CN106855542B - Method of the high performance liquid chromatography detection metadoxine in relation to substance - Google Patents
Method of the high performance liquid chromatography detection metadoxine in relation to substance Download PDFInfo
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Abstract
The invention belongs to Pharmaceutical Analysis technical fields, specifically, it is related to a kind of method of the high performance liquid chromatography detection metadoxine in relation to substance, metadoxine test solution and reference substance solution are detected respectively using high performance liquid chromatography, record the chromatogram of the two and obtains the peak area of vitamin B6 alkali and the main peak area of the reference substance solution in the metadoxine test solution and quantitative analysis is carried out to the related substance of metadoxine with external standard method；The reference substance solution is metadoxine sterling solution.This method separating degree is high, principal component retention time moderate i.e. analysis time is short, at low cost.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, in particular to a kind of high performance liquid chromatography detection metadoxine
Method in relation to substance.
Background technique
Metadoxine, the entitled pyridoxol L-2 pyrrolidone-5-carboxylic acid salt of chemistry, under chemical structure such as formula shown in；
Metadoxine is developed by Italian Laboratori Baldacci SPA company, and in September, 1985 is in Italy
Listing, trade name Metadoxil；Metadoxine can reduce ethyl alcohol in blood, and internal ethyl alcohol mainly turns through alcohol dehydrogenase (ADH)
Acetaldehyde is turned to, is converted into acetaldehyde through microsomal ethanol oxidase on a small quantity, acetaldehyde is converted into acetic acid through acetaldehyde dehydrogenase (ALDH) again,
CO is finally oxidized to through tricarboxylic acid cycle again2And H2O.Because the accretion rate of ethyl alcohol depends primarily on the vigor of intrahepatic metabolism enzyme, therefore
Ying Yuqi can prevent the inactivation of ADH related, and internal ADH can be made to maintain normal level, and there are also studies have shown that metadoxine can add
Through kidney excretion, indication is alcoholic liver disease for fast ethyl alcohol and its metabolite acetaldehyde and ketoboidies.Patients with alcoholic liver disease group
Body is huge, and has growth trend, and metadoxine can improve as caused by long-term alcohol as treatment alcoholic liver medicine
Hepatic disorder.As metadoxine drug is widely used, crowd's concern is benefited from by vast as its quality of drug, and it is existing
Metadoxine quality research is less, and therefore, the quality research of metadoxine is of great significance to the control of its quality.
Currently, be all made of Luna C18 (2), Agilen Zorbax SB-C18 chromatographic column in the prior art detect beauty he
Mostly pungent main component and related substance, when being detected using such chromatographic column, sample retention time is too long, and separating degree is small etc.
Disadvantage；Cause related substance that cannot efficiently separate with main component pyroglutamic acid if attempting to shorten retention time；Therefore it finds
The detection method that a kind of separating degree is high, principal component retention time moderate i.e. analysis time is short, at low cost is necessary.
In view of this, the present invention is specifically proposed.
Summary of the invention
The purpose of the present invention is to provide a kind of method of the high performance liquid chromatography detection metadoxine in relation to substance, to solve
The above problem.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of method of the high performance liquid chromatography detection metadoxine in relation to substance, comprising:
Metadoxine test solution and reference substance solution are detected respectively using high performance liquid chromatography, record two
The chromatogram of person simultaneously obtains the peak area of vitamin B6 alkali and the reference substance solution in the metadoxine test solution
Main peak area simultaneously carries out quantitative analysis to the related substance of metadoxine with external standard method；
The reference substance solution is metadoxine sterling solution.
The present invention carries out quantitative analysis using external standard method, can be right no matter the whether whole appearances of all components in sample
Appearance component does quantitative analysis.For quantitatively reference substance, external standard method is method the most accurate, because being that homogeneity component carries out
Compare.
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the metadoxine
The concentration of test solution be 0.2mg/ml~1mg/ml, more preferably 0.3mg/ml~0.6mg/ml, it is also an option that
0.4mg/ml。
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the reference substance are molten
The concentration of liquid is the 0.04 μ g/ml of μ g/ml~10, the more preferably 0.08 μ g/ml of μ g/ml~8, more preferably 0.5 μ of μ g/ml~6 g/
Ml, it is also an option that 1 μ g/ml, 2 μ g/ml or 4 μ g/ml etc..
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above is carrying out efficient liquid
When phase chromatography detects, the stationary phase of chromatographic column used is that full multi-hole blangel particle is bonded C8 functional group, and mobile phase is acetonitrile-water
Mixed solution.
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the chromatographic column
Specification are as follows:
Internal diameter is 4.2~5.0mm, and length is 200~300mm, and packing material size is 2~8 μm.More preferably internal diameter is
4.6mm, length 250mm, packing material size are 5 μm.
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the chromatographic column are
Inertsil C8-4。
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the acetonitrile-water
The volume ratio of acetonitrile and water is 1:99~10:90 in mixed solution, and adjusting flowing phase pH value with phosphoric acid is 1.0~3.0；It is preferred that
The acetonitrile-water mixed solution in the volume ratio of acetonitrile and water be 1:99~5:90, and with phosphoric acid adjust flowing phase pH value
It is 1.5~2.5；
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the mobile phase
Flow velocity is 0.5ml/min~1.5ml/min；It is furthermore preferred that flow velocity is 0.8ml/min-1.2ml/min, it is also an option that
0.6ml/min, 1.0ml/min etc..
The size of flow velocity directly influences the dosage problem of mobile phase, but from the perspective of economy, it should which setting is smaller
Flow velocity；Since the filling of pillar and the relationship of instrument itself can not set excessive flow velocity.
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above, the chromatographic column
Column temperature is 10 DEG C~40 DEG C, more preferably 25 DEG C~35 DEG C.
Retention time when column temperature is to elution is affected, and with the raising of column temperature, retention time can generally decline.
Preferably, method of the high performance liquid chromatography detection metadoxine in relation to substance as described above is carrying out efficient liquid
When phase chromatography detects, Detection wavelength is 200nm~300nm, more preferably 200nm~210nm, it is also an option that 205nm；Efficiently
Liquid chromatogram single injected sampling amount is the 3 μ l of μ l~7, more preferably 5 μ l.
Compared with prior art, the invention has the benefit that
1), compared with prior art, the method for the present invention has higher separating degree, in metadoxine contained vitamin B6 with
Pyroglutamic acid main component separating degree is greater than 7.0, and chromatography main peak theoretical tray is greater than 10000, and peak shape is sharp, symmetrical.
2), the present invention is that (1%:99%, when phosphoric acid tune pH value is 2.0), that is, can guarantee beauty, he is more for second eyeball-water in mobile phase
The pungent main separating degree of principal component can make principal component and the separating degree of major impurity be greater than 6.0, and when reservation 7.0 or more
Between within 10min, be provided simultaneously with the advantages that separating degree is high, analysis time is short.
3), the present invention is using flowing phased soln metadoxine, solubility is higher, solution rate faster, can be effective
It avoids that solid is precipitated in detection process and leads to the blocking of chromatographic column and chromatographic system, so that testing result is accurate and reliable,
It operates also easier.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is to detect chromatogram to the liquid phase of metadoxine under the conditions of embodiment 1；
Fig. 2 is to detect chromatogram to the liquid phase of metadoxine under the conditions of embodiment 2；
Fig. 3 is to detect chromatogram to the liquid phase of metadoxine under the conditions of embodiment 3；
Fig. 4 is to detect chromatogram to the liquid phase of metadoxine under the conditions of embodiment 4；
Fig. 5 is the linear relationship of detection method.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products obtained can be bought by city.
Test sample, reference substance used in the specific embodiment of the invention, equipment are known product, and wherein reference substance exists
National Institute for Food and Drugs Control's purchase
High performance liquid chromatograph: Angilent1260 high performance liquid chromatograph, DAD detector
Make in detailed below referring to Figure of description in method of the specific embodiment to measurement metadoxine content of the invention
Explanation.
Embodiment 1
Metadoxine high-efficiency liquid chromatography method for detecting:
(1) prepare test solution: precision weighs metadoxine 5mg, sets in 25ml measuring bottle, adds flowing phased soln and dilutes
It to scale, shakes up, as test solution.
Preparation reference substance solution: taking the related substance A 5mg of metadoxine, be placed in 25ml measuring bottle, adds flowing phased soln simultaneously
It is diluted to scale, is shaken up, as reference substance stock solution；Precision measures in right amount, and quantitative dilution is made in every 1ml containing 0.2 μ g's
Solution, as reference substance solution
Preparation system employment and suitability test (E & ST) solution: taking metadoxine 5mg, is placed in 25ml measuring bottle, adds flowing phased soln and dilute
It releases to scale, shakes up, obtain metadoxine solution；Take reference substance stock solution 0.25ml, be placed in 25ml measuring bottle, with it is above-mentioned beauty he
Mostly pungent solution is diluted to scale, shakes up, as system suitability solution；
(2) testing conditions of high performance liquid chromatography are as follows:
Chromatographic column: Inertsil C8-4 (5 μm of 4.6mm × 260mm)
Mobile phase: acetonitrile-water (1%:99%), phosphoric acid tune pH value are 2.0
Flow velocity: 0.8ml/min
Detection wavelength: 205nm
Column temperature: 25 DEG C
According to above-mentioned testing conditions, 5 μ l of system suitability solution is taken to inject liquid chromatograph, records chromatogram, take
5 μ l of reference substance injects liquid chromatograph, adjusts detection sensitivity, making principal component chromatographic peak peak height is about the 10% of full scale；Essence
Close each 5 μ l of measurement test solution and control solution is injected separately into liquid chromatograph, chromatogram is recorded, by external standard method with peak
The content of areal calculation experimental cultivar metadoxine impurity is about 0.02%.
Calculation formula:
The related substance of metadoxine
In formula:
ASample: the peak area of vitamin B6 alkali in confession under directions test sample solution；
AIt is right: refer to reference substance solution main peak area
CSample: the concentration (unit: mg/ml) of confession under directions test sample solution
CIt is right: refer to the concentration (unit: μ g/ml) of reference substance solution
Metadoxine main component vitamin B6, pyroglutamic acid, the separating effect in relation to substance A under the conditions of 1 embodiment 1 of table
Note: the calculated result of 2#, 3# separating degree is with 1# correlation
The result shows that detection method metadoxine principal component vitamin B6 and pyroglutamic acid separating degree are 7.31,
Vitamin B6 alkali and related substance A separating degree 6.53, theoretical tray is all larger than 51000, much higher than the prior art separating degree and
Theoretical cam curve effectively avoids the accuracy of the interference effect testing result of each component；Meanwhile detection method beauty
Principal component and the retention time in relation to substance A have many advantages, such as that analysis time is short, at low cost within 10min in Ta Duoxin.
Embodiment 2
Mobile phase is changed to acetonitrile-water (5%:95%) in testing conditions, and phosphoric acid tune pH value is 2.0, other steps and implementation
Condition is the same as embodiment 1.
According to above-mentioned testing conditions, 5 μ l of system suitability solution is taken to inject liquid chromatograph, records chromatogram, take
5 μ l of reference substance injects liquid chromatograph, adjusts detection sensitivity, making principal component chromatographic peak peak height is about the 10% of full scale；Essence
Close each 5 μ l of measurement test solution and control solution is injected separately into liquid chromatograph, chromatogram is recorded, by external standard method with peak
The content of areal calculation experimental cultivar metadoxine impurity is about 0.02%.
Metadoxine main component vitamin B6, pyroglutamic acid, the separation effect in relation to substance A under the conditions of table 2, embodiment 2
Fruit
Note: the calculated result of 2#, 3# separating degree is with 1# correlation
The result shows that detection method metadoxine principal component vitamin B6 and pyroglutamic acid separating degree are 3.27,
Vitamin B6 alkali and related substance A separating degree 8.43, theoretical tray is all larger than 54000, much higher than the prior art separating degree and
Theoretical cam curve effectively avoids the accuracy of the interference effect testing result of each component；Meanwhile detection method beauty
Principal component and the retention time in relation to substance A have many advantages, such as that analysis time is short, at low cost within 10min in Ta Duoxin.
Embodiment 3
Flow velocity becomes 1.0ml/min in testing conditions, other steps and implementation condition are the same as embodiment 1.
According to above-mentioned testing conditions, 5 μ l of system suitability solution is taken to inject liquid chromatograph, records chromatogram, take
5 μ l of reference substance injects liquid chromatograph, adjusts detection sensitivity, making principal component chromatographic peak peak height is about the 10% of full scale；Essence
Close each 5 μ l of measurement test solution and control solution is injected separately into liquid chromatograph, chromatogram is recorded, by external standard method with peak
The content of areal calculation experimental cultivar metadoxine impurity is about 0.02%.
Metadoxine main component vitamin B6, pyroglutamic acid, the separation effect in relation to substance A under the conditions of table 3, embodiment 3
Fruit
Note: the calculated result of 2#, 3# separating degree is with 1# correlation
The result shows that detection method metadoxine principal component vitamin B6 and pyroglutamic acid separating degree are 6.36,
Vitamin B6 alkali and related substance A separating degree 8.08, theoretical tray is all larger than 44000, much higher than the prior art separating degree and
Theoretical cam curve effectively avoids the accuracy of the interference effect testing result of each component；Meanwhile detection method beauty
Principal component and the retention time in relation to substance A have many advantages, such as that analysis time is short, at low cost within 10min in Ta Duoxin.
Embodiment 4
Column temperature becomes 35 DEG C in testing conditions, other steps and implementation condition are the same as embodiment 1.
According to above-mentioned testing conditions, 5 μ l of system suitability solution is taken to inject liquid chromatograph, records chromatogram, take
5 μ l of reference substance injects liquid chromatograph, adjusts detection sensitivity, making principal component chromatographic peak peak height is about the 10% of full scale；Essence
Close each 5 μ l of measurement test solution and control solution is injected separately into liquid chromatograph, chromatogram is recorded, by external standard method with peak
The content of areal calculation experimental cultivar metadoxine impurity is about 0.02%.
Metadoxine main component vitamin B6, pyroglutamic acid, the separation effect in relation to substance A under the conditions of table 4, embodiment 4
Fruit
Note: the calculated result of 2#, 3# separating degree is with 1# correlation
The result shows that detection method metadoxine principal component vitamin B6 and pyroglutamic acid separating degree are 7.48,
Vitamin B6 alkali and related substance A separating degree 6.86, theoretical tray is all larger than 55000, much higher than the prior art separating degree and
Theoretical cam curve effectively avoids the accuracy of the interference effect testing result of each component；Meanwhile detection method beauty
Principal component and the retention time in relation to substance A have many advantages, such as that analysis time is short, at low cost within 10min in Ta Duoxin.
Test example 1, linear relationship
(1) it takes test solution appropriate respectively, adds mobile phase that the series that concentration is 0.05 μ of μ g/ml~1.5 g/ml is made and supply
Test sample solution；
(2) above-mentioned test solution is detected according to the testing conditions of embodiment 1, records chromatogram, he is more with beauty
The concentration of pungent middle vitamin B6 alkali carries out linear regression to corresponding peak area, linear equation: y=16.20x+0.280, related
Coefficients R2=0.999, as shown in Figure 5.
The experimental results showed that under conditions of detection method, concentration of the metadoxine in relation to substance A and peak area line
Sexual intercourse is good.
Test example 2, detection limit test
The a height of 222uv of reference substance solution main peak of minimum concentration in linear relationship test, baseline noise is about 5uv, noise
Than being about 44:1, according to detection limit require (signal-to-noise ratio should be 3:1), be respectively configured 0.02,0.002,0.0002 μ g/ml beauty he
Mostly pungent to photo solution, according to the testing conditions of embodiment 1, sample introduction is measured, and records chromatogram.
The minimum detectable activity of vitamin B6 is 0.02ng in metadoxine, pyroglutamic acid minimum detectable activity is 0.2ng, test
The result shows that detection method of the invention is low to the main component vitamin B6 of metadoxine, pyroglutamic acid detection limit.
Test example 3, precision test
By preparing potential known impurities, 6 needle of continuous sample introduction records chromatogram, investigates separating degree and peak area, it is desirable that
The RSD for measuring 6 results is not greater than 5.0%, carrys out substantive approach with good sample introduction precision, and measures simultaneously each known
The correction factor of impurityAnd relative retention time.
MT-1, MT-2, MT-3, MT-4 each 5mg of impurity reference substance are weighed respectively, are placed in 25ml measuring bottle, flowing is added to mix
Scale is solved and be diluted to, is shaken up；It takes 1ml to set in 100ml measuring bottle respectively, mobile phase is added to be diluted to scale, shake up molten as testing
Liquid
According to the testing conditions of embodiment 1, test 5 μ l of solution is taken, liquid chromatograph is injected, METHOD FOR CONTINUOUS DETERMINATION 6 times, records
Chromatogram.Testing result is shown in Table 6.
Table 6, each impurity retention time of reference substance precision investigate result
| Component | 1 | 2 | 3 | 4 | 5 | 6 | It is average | RSD% |
| MT-1 | 5.659 | 5.675 | 5.657 | 5.658 | 5.657 | 5.657 | 5.6605 | 0.08 |
| MT-2 | 6.163 | 6.190 | 6.170 | 6.165 | 6.166 | 6.161 | 6.1691 | 0.12 |
| MT-3 | 7.101 | 7.133 | 7.110 | 7.109 | 7.104 | 7.102 | 7.1098 | 0.11 |
| MT-4 | 10.317 | 10.361 | 10.338 | 10.326 | 10.317 | 10.314 | 10.3288 | 0.13 |
According to table 6 as can be seen that after reference substance solution continuous sample introduction 6 times, the equal < 2.0% of the RSD of each impurity retention time,
Sample introduction precision is good.
Test example 4, the specificity of method
The identification and selectivity at the specificity study tour peak of method, it is desirable that: sample introduction blank solution and all positioning respectively
Solution, to determine that the separating degree between all potential impurity, main peak and adjacent chromatographic peak cannot be less than 1.5.
Known impurities MT-1, MT-2, MT-3, MT-4 are configured to the positioning solution that concentration is about 0.2mg/ml respectively, it will
Above-mentioned impurity positioning solution respectively takes 1ml to set in same 10ml measuring bottle, and mobile phase is added to be diluted to scale, shakes up to obtain impurity mixing molten
Liquid.It separately takes metadoxine 5mg into 25ml volumetric flask, and takes impurity mixed solution 0.25ml in this measuring bottle, add mobile phase dilute
It releases to scale, shakes up as mixed solution
According to the testing conditions of embodiment 1, blank (mobile phase), each positioning solution and each 5 μ l of mixed solution are injected
Liquid chromatograph records chromatogram.Testing result is shown in Table 5.
Table 5, mixed solution separating degree test result
| Compound numbers | Retention time (min) | Separating degree | Theoretical cam curve | The purity factor |
| Blank | 2.035 | / | / | / |
| MT-1 | 5.645 | / | 14092 | 999.862 |
| MT-2 | 6.358 | 3.79 | 18863 | 999.452 |
| MT-3 | 7.388 | 5.23 | 20211 | 999.354 |
| MT-4 | 10.855 | 13.55 | 20547 | 999.615 |
According to table 5 as can be seen that blank does not interfere metadoxine in relation to the detection of substance, its defects inspecting is not interfered yet.
Each impurity can be separated efficiently in metadoxine, and separating degree is all larger than 2.0, and peak shape is good, and peak purity is good, theoretical tray
Number is greater than 3000, and tailing factor is complied with standard less than 1.5.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (5)
1. a kind of method of the high performance liquid chromatography detection metadoxine in relation to substance characterized by comprising
Both metadoxine test solution and reference substance solution are detected respectively using high performance liquid chromatography, record
Chromatogram simultaneously obtains vitamin B6 in the metadoxine test solution, pyroglutamic acid, the peak area in relation to substance A and described
The main peak area of reference substance solution simultaneously carries out quantitative analysis to the related substance of metadoxine with external standard method；
When carrying out high performance liquid chromatography detection, the stationary phase of chromatographic column used is that full multi-hole blangel particle is bonded C8 functional group,
Mobile phase is the mixed solution of acetonitrile-water；The volume ratio of acetonitrile and water is 1:99~10 in the mixed solution of the acetonitrile-water:
90, and adjusting flowing phase pH value with phosphoric acid is 1.0~3.0；
The flow velocity of the mobile phase is 0.5ml/min~1.5ml/min；
The column temperature of the chromatographic column is 10 DEG C~40 DEG C；
When carrying out high performance liquid chromatography detection, Detection wavelength is 200nm~300nm；High performance liquid chromatography single injected sampling amount is 3
The μ of μ l~7 l；
The reference substance solution is metadoxine sterling solution.
2. method of the high performance liquid chromatography detection metadoxine in relation to substance according to claim 1, which is characterized in that institute
The concentration for stating metadoxine test solution is 0.2~1mg/ml.
3. method of the high performance liquid chromatography detection metadoxine in relation to substance according to claim 1, which is characterized in that institute
The concentration for stating reference substance solution is 0.04 μ of μ g/ml~10 g/ml.
4. method of the high performance liquid chromatography detection metadoxine in relation to substance according to claim 1, which is characterized in that institute
State the specification of chromatographic column are as follows:
Internal diameter is 4.2~5.0mm, and length is 200~300mm, and packing material size is 2~8 μm.
5. method of the high performance liquid chromatography detection metadoxine in relation to substance according to claim 1, which is characterized in that institute
Stating chromatographic column is Inertsil C8-4.
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