CN103245744B - Method for detecting related substances in azithromycin for injection - Google Patents
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- CN103245744B CN103245744B CN201310172819.1A CN201310172819A CN103245744B CN 103245744 B CN103245744 B CN 103245744B CN 201310172819 A CN201310172819 A CN 201310172819A CN 103245744 B CN103245744 B CN 103245744B
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Abstract
The invention relates to the field of a drug, and in particular relates to a method for detecting related substances in azithromycin for injection. The method comprises the steps of: diluting an azithromycin B reference substance into a solution by sodium chloride injection, orderly carrying out an abnormal toxicity control method test on the solution according to the ascending order of the injection amount, and setting the injection amount in a previous test of the test to be injection amount extreme of the azithromycin B until a mice death result appears in a retest of the test of the azithromycin B injection amount; measuring the injection extremes of azithromycin Gx and erythrocin A iminoether according to the same method; carrying out quantitative analysis on the content C of three substances and the azithromycin in the drug to be tested; calculating according to each maximal dosage and formula to obtain the impurity extremes W1, W2 and W3 of three related substances; if the content of one related substance is not more than W1, not more than W2 and not more than W3, judging that the content of the related substance of the drug achieves the safety level, or else, judging that the content does not achieve the safety level. The target of quantitative evaluation is achieved by the method.
Description
Technical field
The present invention relates to drug world, the inspection method of related substance in azithromycin injection.
Background technology
In azithromycin injection, the inspection of related substance is the important indicator evaluating its security.In azithromycin injection, related substance mainly refers to azithromycin B, azithromycin G
x, Erythromycin A iminoether etc.
In correlation technique, in azithromycin injection, the inspection of related substance adopts thin-layered chromatography (TLC): by test sample (azithromycin injection) and contrast liquid point sample on silica gel g thin-layer plate respectively, judge whether its related substances reaches security level by the amount of speckle and shade comparing both.The kind of contrast liquid and concentration just are slightly done to change by various inspection method, and principle used is all identical, such as, and national drug standards WS
1-(X-296)-2003Z:
Get test sample (azithromycin injection), also dilute with anhydrous alcohol solution and make the solution of every 1ml containing azithromycin 20mg, as need testing solution; Get need testing solution and erythromycin standard items, also dilute the solution made containing azithromycin and each 0.4mg of erythromycin in every 1ml with anhydrous alcohol solution, solution (1) in contrast; Separately get need testing solution two parts, make the solution of every 1ml containing azithromycin 0.6mg and 0.2mg, solution (2) and (3) in contrast with absolute ethyl alcohol respectively.The each 10 μ l of the above-mentioned four kinds of solution of accurate absorption, put respectively on same silica gel g thin-layer plate, with ethyl acetate-normal hexane-diethylamine (10:10:2) for developping agent, dry after expansion, spray (gets sodium molybdate 2.5g, cerous sulfate 1g with developer, add 10% sulfuric acid solution dissolve and be diluted to 100ml), put 105 DEG C of heating several minutes.When in contrast solution (1), azithromycin is separated completely with erythromycin spot, the impurity spot of need testing solution is no more than 3, and each color of impurity spot compares with the principal spot of contrast solution, a maximum impurity spot is not deeper than the principal spot (3%) of contrast solution (2), when other two impurity spots are not deeper than principal spot (1%) of contrast solution (3) respectively, this test sample its related substances reaches security level, otherwise does not reach security level.
From above, the inspection method in correlation technique can only realize the object of semi-quantitative assessment its related substances, cannot realize quantitative evaluation, thus can not carry out studying more scientificly, such as, affect the analysis of causes etc. of its injection security.
Summary of the invention
The object of the present invention is to provide the inspection method of related substance in azithromycin injection, to solve the above problems.
Provide the inspection method of related substance in azithromycin injection in an embodiment of the present invention, comprise the following steps:
Steps A: get azithromycin B reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to azithromycin B injection rate IR, until when there is dead mouse result in the retrial of the test of a certain azithromycin B injection rate IR, azithromycin B injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of azithromycin B;
Step B: get azithromycin G
xreference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, then with these solution according to azithromycin G
xthe order that injection rate IR increases progressively carries out the test of abnormal toxicity tests method successively, until a certain azithromycin G
xwhen there is dead mouse result in the retrial of the test of injection rate IR, by azithromycin G used in the previous test of this test
xinjection rate IR is decided to be azithromycin G
xinjection rate IR limit;
Step C: get Erythromycin A iminoether reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to Erythromycin A iminoether injection rate IR, until when there is dead mouse result in the retrial of the test of a certain Erythromycin A iminoether injection rate IR, Erythromycin A iminoether injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of Erythromycin A iminoether;
Step D: the content C of azithromycin B in quantitative test azithromycin injection to be measured
1, azithromycin G
xcontent C
2, Erythromycin A iminoether content C
3, azithromycin content C;
Step e: according to each research on maximum utilized quantity m of azithromycin injection to be measured, and following formulae discovery, obtain the l.o.i W of azithromycin B
1, azithromycin G
xl.o.i W
2with the l.o.i W of Erythromycin A iminoether
3:
Step F: will
respectively correspondingly with described W
1, W
2, W
3compare; If
and
and
then in described azithromycin injection to be measured, its related substances reaches security level, otherwise does not reach security level.
The inspection method of related substance in the azithromycin injection of the above embodiment of the present invention, can realize azithromycin B in quantitative check azithromycin injection, azithromycin G
x, Erythromycin A iminoether three kinds of related substances object, be specially:
Described steps A adopts abnormal toxicity tests method to C, determines azithromycin B, azithromycin G respectively
x, Erythromycin A iminoether three kinds of related substances injection rate IR limit, and then obtained the l.o.i W of three kinds of related substances by described step e
1, W
2, W
3;
The content C of three kinds of related substances is obtained again by the quantitative test of described step D
1, C
2, C
3, and the content C of the effective constituent azithromycin of this medicine;
Finally calculate the content ratio of three kinds of related substances and effective constituent azithromycin in azithromycin injection to be measured, namely
again by these three values respectively correspondingly with described W
1, W
2, W
3compare, namely
with W
1,
with W
2,
with W
3compare, if
and
and
then in described azithromycin injection to be measured, its related substances reaches security level, otherwise does not reach security level;
It can thus be appreciated that method of the present invention is by quantitative measurement azithromycin B, azithromycin G
x, Erythromycin A iminoether three kinds of impurity related substances l.o.i, and the content of three kinds of related substances in azithromycin injection to be measured, achieve the object of quantitative evaluation, this result can be used for other and further studies.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of the first sample described in test example of the present invention;
Fig. 2 is the high-efficient liquid phase chromatogram of the second sample described in test example of the present invention.
Embodiment
Also by reference to the accompanying drawings the present invention is described in further detail below by specific embodiment.
Embodiment
The embodiment provides the inspection method of related substance in azithromycin injection, comprise the following steps:
Step 101: get azithromycin B reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to azithromycin B injection rate IR, until when there is dead mouse result in the retrial of the test of a certain azithromycin B injection rate IR, azithromycin B injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of azithromycin B;
Step 102: get azithromycin G
xreference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, then with these solution according to azithromycin G
xthe order that injection rate IR increases progressively carries out the test of abnormal toxicity tests method successively, until a certain azithromycin G
xwhen there is dead mouse result in the retrial of the test of injection rate IR, by azithromycin G used in the previous test of this test
xinjection rate IR is decided to be azithromycin G
xinjection rate IR limit;
Step 103: get Erythromycin A iminoether reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to Erythromycin A iminoether injection rate IR, until when there is dead mouse result in the retrial of the test of a certain Erythromycin A iminoether injection rate IR, Erythromycin A iminoether injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of Erythromycin A iminoether;
Step 104: the content C of azithromycin B in quantitative test azithromycin injection to be measured
1, azithromycin G
xcontent C
2, Erythromycin A iminoether content C
3, azithromycin content C;
Step 105: according to each research on maximum utilized quantity m of azithromycin injection to be measured, and following formulae discovery, obtain the l.o.i W of azithromycin B
1, azithromycin G
xl.o.i W
2with the l.o.i W of Erythromycin A iminoether
3:
Step 106: will
respectively correspondingly with described W
1, W
2, W
3compare; If
and
and
then in described azithromycin injection to be measured, its related substances reaches security level, otherwise does not reach security level.
The inspection method of related substance in the azithromycin injection of above-described embodiment, can realize azithromycin B in quantitative check azithromycin injection, azithromycin G
x, Erythromycin A iminoether three kinds of related substances object, be specially:
Described step 101 adopts abnormal toxicity tests method to 103, determines azithromycin B, azithromycin G respectively
x, Erythromycin A iminoether three kinds of related substances injection rate IR limit, and then obtained the l.o.i W of three kinds of related substances by described step 105
1, W
2, W
3;
The content C of three kinds of related substances is obtained again by the quantitative test of described step 104
1, C
2, C
3, and the content C of the effective constituent azithromycin of this medicine;
Finally calculate the content ratio of three kinds of related substances and effective constituent azithromycin in azithromycin injection to be measured, namely
again by these three values respectively correspondingly with described W
1, W
2, W
3compare, namely
with W
1,
with W
2,
with W
3compare, if
and
and
then in described azithromycin injection to be measured, its related substances reaches security level, otherwise does not reach security level;
It can thus be appreciated that method of the present invention is by quantitative measurement azithromycin B, azithromycin G
x, Erythromycin A iminoether three kinds of related substances l.o.i, and the content of three kinds of related substances in azithromycin injection to be measured, achieve the object of quantitative evaluation, this result can be used for other and further studies.Visible, the present invention is that the safety evaluatio of Drug-related provides a new Scientific Approaches, and the method can also be used for other related substance of checking in azithromycin injection, and concrete test condition can be drawn by the test of limited number of time.
Wherein, described abnormal toxicity tests method is see Pharmacopoeia of the People's Republic of China version annex XIC in 2010: get the healthy mice 5 that body weight is 17-20g, reference substance solution is injected mouse tail vein, at the uniform velocity should inject complete within 4-5 second, dead mouse situation in 48 hours after record administration; During if any death, separately get healthy mice 10 retrials of body weight 18-19g, dead mouse situation in 48 hours after record administration.
Described m, can be different for different treatment targets, and common people are 0.5g with the m of this medicine.(can see the instructions of specific product)
Described quantitative analysis method can adopt high efficiency liquid phase chromatographic analysis method, or other is suitable for the method for quantitative measurment three kinds of related substances and effective constituent.
In the described step 101 of said method to 103, often will walk with sodium chloride injection the solution that corresponding reference substance dilution is variable concentrations, then these solution getting same dose carry out the test of abnormal toxicity tests method successively according to the order of increasing concen-trations.Adopt the mode of this " dosage is identical, concentration is different " to change injection rate IR, the impact of the other factors between each test group can be reduced, the accuracy of raising method.
When described step 104 uses high efficiency liquid phase chromatographic analysis method to carry out quantitative test, in order to accuracy, the science of further this inspection method, the method can also be improved in the following areas.
(1) preferably, described high performance liquid chromatography detects C
1, C
2, C
3, C filling agent used is octadecylsilane chemically bonded silica, mobile phase used is the mixture of acetonitrile-phosphate buffer that volume ratio is 45:55; Determined wavelength is 210nm.Prove through test, adopt this analysis condition, analysis result accuracy and degree of accuracy higher, and detection time is short.
(2) preferably, the pH value of described phosphate buffer is 8.2-8.4, is more preferably wherein 8.2.Prove through test, adopt the damping fluid of this pH value, detection time is shorter, improves detection efficiency.Wherein, preferably, the compound method of described phosphate buffer is: get 0.05mol/L dipotassium hydrogen phosphate solution, and by the phosphoric acid solution adjust ph to 8.2 of 0.2g/mL, the method two kinds of reagent costs used are low, and easily obtain, and reduce experimentation cost.
(3) preferably, described high performance liquid chromatography is: dilute for certain density solution by azithromycin injection to be measured, as the first sample with acetonitrile; Sample Dilution n is detected doubly as the second sample again using first; Inject described first sample to high performance liquid chromatograph, detect C
1, C
2, C
3; In high performance liquid chromatograph, inject described second sample, detect C; Described n is 50-150.Azithromycin and the solubleness of three kinds of related substances in acetonitrile high, be more conducive to detect.And adopt the solution of variable concentrations to detect three kinds of materials and effective constituent respectively simultaneously, the accuracy of method can be improved: related substance (impurity) content in usual azithromycin injection to be measured is lower, namely in same solution, the concentration of three kinds of related substances and the concentration of azithromycin have big difference, if adopt the solution of same concentration to detect this four kinds of materials simultaneously, can exceed instrument detectability or too close to the detectability of instrument, the accuracy of reduction method.
(4) preferably, in described first sample, the concentration of azithromycin injection is 8-10mg/mL, and described n=100.Prove through overtesting, accuracy and the precision of this detection method are higher.In like manner, preferably, the injection rate IR of described first sample and the second sample is 50 μ L.
In order to illustrate in greater detail the performance of method of the present invention, below additionally provide concrete test example.
Test example
Test method:
Abnormal toxicity tests method is tested: get azithromycin B, azithromycin G respectively
x, Erythromycin A iminoether reference substance, the solution of variable concentrations is made with sodium chloride injection, get healthy mice (body weight 17-20g) 5, need testing solution is injected mouse tail vein, at the uniform velocity should inject complete second at 4-5, every mouse gives need testing solution 0.5ml respectively, dead mouse situation in 48 hours after record administration; During if any death, separately get healthy mice 10 retrials of body weight 18-19g, dead mouse situation in 48 hours after record administration.
High performance liquid chromatography is tested:
Precision takes azithromycin injection 98.21mg, adds acetonitrile and dissolves and dilute and make the solution that concentration is 9.821mg/ml, as the first sample; Precision measures 1ml, puts in 100ml volumetric flask, by dilution in acetonitrile to scale, shakes up, and as the second sample, is filling agent with octadecylsilane chemically bonded silica; Be mobile phase with phosphate buffer (getting 0.05mol/L dipotassium hydrogen phosphate solution, the phosphoric acid solution adjust ph to 8.2 with 20%)-acetonitrile (volume ratio, 45:55); Determined wavelength is 210nm, and precision measures the first sample and each 50 μ L of the second sample, respectively injection liquid chromatography, and record chromatogram is to 2 times of major component peak (peak of azithromycin) retention time.
Due to azithromycin B, azithromycin G
x, the absorptivity of Erythromycin A iminoether and azithromycin four kinds of materials under same liquid phase testing conditions be different, so for the ease of the comparison of later stage four kinds of material concentrations, this test also have detected azithromycin B, azithromycin G
x, Erythromycin A iminoether three kinds of materials are relative to the correction factor f of azithromycin.
The measuring method of f: get azithromycin and impurity azithromycin B, azithromycin G
x, Erythromycin A iminoether four materials reference substance in right amount each, put in same volumetric flask and add mobile phase { phosphate buffer (gets 0.05mol/L dipotassium hydrogen phosphate solution, phosphoric acid solution adjust ph to 8.2 with 20%)-acetonitrile (45:55) } dissolve, and be diluted to four kinds of materials respectively containing the solution of about 10mg/ml, as mixed solution.Measure above-mentioned mixed solution 50 μ l injection liquid chromatography, record chromatogram, read the correction factor that each material peak-to-peak area is calculated as follows each impurity:
M
impurity: impurity sample quality
M
archie: azithromycin sample quality
A
impurity: the peak area of impurity
A
archie: the peak area of azithromycin
Test findings:
Abnormal toxicity tests method is tested: from table one to table three, azithromycin B injection rate IR limit is 3.73mg, azithromycin G
xinjection rate IR limit is 1.91mg, and Erythromycin A iminoether injection rate IR limit is 1.75mg.
This test is with artificial medicine use object in the future, and each research on maximum utilized quantity m of its azithromycin injection is 0.5g.The l.o.i obtaining azithromycin B is thus 0.746%(3.73/500), azithromycin G
xl.o.i be 0.382%(1.91/500), the l.o.i of Erythromycin A iminoether is 0.35%(1.75/500).
The undue toxicity experiment of table one azithromycin B reference substance
Table two azithromycin G
xthe undue toxicity experiment of reference substance
The undue toxicity experiment of table three Erythromycin A iminoether reference substance
High performance liquid chromatography is tested:
As depicted in figs. 1 and 2, azithromycin B, azithromycin G
x, the retention time of Erythromycin A iminoether, azithromycin is respectively: 24.856, and 9.786,4.216,15.630.Fig. 1 is the chromatogram of described first sample; Fig. 2 is the chromatogram of described second sample.
The correction factor of each impurity as shown in Table 4.
Table four each impurity correction factor measurement result
| Impurity title | Azithromycin B | Azithromycin G x | Erythromycin A iminoether |
| Correction factor | 1.01 | 0.11 | 0.42 |
Finally, by azithromycin B, azithromycin G in described first sample
x, Erythromycin A iminoether peak area be multiplied by respective correction factor respectively, concentration due to described first sample is 100 times of described second sample, again the peak area of azithromycin in described second sample is multiplied by 100, be divided by with the peak area of above-mentioned corrected three impurity again, obtain the content ratio of three kinds of impurity and azithromycin: azithromycin B is 0.434%, azithromycin G
xbe 0.148%, Erythromycin A iminoether is 0.179%, the l.o.i of these three values and abnormal toxicity test gained is compared correspondingly: 0.434%<0.746%, 0.148%<0.382%, 0.179%<0.35%.
Visible, the content of the azithromycin injection product related substance checked in this test example reaches security level.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. the inspection method of related substance in azithromycin injection, is characterized in that, comprise the following steps:
Steps A: get azithromycin B reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to azithromycin B injection rate IR, until when there is dead mouse result in the retrial of the test of a certain azithromycin B injection rate IR, azithromycin B injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of azithromycin B;
Step B: get azithromycin G
xreference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, then with these solution according to azithromycin G
xthe order that injection rate IR increases progressively carries out the test of abnormal toxicity tests method successively, until a certain azithromycin G
xwhen there is dead mouse result in the retrial of the test of injection rate IR, by azithromycin G used in the previous test of this test
xinjection rate IR is decided to be azithromycin G
xinjection rate IR limit;
Step C: get Erythromycin A iminoether reference substance, and to be diluted with sodium chloride injection be the solution of same concentration or variable concentrations, the test of abnormal toxicity tests method is carried out successively again by the order that these solution increase progressively according to Erythromycin A iminoether injection rate IR, until when there is dead mouse result in the retrial of the test of a certain Erythromycin A iminoether injection rate IR, Erythromycin A iminoether injection rate IR used in the previous test of this test is decided to be the injection rate IR limit of Erythromycin A iminoether;
Step D: adopt high efficiency liquid phase chromatographic analysis method to analyze the content C of azithromycin B in azithromycin injection to be measured
1, azithromycin G
xcontent C
2, Erythromycin A iminoether content C
3, azithromycin content C;
The testing conditions of described high performance liquid chromatography is: filling agent is octadecylsilane chemically bonded silica, and mobile phase used is the mixture of acetonitrile-phosphate buffer that volume ratio is 45:55; Determined wavelength is 210nm; The compound method of described phosphate buffer is: get 0.05mol/L dipotassium hydrogen phosphate solution, by the phosphoric acid solution adjust ph to 8.2 of 0.2g/mL;
Described high efficiency liquid phase chromatographic analysis method is: with the solution of acetonitrile to be concentration by azithromycin injection to be measured dilution be 8-9.821mg/mL, as the first sample; Sample Dilution 100 is detected doubly as the second sample again using first; Inject described first sample to high performance liquid chromatograph, detect C1, C
2, C
3; In high performance liquid chromatograph, inject described second sample, detect C;
Step e: according to each research on maximum utilized quantity m of azithromycin injection to be measured, and following formulae discovery, obtain the l.o.i W of azithromycin B
1, azithromycin G
xl.o.i W
2with the l.o.i W of Erythromycin A iminoether
3:
Step F: will
respectively correspondingly with described W
1, W
2, W
3compare; If
and
and
then in described azithromycin injection to be measured, its related substances reaches security level, otherwise does not reach security level.
2. method according to claim 1, it is characterized in that, described steps A, in C, will often walk the solution that corresponding reference substance dilution is variable concentrations, then these solution getting same dose carries out the test of abnormal toxicity tests method successively according to the order of increasing concen-trations with sodium chloride injection.
3. method according to claim 1, is characterized in that, the injection rate IR of described first sample and the second sample is 50 μ L.
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| CN104730153A (en) * | 2013-12-20 | 2015-06-24 | 辰欣药业股份有限公司 | Method for determining content of azithromycin for injection and related substances by high performance liquid chromatography |
| 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 |
| CN109870528B (en) * | 2019-02-21 | 2022-07-15 | 北京悦康科创医药科技股份有限公司 | Method for determining azithromycin capsule related substances by high performance liquid chromatography |
| 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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| EP1878432A1 (en) * | 2003-07-24 | 2008-01-16 | Pliva - Research and Development Ltd. | Single dose fast dissolving azithromycin |
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| EP1878432A1 (en) * | 2003-07-24 | 2008-01-16 | Pliva - Research and Development Ltd. | Single dose fast dissolving azithromycin |
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