioned three kinds of materials and azithromycin in quantitative test medicine to be measured; According to each research on maximum utilized quantity and formulae discovery, obtain the l.o.i W1 of three kinds of related substances, W2 and W3; If≤W1, and≤W2, and≤W3, then the relevant thing content of medicine reaches security level, otherwise does not reach security level, and then reaches the object achieving quantitative evaluation.
Therefore in the prior art, all openly do not solve ionic compound (as preservative benzalkonium chloride) and affect the method that Azithromycin eye-drops related substance accurately detects.
The invention provides the method that one can get rid of ionic compound (as preservative benzalkonium chloride) interference that related substance detects in Azithromycin eye-drops, and then reach the related substance of Accurate Determining Azithromycin eye-drops.
Summary of the invention
Summary of the invention
The present inventor by test of many times, finally obtains one and effectively gets rid of the method that ionic compound (as preservative benzalkonium chloride) disturbs Azithromycin eye-drops related substance to detect.The method make use of ion exchange resin to eliminate ionic compound (as preservative benzalkonium chloride) in Azithromycin eye-drops sample solution, overcome when to detect difference/same batch Azithromycin eye-drops related substance under different time identical chromatographic conditions, because of ionic compound (as preservative benzalkonium chloride), to go out peak position drift indefinite and cause the problem of interference, ensure that each impurity accuracy detects simultaneously, as peak area, be not affected.Whether the application of usual sample-pretreating method in concrete analytical approach be suitable, is not that those skilled in the art can predict, needs tried inspection just can determine.
The invention provides a kind of Azithromycin eye-drops related substance detection method, described method specificity is good, favorable reproducibility.
Term definition
The present invention " v/v " refers to volume ratio.
Detailed Description Of The Invention
Azithromycin eye-drops related substance detection method provided by the invention, is characterized in that:
A) get Azithromycin eye-drops sample solution, remove ionic compound by ion exchange resin column, then obtain Azithromycin eye-drops liquid to be measured by the organic membrane filtration being connected to ion-exchange column outlet;
B) liquid to be measured configured is injected HPLC to detect, measure the content of Azithromycin eye-drops related substance;
C) measure the percentage composition of each impurity by area normalization method or calculate the content of each impurity by external standard method.
The ionic compound of removing of the present invention can be by anion-exchange resin column removing anionic compound or remove cationic compound by cation exchange resin column.
The method of described cation exchange resin column removing ionic compound first gets Azithromycin eye-drops sample solution quickly through cation exchange resin column, rinse adsorption column; Get above-mentioned Azithromycin eye-drops sample solution again and slowly add cation exchange resin column, leave standstill, discard just filtrate, get subsequent filtrate as Azithromycin eye-drops liquid to be measured.Time of repose can be 10 ~ 20min.
In certain embodiments, referred to by using cation exchange resin column removing preservative benzalkonium chloride by cation exchange resin column removing ionic compound.
In certain embodiments, the cation exchange resin column used, preparation method: get 001 × 7 type Zeo-karb and be about 500g, with 95% (volume ratio) alcohol immersion 24h, washes with water to without alcohol taste; The hydrochloric acid solution adding 1mol/L again soaks 4h, washes with water to neutrality; Soak 4h with 1mol/L sodium hydrate aqueous solution again, wash with water to neutrality; Finally soak with dilution and preserve, wherein said dilution is the mixed solution of the 1.73g/L ammonium dihydrogen phosphate aqueous solution-acetonitrile-methanol regulating about pH10.0 with ammoniacal liquor, and volume ratio is 7:6:7; Before use, get Zeo-karb, with Buchner funnel suction filtration to not dripping, load in the syringe of a small amount of absorbent cotton of bottom pad.
In certain embodiments, Azithromycin eye-drops related substance detection method provided by the invention, wherein the chromatographic condition of HPLC can be:
Instrument: high performance liquid chromatograph;
Chromatographic column: waters Xbridge C18,4.6 × 250mm, 5um;
Detecting device: UV-detector, determined wavelength 210nm;
Flow velocity: 1.0mL/min;
Column temperature: 60 DEG C;
Sample size: 100 μ L;
Gradient elution mode
Mobile phase A: take in ADSP 1.8g to 1L water, adds phosphoric acid,diluted or diluted sodium hydroxide solution adjusts pH to 8.9;
Mobile phase B: acetonitrile: methyl alcohol=3:1, volume ratio;
Working time: 93min.
Azithromycin eye-drops related substance detection method provided by the present invention, effectively can get rid of ionic compound in Azithromycin eye-drops to the interference of other related substance Accurate Determinings, particularly get rid of preservative benzalkonium chloride to the interference of other related substance Accurate Determinings, be suitable for the content measuring Azithromycin eye-drops related substance.
Accompanying drawing explanation
Fig. 1 shows the detection chromatogram of sample 1 in embodiment 1
Fig. 2 shows the detection chromatogram of sample 2 in embodiment 1
Fig. 3 shows the detection chromatogram of sample 3 in embodiment 1
Fig. 4 shows the detection chromatogram of sample 4 in embodiment 1
Fig. 5 shows the detection chromatogram of sample 5 in embodiment 2
Fig. 6 shows the detection chromatogram of sample 6 in embodiment 2
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
The preservative benzalkonium chloride that in embodiment 1, Azithromycin eye-drops is used only has n=12 benzalkonium chloride.
The preservative benzalkonium chloride that in embodiment 2, Azithromycin eye-drops is used includes n=12 and n=14 two kinds of benzalkonium chlorides.
Embodiment 1
Get Azithromycin eye-drops (AZASITE) about 10.0g, accurately weighed, put in 50mL measuring bottle, add dilution and be about 30mL, jolting 20min, then be settled to scale with dilution, shake up.Get supernatant 5mL, organic filter membrane (nylon, 0.45 μm, Φ 13mm, Tianjin is risen) filter, get subsequent filtrate, obtain the Azithromycin eye-drops liquid to be measured without Zeo-karb process.
Chromatographic condition:
Instrument: high performance liquid chromatograph;
Chromatographic column: waters Xbridge C18,4.6 × 250mm, 5um;
Detecting device: UV-detector, determined wavelength 210nm;
Flow velocity: 1.0mL/min;
Column temperature: 60 DEG C;
Sample size: 100 μ L;
Gradient elution mode
Mobile phase A: take in ADSP 1.8g to 1L water, adds phosphoric acid,diluted or diluted sodium hydroxide solution adjusts pH to 8.9;
Mobile phase B: acetonitrile: methyl alcohol=3:1, volume ratio;
Working time: 93min.
At different time by above-mentioned sample preparation method sample, be respectively sample 1,2,3,4, under identical chromatographic condition, under same detection environment, sample detection investigates the reservation situation of benzalkonium chloride.And pass through the position of sample introduction benzalkonium chloride reference substance determination benzalkonium chloride.
Detect 4 liquid to be measured of the Azithromycin eye-drops without Zeo-karb process respectively, detect collection of illustrative plates and see Fig. 1, Fig. 2, Fig. 3 and Fig. 4.
Testing result is as table 1
Show that benzalkonium chloride is detecting the instability of the retention time in sample, can constantly drift about through table results table 1 and profiling results Fig. 1, Fig. 2, Fig. 3 and Fig. 4.
Embodiment 2
Azithromycin eye-drops without Zeo-karb process liquid to be measured, hereinafter referred to as sample 5, prepares by embodiment 1 method.
Get Azithromycin eye-drops (AZASITE) about 10.0g, accurately weighed, put in 50mL measuring bottle, add dilution and be about 30mL, jolting 20min, then be settled to scale with dilution, shake up.Get supernatant 5mL, quickly through cation exchange resin column (rinse adsorption column), be connected with machine filter film (nylon, 0.45 μm, Φ 13mm, Tianjin is risen), then get supernatant 3mL, slowly add cation exchange resin column, filter after leaving standstill 15min, discard just filtrate 2mL, get subsequent filtrate and namely obtain Azithromycin eye-drops liquid to be measured after Zeo-karb process, hereinafter referred to as sample 6.
Chromatographic condition:
Instrument: high performance liquid chromatograph;
Chromatographic column: waters Xbridge C18,4.6 × 250mm, 5um;
Detecting device: UV-detector, determined wavelength 210nm;
Flow velocity: 1.0mL/min;
Column temperature: 60 DEG C;
Sample size: 100 μ L;
Gradient elution mode
Mobile phase A: take in ADSP 1.8g to 1L water, adds phosphoric acid,diluted or diluted sodium hydroxide solution adjusts pH to 8.9;
Mobile phase B: acetonitrile: methyl alcohol=3:1, volume ratio;
Working time: 93min.
Sample detection sample 5 and sample 6 under identical chromatographic condition, record chromatogram, investigates after cation exchange resin column process, the removal situation of benzalkonium chloride and the detection case of each impurity in sample.Testing result is as table 2, and chromatogram is as Fig. 5 and Fig. 6.
Visible, effectively get rid of the interference of benzalkonium chloride after treatment, little to each defects inspecting Influence on test result.
Table 2
To sum up embodiment 1 and embodiment 2 known, embodiment 1 shows that the related substance of the Azithromycin eye-drops containing benzalkonium chloride detects, and benzalkonium chloride will have a strong impact on the detection of the related substance of Azithromycin eye-drops due to peak transience.Embodiment 2 shows that the liquid to be measured of the Azithromycin eye-drops after cation exchange resin column detects, and effectively can get rid of the interference of benzalkonium chloride; Azithromycin eye-drops liquid to be measured testing result before and after the process of contrast cation exchange resin column is known, and the fluctuation of each impurity of the liquid to be measured after cation exchange resin column process is little, and maximum percentage composition deviation is 0.05%, and error is less.
Therefore a kind of Azithromycin eye-drops related substance detection method provided by the invention, effectively can get rid of the interference of benzalkonium chloride or other ionic compounds, the related substance of Accurate Determining Azithromycin eye-drops.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (7)
1. an Azithromycin eye-drops related substance detection method, is characterized in that:
A) get Azithromycin eye-drops sample solution, remove ionic compound by ion exchange resin column, then obtain Azithromycin eye-drops liquid to be measured by the organic membrane filtration being connected to ion-exchange column outlet;
B) liquid to be measured configured is injected HPLC to detect, measure the content of Azithromycin eye-drops related substance;
C) measure the percentage composition of each impurity by area normalization method or calculate the content of each impurity by external standard method.
2. method according to claim 1, wherein said is remove anionic compound by anion-exchange resin column or remove cationic compound by cation exchange resin column by ion exchange resin column removing ionic compound.
3., according to the method for claim 1 or 2, by the method for ion exchange resin column removing ionic compound be wherein:
A) Azithromycin eye-drops sample solution is first got by ion exchange resin column, rinse adsorption column;
B) get above-mentioned Azithromycin eye-drops sample solution again and add ion exchange resin column, leave standstill;
C) discard just filtrate, get subsequent filtrate as Azithromycin eye-drops liquid to be measured.
4. method according to claim 3, wherein said time of repose is 10 ~ 20min.
5. method according to claim 4, wherein ion exchange resin column removing ionic compound removes benzalkonium chloride by cation exchange resin column.
6. method according to claim 5, the preparation method of wherein said cation exchange resin column is:
A) get 001 × 7 type Zeo-karb and be about 500g, use 95% ethanol, volume ratio, soak 24h, wash with water to without alcohol taste;
B) hydrochloric acid solution adding 1mol/L again soaks 4h, washes with water to neutrality;
C) soak 4h with 1mol/L sodium hydrate aqueous solution again, wash with water to neutrality;
D) finally soak preservation with dilution, wherein said dilution is the mixed solution of the 1.73g/L ammonium dihydrogen phosphate aqueous solution-acetonitrile-methanol regulating about pH 10.0 with ammoniacal liquor, and volume ratio is 7:6:7;
E) before use, get Zeo-karb, with Buchner funnel suction filtration to not dripping, load in the syringe of a small amount of absorbent cotton of bottom pad.
7. method according to claim 6, the chromatographic condition that wherein HPLC detects is:
Instrument: high performance liquid chromatograph;
Chromatographic column: waters Xbridge C18,4.6 × 250mm, 5um;
Detecting device: UV-detector, determined wavelength 210nm;
Flow velocity: 1.0mL/min;
Column temperature: 60 DEG C;
Sample size: 100 μ L;
Gradient elution mode
Mobile phase A: take in ADSP 1.8g to 1L water, adds phosphoric acid,diluted or diluted sodium hydroxide solution adjusts pH to 8.9;
Mobile phase B: acetonitrile: methyl alcohol=3:1, volume ratio;
Working time: 93min.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109633034A (en) * | 2019-01-29 | 2019-04-16 | 宜昌东阳光药业股份有限公司 | The detection method of azithromycin genotoxicity impurity |
| CN109870528A (en) * | 2019-02-21 | 2019-06-11 | 北京悦康科创医药科技股份有限公司 | A kind of method of the azithromycin capsules by HPLC in relation to substance |
| CN111024844A (en) * | 2019-12-18 | 2020-04-17 | 湖北省宏源药业科技股份有限公司 | Method for detecting related impurities of azithromycin capsules |
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| US20100272769A1 (en) * | 2005-08-03 | 2010-10-28 | Amcol International | Virus-, Bacteria-, and Fungi-Interacting Layered Phyllosilicates and Methods of Use |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109633034A (en) * | 2019-01-29 | 2019-04-16 | 宜昌东阳光药业股份有限公司 | The detection method of azithromycin genotoxicity impurity |
| CN109633034B (en) * | 2019-01-29 | 2021-05-14 | 宜昌东阳光生化制药有限公司 | Method for detecting azithromycin genotoxic impurity |
| CN109870528A (en) * | 2019-02-21 | 2019-06-11 | 北京悦康科创医药科技股份有限公司 | A kind of method of the azithromycin capsules by HPLC in relation to substance |
| CN111024844A (en) * | 2019-12-18 | 2020-04-17 | 湖北省宏源药业科技股份有限公司 | Method for detecting related impurities of azithromycin capsules |
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Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |