CN103983730B - Determination of foreign matter method in azithromycin or its preparation - Google Patents
Determination of foreign matter method in azithromycin or its preparation Download PDFInfo
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Abstract
The present invention relates to drug world, be specifically related to the determination of foreign matter method in azithromycin or its preparation.Especially, the present invention relates to azithromycin pharmaceutical salts or its formulation example as the determination of foreign matter method in azithromycin injection preparation, described azithromycin pharmaceutical salts is azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate such as, described impurity such as impurity a and optional with its impurity having chromatogram to associate.The invention still further relates to azithromycin pharmaceutical salts or its formulation example as azithromycin injection preparation.The inventive method uses GC method to carry out, and comprises step: the preparation of (1) test fluid; (2) GC conditions; (3) gas Chromatographic Determination; (4) four steps are calculated.The inventive method can evaluate the quality of azithromycin pharmaceutical salts or its preparation valuably.
Description
Technical field
The present invention relates to drug world, be specifically related to the determination of foreign matter method in azithromycin or its preparation.Especially, the present invention relates to azithromycin pharmaceutical salts or its formulation example as the determination of foreign matter method in azithromycin injection preparation, described azithromycin pharmaceutical salts is azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate such as, described impurity such as 3-methylfuran and optional with its impurity having chromatogram to associate.The invention still further relates to azithromycin pharmaceutical salts or its formulation example as azithromycin injection preparation.
Background technology
Azithromycin (azithromycin) is 15 member cyclic macrolide class microbiotic, azithromycin has antimicrobial spectrum widely than erythromycin, has very strong inhibiting effect to the Grain-positive cause of disease bacterium such as streptococcus pneumonia and haemophilus influenzae, beta-lactamase producing strains and Moraxella catarrhalis.Azithromycin has higher stability in slant acidity environment, has the advantages such as good absorbing, bioavilability are high, long half time.
In addition, because the solubleness of azithromycin is low, for making the azithromycin formulations that can be used for injecting, usually acid-addition salts is formed, such as make azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate etc., then be made into injectable formulation example as freeze drying powder-injection.
But well-known, the impurity existed in preparation can affect the quality of preparation usually.Therefore, providing the method for the azithromycin formulations quality of a kind of effective monitoring azithromycin formulations such as injection, is that those skilled in the art urgently expect equally.
Summary of the invention
The object of the invention is to, a kind of determination of foreign matter method in azithromycin or its preparation is provided, expect the method can effective monitoring azithromycin or its formulation example as the method for the azithromycin formulations quality of injection.Especially, the object of the invention is to provide the azithromycin pharmaceutical salts or its preparation that can be used as bulk drug, and the detection method of impurity in them.
For this reason, first aspect present invention provides a kind of method of the impurity detected in azithromycin pharmaceutical salts or its preparation, and the method uses vapor-phase chromatography (i.e. GC) to detect, and comprises the following steps:
(1) preparation of test fluid:
The preparation of need testing solution: be taken as the azithromycin pharmaceutical salts 0.2g for test sample or the preparation be equivalent to containing azithromycin pharmaceutical salts 0.2g as test sample, accurately weighed, put in the ml headspace bottle of 20mL, the 5ml that adds water dissolves, as need testing solution;
The preparation of 3-methylfuran reference substance solution: get 3-methylfuran reference substance 30mg, accurately weighed, put in the measuring bottle of 100mL, be dissolved in water and be diluted to scale, shaking up; The accurate 2mL that draws puts in the measuring bottle of 100mL, is diluted with water to scale, shakes up; The accurate 5mL that draws puts in the ml headspace bottle of 20mL, as 3-methylfuran reference substance solution (the 3-methylfuran concentration be equivalent in this solution is 0.03mg/5ml) again;
(2) GC conditions:
Chromatographic column: DB-624 capillary column (its specification can be 30m × 0.53mm × 3.0 μm, and it can be such as the product of J & WScientific company);
Temperature programme: post initial temperature 40 DEG C, keeps 5min; Be warming up to 60 DEG C with 5 DEG C/min, keep 5min; Be warming up to 150 DEG C with the speed of 7 ~ 9 DEG C/min, keep 10min;
Injector temperature is 180 DEG C;
Carrier gas is nitrogen, flow 2.0mL/min, not shunt mode sample introduction;
Headspace sampling: headspace sample equilibrium temperature is 40 DEG C ~ 70 DEG C, and headspace sample equilibration time is 5min ~ 20min;
Detecting device is FID, temperature 250 DEG C, hydrogen 40mL/min, air 350mL/min, nitrogen 25mL/min;
Sample size: 1min;
(chromatographic apparatus can be the gas chromatograph of disposable type, such as, can use Agilent7890A gas chromatograph in the present invention, can also use Agilent7697A headspace sampling system);
(3) gas Chromatographic Determination:
According to the vapor-phase chromatography that the version Pharmacopoeia of the People's Republic of China in 2010 two annex V E are contained, measure by above-mentioned GC conditions;
Get 3-methylfuran reference substance solution to measure, obtain chromatogram 1; Get need testing solution in addition to measure, obtain chromatogram 2;
(4) calculate:
Read retention time (it can be labeled as t1 in the present invention) and the peak area (it can be labeled as A1 in the present invention) of main peak 3-methylfuran in chromatogram 1;
Read retention time and the peak area of each chromatographic peak in chromatogram 2;
In this chromatogram 2, the chromatographic peak consistent with main peak 3-methylfuran retention time in chromatogram 1 is 3-methylfuran peak, and this chromatographic peak is designated as peak a in FIG, and its retention time is designated as ta (suitable with t1), and its peak area is designated as Aa;
In this chromatogram 2, if there is chromatographic peak at retention time tb place, it is designated as peak b, and the peak area of this peak b is designated as Ab, and wherein tb is 1.8 ~ 2.2 times of ta;
By external standard method with the content (%) of 3-methylfuran in calculated by peak area test sample relative to azithromycin pharmaceutical salts;
Calculate the ratio of peak b peak area and peak a peak area, i.e. Ab/Aa value.
In the present invention, some typical embodiments of above-mentioned vapor-phase chromatography, particularly indivedual typical condition determination wherein and assay method are particularly preferred.The typical condition determination such as provided in the method example 1 of specific embodiment of the invention part and assay method, it can be described as in the present invention [vapor-phase chromatography A], and preferably as the concrete grammar that the present invention measures.
Method according to a first aspect of the present invention, wherein said azithromycin pharmaceutical salts is the acid-addition salts of azithromycin.
Method according to a first aspect of the present invention, wherein said azithromycin pharmaceutical salts is selected from azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate.
Method according to a first aspect of the present invention, the preparation of wherein said azithromycin pharmaceutical salts is the preparation of injection.
Method according to a first aspect of the present invention, the preparation of wherein said azithromycin pharmaceutical salts is the preparation of injection, and it is selected from: the parenteral solution of freeze drying powder-injection, solution-type.
Method according to a first aspect of the present invention, wherein said 3-methylfuran reference substance uses described [vapor-phase chromatography A] to measure, the sample that its chromatographic purity is greater than 98%.
Method according to a first aspect of the present invention, wherein tb is 1.85 ~ 2.15 times of ta.
Method according to a first aspect of the present invention, wherein tb is 1.9 ~ 2.1 times of ta.
Method according to a first aspect of the present invention, wherein tb is 1.95 ~ 2.05 times of ta.
Method according to a first aspect of the present invention, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 70 DEG C, and Sample equilibration time is 5min, shakes with the rotating speed of 200rpm simultaneously.
Method according to a first aspect of the present invention, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 60 DEG C, and Sample equilibration time is 10min, shakes with the rotating speed of 200rpm simultaneously.
Method according to a first aspect of the present invention, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 50 DEG C, and Sample equilibration time is 15min, shakes with the rotating speed of 200rpm simultaneously.
Method according to a first aspect of the present invention, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 40 DEG C, and Sample equilibration time is 20min, shakes with the rotating speed of 200rpm simultaneously.
Method according to a first aspect of the present invention, 3-methylfuran wherein in test sample exists as impurity, this 3-methylfuran also can be described as impurity a in the present invention, and the peak b in test sample gas chromatogram is also a kind of impurity existed in test sample, it also can be described as impurity b in the present invention.
Method according to a first aspect of the present invention, 3-methylfuran wherein in test sample exists as impurity, its content (%) in test sample by well known to a person skilled in the art that external standard method calculates, namely can be calculated by the relation of solute concentration and chromatogram 2 peak area Aa three in chromatogram 1 peak area A1 and 3-methylfuran reference substance solution.Such as, comprise the azithromycin pharmaceutical salts of 200mg in test sample sampling, obtain containing 0.03mg impurity 3-methylfuran if measured in the test sample of this sampling, then the content of impurity in test sample is 0.015%.The 3-methylfuran of product can easily be buied from the market in contrast in the present invention, and the 3-methylfuran that such as the present invention uses is purchased from Sigma-Aldrich company, and its purity is more than 99.5%.
Method according to a first aspect of the present invention, wherein in test sample, peak b is as a kind of impurity, i.e. impurity b, its content in test sample, can calculate by reference to the gauge of impurity 3-methylfuran contained in same test sample, namely with Ab/Aa value calculating mentioned above.Namely, for a collection of test sample material, no matter it is the azithromycin pharmaceutical salts as bulk drug, or as the azithromycin pharmaceutical salts preparation of pharmaceutical preparation, wherein the content (%) of impurity 3-methylfuran (relative to azithromycin pharmaceutical salts in this batch materials) measures by [vapor-phase chromatography A] of the present invention and obtains, and on this basis, can measure and obtain Ab/Aa value, and the relative content of impurity b can be characterized by Ab/Aa value.
Generally speaking, method according to a first aspect of the present invention, can evaluate the existence of impurity in azithromycin pharmaceutical salts or its preparation particularly impurity a and impurity b effectively.Certainly, the azithromycin pharmaceutical salts ideal for quality or its preparation, impurity a wherein may not exist or can't detect lower than the detectability of method, now in this azithromycin pharmaceutical salts or its preparation, quantitatively can add a certain amount of impurity a, thus Ab/Aa value still can be used effectively to evaluate the existence of impurity b.
Therefore, method according to a first aspect of the present invention, when the impurity a in azithromycin pharmaceutical salts or its preparation can't detect lower than the detectability of method, quantitatively a certain amount of impurity a reference substance is added, to calculate and to use Ab/Aa value to there is situation to what evaluate impurity b in this azithromycin pharmaceutical salts or its preparation.Like this, in one embodiment, by the method that impurity a reference substance adds in azithromycin pharmaceutical salts or its preparation be, or the method preparing need testing solution is: using the azithromycin pharmaceutical salts 0.2g as test sample or the preparation be equivalent to containing azithromycin pharmaceutical salts 0.2g as test sample accurately weighed, put in the ml headspace bottle of 20mL, the 3-methylfuran reference substance solution adding 5mL is dissolved, as need testing solution.
In addition, have been found that and suitably regulate temperature programme curve, the retention time of peak a and peak b will be changed, but the relative retention time of the two (that is, be tb/ta in the present invention, or be called that tb is the multiple of ta) remains unchanged substantially.It is expected to although this phenomenon is Pharmaceutical Analysis those skilled in the art, but have been surprisingly found that: when need testing solution being repeated sample introduction and measuring (at least 10 times), when using said procedure heating curve of the present invention, peak b peak area wherein and the relative standard deviation RSD of Ab very little, be less than 1.3%; But RSD still can maintain the scope being less than 1.5% when being warming up to that in the process of 150 DEG C, programming rate is at 7.8 ~ 8.2 DEG C/min from 60 DEG C; Such as, but when programming rate is greater than 5.5% lower than RSD during 7.5 DEG C/min, and the lower RSD of programming rate is larger, and when programming rate is 6.5 DEG C/min, RSD reaches 9.52%; And programming rate when being greater than 8.5 DEG C/min RSD be greater than 6.2%, and the higher RSD of programming rate is larger, and such as, when programming rate is 9.5 DEG C/min, RSD reaches 8.23%.In addition, if other stage changing heating schedule will affect the RSD value of above-mentioned Ab more significantly, such as 60 DEG C of equilibration times extended to 8 minutes or shorten to 3 minutes, RSD will reach 7.34% and 8.16% respectively.The relative standard deviation RSD of above-mentioned Ab is less, show assay method more stable, more accurately, more reliable, otherwise method is inaccurate.It is the unprecedented instruction of prior art that the change of this heating schedule can affect chromatographic peak area, and applicant tastes and do not find any theory can explain this phenomenon.
Therefore, in an embodiment in the present invention, in the temperature programme of vapor-phase chromatography, 150 DEG C are warming up to the speed of 7.5 ~ 8.5 DEG C/min from 60 DEG C.In an embodiment in the present invention, in the temperature programme of vapor-phase chromatography, be warming up to 150 DEG C with the speed of 7.8 ~ 8.2 DEG C/min from 60 DEG C.In an embodiment in the present invention, in the temperature programme of vapor-phase chromatography, be warming up to 150 DEG C with the speed of 8 DEG C/min from 60 DEG C.
Method according to a first aspect of the present invention, described DB-624 capillary column is middle polarity chromatographic column.
Further, third aspect present invention provides the bulk drug of azithromycin pharmaceutical salts, wherein contains the azithromycin pharmaceutical salts of more than 96.0%.
Bulk drug according to a third aspect of the present invention, wherein said azithromycin pharmaceutical salts is the acid-addition salts of azithromycin.
Bulk drug according to a third aspect of the present invention, wherein said azithromycin pharmaceutical salts is selected from azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate.
Further, fourth aspect present invention provides the pharmaceutical composition of azithromycin pharmaceutical salts, wherein comprises the bulk drug of the azithromycin pharmaceutical salts described in the arbitrary embodiment of third aspect present invention, and optional pharmaceutic adjuvant.
Pharmaceutical composition according to a fourth aspect of the present invention, wherein azithromycin pharmaceutical salts accounts for 1 ~ 100% of composition total weight, surplus be pharmaceutic adjuvant.
Pharmaceutical composition according to a fourth aspect of the present invention, it is the preparation of injection.
Pharmaceutical composition according to a fourth aspect of the present invention, it is the preparation of injection, is selected from: the parenteral solution of freeze drying powder-injection, solution-type.
Pharmaceutical composition according to a fourth aspect of the present invention, wherein said azithromycin pharmaceutical salts is the acid-addition salts of azithromycin.
Pharmaceutical composition according to a fourth aspect of the present invention, wherein said azithromycin pharmaceutical salts is selected from azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate.
Further, fifth aspect present invention provides the method that preparation comprises the pharmaceutical composition of azithromycin pharmaceutical salts, the method comprises the bulk drug of the azithromycin pharmaceutical salts described in arbitrary for third aspect present invention embodiment, and optional pharmaceutic adjuvant, the preparation technology of pharmaceutical preparation routinely, makes the pharmaceutical composition in pharmaceutical dosage forms.
Method according to a fifth aspect of the present invention, wherein said pharmaceutical composition is the pharmaceutical composition as described in embodiment as arbitrary in fourth aspect present invention.
Method according to a fifth aspect of the present invention, wherein azithromycin pharmaceutical salts accounts for 1 ~ 100% of composition total weight, surplus be pharmaceutic adjuvant.
Method according to a fifth aspect of the present invention, wherein said pharmaceutical composition is the preparation of injection.
Method according to a fifth aspect of the present invention, wherein said pharmaceutical composition is the preparation of injection, is selected from: the parenteral solution of freeze drying powder-injection, solution-type.
Method according to a fifth aspect of the present invention, wherein said azithromycin pharmaceutical salts is the acid-addition salts of azithromycin.
Method according to a fifth aspect of the present invention, wherein said azithromycin pharmaceutical salts is selected from azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate.
Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Be further described to various aspects of the present invention below.
Azithromycin (azithromycin) is 15 member cyclic macrolide class microbiotic, and its chemical structural formula is as follows:
Azithromycin has the forms such as anhydride, monohydrate, dihydrate, and such as Chinese Pharmacopoeia version in 2010 is recorded, American Pharmacopeia USP35 version is recorded.It is easily molten in methyl alcohol, acetone, methenyl choloride, absolute ethyl alcohol or watery hydrochloric acid, dissolves in acetonitrile, almost insoluble in water.In view of the problem of its water-soluble deficiency, there are technology barriers when being prepared into injection preparation.The azithromycin of free alkali form is often prepared into the pharmaceutical salts meeting formulation dissolution and require by people for this reason, then prepares formulation example as freeze drying powder-injection by this pharmaceutical salts.
In the present invention, prepare the preparation particularly freeze drying powder-injection of azithromycin pharmaceutical salts, can by well known to a person skilled in the art mode to prepare, freeze-drying method is documented in " pharmacy " textbook, and as the auxiliary material of freeze drying powder-injection, can add, can not also add, when added, lactose, sweet mellow wine, dextran etc. are conventional, their consumption is normally determined according to technological requirement, such as, usually make the content of solid content in the solution before freeze drying in 2 ~ 20% scopes.
The technology of the present invention feature: the present invention adopts headspace gas chromatography, impurity such as 3-methylfuran and impurity b in mensuration azithromycin injection that can be quick, accurate, easy, and residual solvent (such as but not limited to methylene chloride, methyl alcohol, ethanol and acetone etc.) that can be common in Simultaneously test azithromycin formulations, the peak-to-peak degree of separation of each chromatogram all meets the requirements.
In sum, adopt headspace gas chromatography of the present invention to check in azithromycin drug or azithromycin injection preparation the impurity such as 3-methylfuran, achieve effective control of azithromycin drug and preparation.
Accompanying drawing explanation
The 3-methylfuran reference substance chromatogram that Fig. 1 measures for using the present invention [vapor-phase chromatography A], wherein chromatographic peak a is 3-methylfuran, and its retention time is 11.354min.
The test sample chromatogram of the azithromycin dihydrochloride freeze drying powder-injection (powder pin 1F1-1) that Fig. 2 measures for use the present invention [vapor-phase chromatography A], wherein occur 3-methylfuran impurity peaks (namely peak is a) at retention time 11.358min place; In addition, there is another impurity peaks (i.e. peak b) in this test sample at retention time 22.644min place; Tb is 1.99 times (in the present invention, this parameter also can be expressed as tb/ta=1.99) of ta.
Embodiment
The following examples provided only for task of explanation instead of for, should not be interpreted as limiting the present invention by any way yet.Those skilled in the art will recognize that can make routine to following examples when not surmounting the spirit or scope of the present invention changes and amendment.
a, method example part
method example 1: method for detecting impurities
There is provided following and can be described as in the present invention the gas chromatography of [vapor-phase chromatography A], it is in instantiation of the present invention, and for detecting the impurity in azithromycin pharmaceutical salts or its preparation, its concrete steps have:
(1) preparation of test fluid:
The preparation of need testing solution: be taken as the azithromycin pharmaceutical salts 0.2g for test sample or the preparation be equivalent to containing azithromycin pharmaceutical salts 0.2g as test sample, accurately weighed, put in the ml headspace bottle of 20mL, the 5ml that adds water dissolves, as need testing solution;
The preparation of 3-methylfuran reference substance solution: get 3-methylfuran reference substance 30mg, accurately weighed, put in the measuring bottle of 100mL, be dissolved in water and be diluted to scale, shaking up; The accurate 2mL that draws puts in the measuring bottle of 100mL, is diluted with water to scale, shakes up; The accurate 5mL that draws puts in the ml headspace bottle of 20mL, as 3-methylfuran reference substance solution (the 3-methylfuran concentration be equivalent in this solution is 0.03mg/5ml) again;
(2) GC conditions:
Chromatographic column: DB-624 capillary column (its specification is 30m × 0.53mm × 3.0 μm, the product of J & W Scientific company);
Temperature programme: post initial temperature 40 DEG C, keeps 5min; Be warming up to 60 DEG C with 5 DEG C/min, keep 5min; Be warming up to 150 DEG C with the speed of 8 DEG C/min, keep 10min;
Injector temperature is 180 DEG C;
Carrier gas is nitrogen, flow 2.0mL/min, not shunt mode sample introduction;
Headspace sampling: headspace sample equilibrium temperature is 60 DEG C, headspace sample equilibration time is 10min, shakes with the rotating speed of 200rpm simultaneously;
Detecting device is FID, temperature 250 DEG C, hydrogen 40mL/min, air 350mL/min, nitrogen 25mL/min;
Sample size: 1min;
(chromatographic apparatus uses Agilent7890A gas chromatograph, Agilent7697A headspace sampling system);
(3) gas Chromatographic Determination:
According to the vapor-phase chromatography that the version Pharmacopoeia of the People's Republic of China in 2010 two annex V E are contained, measure by above-mentioned GC conditions;
Get 3-methylfuran reference substance solution to measure, obtain chromatogram 1; Get need testing solution in addition to measure, obtain chromatogram 2;
(4) calculate:
Read retention time (it can be labeled as t1 in the present invention) and the peak area (it can be labeled as A1 in the present invention) of main peak 3-methylfuran in chromatogram 1;
Read retention time and the peak area of each chromatographic peak in chromatogram 2;
In this chromatogram 2, the chromatographic peak consistent with main peak 3-methylfuran retention time in chromatogram 1 is 3-methylfuran peak, and this chromatographic peak is designated as peak a in FIG, and its retention time is designated as ta (suitable with t1), and its peak area is designated as Aa;
In this chromatogram 2, if there is chromatographic peak at retention time tb place, it is designated as peak b, and the peak area of this peak b is designated as Ab, and wherein tb is 1.9 ~ 2.1 times of ta;
By external standard method with the content (%) of 3-methylfuran in calculated by peak area test sample relative to azithromycin pharmaceutical salts;
Calculate the ratio of peak b peak area and peak a peak area, i.e. Ab/Aa value.
method example 2: study on the stability method
For the bulk drug of azithromycin pharmaceutical salts, be sealed in vial; Be that namely original packaging is sealed in vial for freeze drying powder-injection; For raw material or the preparation of other form, them are made to wrap up with suitable material.Then these sample shade bag attached bags are wrapped up in, then place them in the constant temperature oven of 42 DEG C, place 3 months.Investigate/test each sample 0 month time and March time performance, such as user's rule 1 it [vapor-phase chromatography A] measures impurity 3-methylfuran content in various sample and impurity b (in 3-methylfuran) amount relatively.
The method of user's rule 3 can also measure the related substance of each sample when 0 month and March or content.
method example 3: product property method of testing
About the assay method of " injection " and quality index under the Related substances separation item of reference Chinese Pharmacopoeia version in 2010 two 395 pages " azithromycin " kinds, investigate the related substance of the bulk drug related in instantiation of the present invention.
Contain by anhydride calculating the index that C38H72N2O12 should be 96.0% ~ 102.0% with reference to the assay method under the assay item of Chinese Pharmacopoeia version in 2010 two 395 pages " azithromycin " kinds with about this kind, investigate the content of the bulk drug related in instantiation of the present invention.
With reference to the assay method under the Related substances separation item of Chinese Pharmacopoeia version in 2010 two 396 pages " Azithromycin for Suspension " kinds and quality index, investigate the related substance of the various compositions (preparation) related in instantiation of the present invention.
For various composition (preparation), with reference to the assay method under the assay item of Chinese Pharmacopoeia version in 2010 two 396 pages " Azithromycin for Suspension " kinds with about the index of this kind by the theoretical labelled amount percentage relative to said composition of azithromycin (C38H72N2O12), investigate the content of the various compositions (preparation) related in instantiation of the present invention.
b, bulk drug preparation example part
preparation example 1: prepare azithromycin dihydrochloride bulk drug
With reference to the method for CN1803821A (Chinese Patent Application No. 200610037900.9, long Australia) instructions embodiment 1, azithromycin dihydrochloride can be prepared, is designated as Y1.
preparation example 2: prepare azithromycin dihydrochloride bulk drug
With reference to the method for CN102746350A (Chinese Patent Application No. 201110101256.8, Tai Kang) instructions embodiment 1, azithromycin dihydrochloride can be prepared, is designated as Y2.
preparation example 3: prepare asparagic acid azithromycin bulk drug
With reference to the method for CN1861623A (Chinese Patent Application No. 200610083980.1, Si Da) instructions embodiment 1, asparagic acid azithromycin can be prepared, is designated as Y3.
preparation example 4: prepare malate bulk drug
With reference to the method for CN101193904A (Chinese Patent Application No. 200680020147.0, S. Korea and the USA) instructions embodiment 1, malate can be prepared, is designated as Y4.
preparation example 5: prepare lactobionic acid azithromycin bulk drug
With reference to the method for CN101381386A (Chinese Patent Application No. 200810215777.4, Liu Li) instructions embodiment 1, lactobionic acid azithromycin can be prepared, is designated as Y5.
preparation example 6: prepare Azithromycin Sulfate bulk drug
With reference to the method for CN101092440A (Chinese Patent Application No. 200710070087.X, spike) instructions embodiment 1, can prepare
sulphuracid azithromycin, is designated as Y6.
preparation example 7: maleic acid azithromycin drug
Can be directly purchased from the maleic acid azithromycin that is produced from pharmaceutical factory, Tianjin, be designated as Y7.
the embodiment part of C, freeze drying powder-injection
embodiment 1: the freeze drying powder-injection preparing azithromycin pharmaceutical salts
The various azithromycins using preparation example 1 ~ preparation example 7 to obtain respectively are raw material, according to CN101327191A (Chinese Patent Application No. 200810126746.1, brocade is auspicious) composition and engineering of instructions embodiment 1, be prepared into freeze drying powder-injection, every bottle of active component loading amount 0.25g.
The numbering of different powder-injection makes to number corresponding with its raw material with the following methods: be numbered F1 for the powder-injection using raw material Y1 to prepare, and the powder-injection using raw material Y2 to prepare is numbered F2; The rest may be inferred by analogy for it.
the test example part of D, investigation the inventive method and sample
test example 1: investigate GC method of the present invention
(1) B above about bulk drug preparation example part and above C about the embodiment part of freeze drying powder-injection, use whole samples that [vapor-phase chromatography A] measures, when impurity a and impurity b being detected, their tb/ta, all in 1.9 ~ 2.1 scopes, shows that two impurity relative retention time is in the methods of the invention constant.
(2) for bulk drug Y1, bulk drug Y2, these four samples of powder-injection F1, powder-injection F2, measure with reference to the condition of the inventive method example 1 about [vapor-phase chromatography A], but the processing mode of headspace sampling wherein changes into: Sample equilibration temperature is 70 DEG C, Sample equilibration time is 5min, shakes with the rotating speed of 200rpm simultaneously.What the result of four Specimen Determinations measured with [vapor-phase chromatography A] as a result comes to the same thing, such as: tb/ta is all in 1.9 ~ 2.1 scopes, and impurity a content and Ab/Aa value differ with [vapor-phase chromatography A] measurement result and be all no more than 5% respectively.
(3) for bulk drug Y1, bulk drug Y2, these four samples of powder-injection F1, powder-injection F2, measure with reference to the condition of the inventive method example 1 about [vapor-phase chromatography A], but the processing mode of headspace sampling wherein changes into: Sample equilibration temperature is 50 DEG C, Sample equilibration time is 15min, shakes with the rotating speed of 200rpm simultaneously.What the result of four Specimen Determinations measured with [vapor-phase chromatography A] as a result comes to the same thing, such as: tb/ta is all in 1.9 ~ 2.1 scopes, and impurity a content and Ab/Aa value differ with [vapor-phase chromatography A] measurement result and be all no more than 5% respectively.
(4) for bulk drug Y3, bulk drug Y4, these four samples of powder-injection F3, powder-injection F4, measure with reference to the condition of the inventive method example 1 about [vapor-phase chromatography A], but the processing mode of headspace sampling wherein changes into: Sample equilibration temperature is 40 DEG C, Sample equilibration time is 20min, shakes with the rotating speed of 200rpm simultaneously.What the result of four Specimen Determinations measured with [vapor-phase chromatography A] as a result comes to the same thing, such as: tb/ta is all in 1.9 ~ 2.1 scopes, and impurity a content and Ab/Aa value differ with [vapor-phase chromatography A] measurement result and be all no more than 5% respectively.
(5) for bulk drug Y5, bulk drug Y6, powder-injection F5, powder-injection F6 these four has sample, measure with reference to the condition of the inventive method example 1 about [vapor-phase chromatography A], but temperature programme curve wherein changes into: (i) to be warming up to the process of 150 DEG C programming rate at 7.8 DEG C/min from 60 DEG C, or (ii) to be warming up to the process of 150 DEG C programming rate at 8.2 DEG C/min from 60 DEG C, these samples are repeated respectively under this (i) and (ii) condition sample introduction when measuring 10 times, when using said procedure heating curve of the present invention, wherein the RSD of Ab is all in 0.06% ~ 1.21% scope.With reference to the result of this test method reprogramming heating curve gained see described in detail above.Visible, in vapor-phase chromatography of the present invention, it is extremely useful for being warming up to the process of 150 DEG C programming rate at 7.8 ~ 8.2 DEG C/min from 60 DEG C.
test example 4: product property is investigated
According to the method for the inventive method example 3, test preparation example 1 ~ preparation example 7 and the various azithromycin pharmaceutical salts bulk drug of embodiment and the character of azithromycin pharmaceutical salts powder-injection.Result shows, and use HPLC to measure, the related substance of various bulk drug all can meet States Pharmacopoeia specifications, and content is pressed anhydride and calculated containing C38H72N2O12 all in 96.5% ~ 101.0% scope; The related substance of various powder-injection all can meet said method regulation, and content is all in 96% ~ 104% scope of labelled amount.For the various bulk drug disposed through 42 DEG C-March in test example 2 of the present invention and powder-injection sample, their use HPLC to measure also can meet the requirement of the above-mentioned specifications of quality equally; But when these samples through high-temperature treatment use [vapor-phase chromatography A] to measure, display impurity a has significant increase.This shows to use HPLC to be not enough to accurately pass judgment on the quality of azithromycin pharmaceutical salts bulk drug and preparation, uses GC method of the present invention to be useful.
Claims (15)
1. detect the method for impurity a in azithromycin pharmaceutical salts or its preparation and impurity b, described impurity a is 3-methylfuran, and described impurity b is the peak b of the retention time tb determined by following vapor-phase chromatography; The method uses vapor-phase chromatography to detect, and comprises the following steps:
(1) preparation of test fluid:
The preparation of need testing solution: be taken as the azithromycin pharmaceutical salts 0.2g for test sample or the preparation be equivalent to containing azithromycin pharmaceutical salts 0.2g as test sample, accurately weighed, put in the ml headspace bottle of 20mL, the 5ml that adds water dissolves, as need testing solution;
The preparation of 3-methylfuran reference substance solution: get 3-methylfuran reference substance 30mg, accurately weighed, put in the measuring bottle of 100mL, be dissolved in water and be diluted to scale, shaking up; The accurate 2mL that draws puts in the measuring bottle of 100mL, is diluted with water to scale, shakes up; The accurate 5mL that draws puts in the ml headspace bottle of 20mL again, and as 3-methylfuran reference substance solution, its 3-methylfuran concentration be equivalent in this solution is 0.03mg/5ml;
(2) GC conditions:
Chromatographic column: DB-624 capillary column, it is 30m × 0.53mm × 3.0 μm, is the product of J & W Scientific company;
Temperature programme: post initial temperature 40 DEG C, keeps 5min; Be warming up to 60 DEG C with 5 DEG C/min, keep 5min; Be warming up to 150 DEG C with the speed of 7.5 ~ 8.5 DEG C/min, keep 10min;
Injector temperature is 180 DEG C;
Carrier gas is nitrogen, flow 2.0mL/min, not shunt mode sample introduction;
Headspace sampling: headspace sample equilibrium temperature is 40 DEG C ~ 70 DEG C, and headspace sample equilibration time is 5min ~ 20min;
Detecting device is FID, temperature 250 DEG C, hydrogen 40mL/min, air 350mL/min, nitrogen 25mL/min;
Sample size: 1min;
(3) gas Chromatographic Determination:
According to the vapor-phase chromatography that the version Pharmacopoeia of the People's Republic of China in 2010 two annex V E are contained, measure by above-mentioned GC conditions;
Get 3-methylfuran reference substance solution to measure, obtain chromatogram 1; Get need testing solution in addition to measure, obtain chromatogram 2;
(4) calculate:
Read retention time and the peak area of main peak 3-methylfuran in chromatogram 1, this retention time is labeled as t1, and this peak area is designated as A1;
Read retention time and the peak area of each chromatographic peak in chromatogram 2;
In this chromatogram 2, the chromatographic peak consistent with main peak 3-methylfuran retention time in chromatogram 1 is 3-methylfuran peak, and this chromatographic peak is designated as peak a in fig. 2, and its retention time is designated as ta, and it is suitable with t1, and its peak area is designated as Aa;
In this chromatogram 2, if there is chromatographic peak at retention time tb place, it is designated as peak b, and the peak area of this peak b is designated as Ab, and wherein tb is 1.8 ~ 2.2 times of ta;
For impurity a, by external standard method with the content (%) of 3-methylfuran in calculated by peak area test sample relative to azithromycin pharmaceutical salts;
For impurity b, calculate the ratio of peak b peak area and peak a peak area, i.e. Ab/Aa value.
2. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein said azithromycin pharmaceutical salts is the acid-addition salts of azithromycin.
3. the impurity a in detection azithromycin pharmaceutical salts according to claim 2 or its preparation and the method for impurity b, described azithromycin pharmaceutical salts is selected from azithromycin dihydrochloride, lactobionic acid azithromycin, maleic acid azithromycin, Azithromycin Sulfate, fumaric acid azithromycin, asparagic acid azithromycin, malate.
4. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, the preparation of wherein said azithromycin pharmaceutical salts is the preparation of injection.
5. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, the preparation of described azithromycin pharmaceutical salts is the preparation of injection, and it is selected from: the parenteral solution of freeze drying powder-injection, solution-type.
6. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein tb is 1.85 ~ 2.15 times of ta.
7. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein tb is 1.9 ~ 2.1 times of ta.
8. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein tb is 1.95 ~ 2.05 times of ta.
9. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 70 DEG C, and Sample equilibration time is 5min, shakes with the rotating speed of 200rpm simultaneously.
10. the impurity a in detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 60 DEG C, Sample equilibration time is 10min, shakes with the rotating speed of 200rpm simultaneously.
Impurity a in 11. detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 50 DEG C, Sample equilibration time is 15min, shakes with the rotating speed of 200rpm simultaneously.
Impurity a in 12. detection azithromycin pharmaceutical salts according to claim 1 or its preparation and the method for impurity b, wherein the processing mode of headspace sampling is: Sample equilibration temperature is 40 DEG C, Sample equilibration time is 20min, shakes with the rotating speed of 200rpm simultaneously.
The method of the 13. detection azithromycin pharmaceutical salts according to any one of claim 1 to 12 or the impurity a in its preparation and impurity b, in the temperature programme of vapor-phase chromatography, is warming up to 150 DEG C with the speed of 7.8 ~ 8.2 DEG C/min from 60 DEG C.
The method of the 14. detection azithromycin pharmaceutical salts according to any one of claim 1 to 12 or the impurity a in its preparation and impurity b, in the temperature programme of vapor-phase chromatography, is warming up to 150 DEG C with the speed of 8 DEG C/min from 60 DEG C.
The method of the 15. detection azithromycin pharmaceutical salts according to any one of claim 1 to 12 or the impurity a in its preparation and impurity b, described DB-624 capillary column is middle polarity chromatographic column.
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