CN108254463A - A kind of analysis method for detecting aspartic acid ornithine impurity - Google Patents
A kind of analysis method for detecting aspartic acid ornithine impurity Download PDFInfo
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- CN108254463A CN108254463A CN201711498684.2A CN201711498684A CN108254463A CN 108254463 A CN108254463 A CN 108254463A CN 201711498684 A CN201711498684 A CN 201711498684A CN 108254463 A CN108254463 A CN 108254463A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses a kind of analysis methods for detecting impurity in aspartic acid ornithine, belong to analytical chemistry field;This method uses liquid chromatogram, amino bonded silicone filler agent, Thermo APS 2 4.6 × 250mm, 5 μm, with 0.1mol/L potassium phosphate buffer acetonitriles(35:65)For mobile phase A, with 0.1mol/L potassium phosphate buffer acetonitriles(50:50)For Mobile phase B;Detection wavelength is 200nm;Flow velocity is 1.0ml per minute;Column temperature is 30 DEG C, gradient elution is analyzed, the technical program can carry out qualitative and quantitative analysis to 3 amino, 2 piperidones, two poly arginines, α L-aminobutanedioic acids dimer, L-aminobutanedioic acid condensation product in impurity aspartic acid ornithine rapidly, accurately, and separating degree is good, detection limit and quantitative limit are all relatively low, the range of linearity is wider, and so as to more accurately calculate the content of different impurities, further monitoring, research for impurity in aspartic acid ornithine provide technical support.
Description
Technical field:The invention belongs to analytical chemistry fields, and in particular to a kind of to use HPLC methods analysis detection door winter ammonia
The method of sour ornithine impurity, more specifically to 3- amino -2- piperidines in a kind of analysis detection aspartic acid ornithine
The method of four kinds of ketone, two poly arginines, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product impurity.
Background technology:
Aspartic acid ornithine (chemical name is (S) -2,5- diaminovaleric acid (s) -2- aminosuccinic acids salt), 20th century
The seventies records Deutscher Arzneibucs, import listing at home in 2000, domestic manufacturer's life in 2006 for 1991 in Germany for clinic
Production listing, hyperammonemia caused by for treating hepatic disease, aspartic acid ornithine can provide urea and glutamy in vivo
The substrate of amine synthesis.Under physiology and pathological conditions, the synthesis of urea and the synthesis of glutamine can be by ornithine, door winter ammonia
The influence of sour and other dicarboxylic compounds;Ornithine is almost related to the overall process of the activation of urea cycle and the removing toxic substances of ammonia;
Arginine is formed during this, urea is then isolated and forms ornithine;L-aminobutanedioic acid participates in the synthesis of liver cell nucleic acid, with
The liver cell being damaged conducive to reparation.
Pharmaceutical preparation containing aspartic acid ornithine ingredient used in clinical at present, there is aspartic acid ornithine particle
3 kinds of agent, powder ampoule agent for injection and parenteral solution preparation formulations;Mass analyzed discovery, in aspartic acid ornithine synthesis and preparation
Storage during often occur 3- amino -2- piperidones, two poly arginines, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid together
Four kinds of impurity of condensation product, these four substances easily cause human body adverse reaction and medicine irritation in itself without therapeutic effect,
How much content directly affects aspartic acid ornithine or the quality of its preparation, also determines the shelf-life length of drug.
About the detection method of impurity in aspartic acid ornithine, CN104807924A aspartic acid ornithines raw material and system
It is possible that aspartic acid ornithine prepared by a kind of accurately analysis detection synthesis technology is provided in agent specific impurities detection method
The impurity contained:Fumaric acid, arginine, urea, succinic acid, malic acid, lactams high-efficient liquid phase analysis detection method;
A kind of analyzing detecting methods of aspartic acid ornithine impurity of CN102288687A also provide only ornithyl amine or impure bird
The detection method of the drug of glutamine and its impurity ornithyl amine of preparation;In more than patent do not disclose two poly arginines,
The qualitative and quantitative analysis method of α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product.And existing aspartic acid ornithine and
The method qualitatively and quantitatively of related above four kinds of impurity, the application are not included in the drug standard of its preparation clearly yet
The research carried out mainly for the qualitative and quantitative approach of above four kinds of impurity.
Invention content
The application be directed to aspartic acid ornithine raw material and preparation in impurity 3- amino -2- piperidones, two poly arginines,
α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product carry out qualitative and quantitative study.
The technology contents of the present invention are as follows:
A kind of analysis method for detecting aspartic acid ornithine impurity, is measured, chromatostrip using high performance liquid chromatograph
Part is:
Chromatographic column:Amino bonded silicone filler agent, ThermoAPS-2 chromatographic columns specification are 4.6mm × 250mm × 5 μm;
Flow velocity:0.8-1.2ml/min;
Column temperature:30-40℃;
UV detector Detection wavelength:190-220nm;
Sample size:10-30μl;
Mobile phase:A phases:0.1mol/L potassium phosphate buffers-acetonitrile;B phases:0.1mol/L potassium dihydrogen phosphates buffer
Liquid-acetonitrile;
Mobile phase A, B are carried out by Gradient program:
The preparation method of above-mentioned potassium phosphate buffer adds water 1000ml to make dissolving, uses to take potassium dihydrogen phosphate 13.7g
Phosphorus acid for adjusting pH value is to 4.3.
The volume ratio of 0.1mol/L potassium phosphate buffers and acetonitrile is 25-45 in mobile phase A:55-75;
The volume ratio of 0.1mol/L potassium phosphate buffers and acetonitrile is 40-60 in Mobile phase B:40-60;
Preferably, the volume ratio of 0.1mol/L potassium phosphate buffers and acetonitrile is 35 in mobile phase A:65;Mobile phase B
The volume ratio of middle 0.1mol/L potassium phosphate buffers and acetonitrile is 50:50;
Preferably, mobile phase A, B are carried out by following Gradient program:
Preferably, sample size is 20 μ l, flow velocity 1.0ml/min;The column temperature:35℃;The UV detector detection
Wavelength:200nm.
The technical method can be used for detection aspartic acid ornithine raw material and preparation or containing aspartic acid ornithine original
Contain 3- amino -2- piperidones, two poly arginines, α-L-aminobutanedioic acid dimer, door in the food of material, health products and medicine preparation
The method of winter propylhomoserin condensation product impurity.
Advantageous effect:
By the technical solution of the application, analysis below effect can be reached:
(1) it can detach simultaneously containing 3- amino -2- piperidones, two poly arginines, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid
The ornithine aspartate composition of four kinds of impurity of condensation product, mutual separating degree are both greater than 1.5, meet qualitative and quantitative
The requirement of analysis;
(2) detection limit is relatively low:L-aminobutanedioic acid condensation analyte detection is limited to 0.6ng, α-L-aminobutanedioic acid dimerization analyte detection limit
For 1.0ng, the detection of two poly arginines is limited to 3.4ng, and ornithine detection is limited to 16.7ng, and L-aminobutanedioic acid detection is limited to 5.0ng, 3-
The detection of amino -2- piperidones is limited to 0.13ng;
(3) quantitative limit is relatively low:L-aminobutanedioic acid condensation product is quantitatively limited to 1.8ng, α-L-aminobutanedioic acid dimer quantitative limit
For 3.0ng, two poly arginine quantitative limits are 10.2ng, and ornithine is quantitatively limited to 50.0ng, and L-aminobutanedioic acid is quantitatively limited to 15.0ng,
3- amino -2- piperidones is quantitatively limited to 0.4ng;
(4) range of linearity is wider:
In the range of the μ g/ml of 0.09 μ g/ml~38.5, L-aminobutanedioic acid condensation product peak area and concentration linear relationship are good, r
Be worth is 0.9992;
In the range of the μ g/ml of 0.15 μ g/ml~20.25, α-L-aminobutanedioic acid dimer peak area and concentration linear relationship are good
Good, r values are 0.9997;
In the range of the μ g/ml of 0.15 μ g/ml~20.30, two poly arginine peak areas and concentration linear relationship are good, r values
It is 0.9997;
In the range of the μ g/ml of 2.5 μ g/ml~99.88, ornithine peak area and concentration linear relationship are good, and r values are
0.9999;
In the range of the μ g/ml of 0.75 μ g/ml~99.88, L-aminobutanedioic acid peak area and concentration linear relationship are good, and r values are
0.9999;
In the range of the μ g/ml of 0.02 μ g/ml~383.61,3- amino -2- piperidones peak area and concentration linear relationship are good
Good, r values are 0.9990;
The technical solution of the application 3- amino -2- piperidones, two poly arginines, α-door in aspartic acid ornithine is analyzed
Separating degree is good when winter propylhomoserin dimer, L-aminobutanedioic acid condensation product, and detection limit and quantitative limit are all relatively low, and the range of linearity is wider to be met calmly
Property quantitative requirement, so as to accurately calculate the content of different impurities, be in aspartic acid ornithine impurity into one
Step monitoring, research provide technical support.
Specific embodiment
The present invention is described in detail with reference to embodiment, following embodiment is detailed to one kind of the present invention
Illustrate rather than be limitation of the present invention.
Liquid-phase chromatography method employed in example 1 below -4 carries out with the following method:
Chromatographic condition is as follows:
Chromatographic column:Amino bonded silicone filler agent ThermoAPS-2,250mm × 4.6mm × 5 μm;
Detection wavelength:200nm
Flow velocity:1.0ml/min
Column temperature:35℃.
Mobile phase A:With 0.1mol/L potassium phosphate buffers-acetonitrile (35:65);
Mobile phase B:With 0.1mol/L potassium phosphate buffers-acetonitrile (50:50).
It is analyzed using such as Gradient:
1 separating degree of embodiment detects
1), specific experiment operates:
Each impurity reference substance positions solution:Precision weighs 3- amino -2- piperidones, α-L-aminobutanedioic acid dimer, door winter ammonia
Sour condensation product, each 10mg of two poly arginines, put respectively in 50ml measuring bottles, and Mobile phase B is added to dissolve and is diluted to scale, is shaken up, i.e.,
.
Test sample positions solution:Precision weighs each 100mg of ornithine hcl 99, L-aminobutanedioic acid, aspartic acid ornithine, respectively
Put in 10ml measuring bottles, Mobile phase B is added to dissolve and be diluted to scale, shake up to get.
Mixed solution:Precision weighs aspartic acid ornithine, puts in 10ml measuring bottles, precision measurement 3- amino -2- piperidones,
α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product, two poly arginine reference substances each 0.5ml of positioning solution add stream with putting wherein
Dynamic phase B dissolves and is diluted to scale, shake up to get.
2), testing result
Precision measures Mobile phase B and each 20 μ l of above-mentioned solution, liquid chromatograph is injected separately into, according to above-mentioned gradient elution journey
Sequence is analyzed, and data statistics see the table below:
Table 1:Separating degree result of the test
Title | Retention time (min) | Maximum absorption wavelength (nm) | Separating degree |
Solvent peak | 2.0min before | —— | —— |
Succinic acid | 2.6425 | About 200 | —— |
3- amino -2- piperidones | 4.166 | 198 | 6.155 |
L-aminobutanedioic acid | 9.0665 | 195 | 4.325 |
Ornithine | 20.2155 | About 200 | 5.48 |
L-aminobutanedioic acid condensation product | 24.3965 | 195 | 2.17 |
α-L-aminobutanedioic acid dimer | 27.3415 | 195 | 1.785 |
Two poly arginines | 38.624 | 195 | 8.865 |
Result of the test:3- amino -2- piperidones, L-aminobutanedioic acid, ornithine, L-aminobutanedioic acid condensation product, α-L-aminobutanedioic acid two
The arginic separating degree of polymers, dimerization is both greater than 1.5, meets the requirement of qualitative and quantitative analysis.
2 range of linearity of embodiment measures
1) configuration of solution
Precision weighs α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product, each 10mg of two poly arginines, puts 10ml volumetric flasks
In, solubilizer makes dissolving and is diluted to scale in right amount, shakes up, as the linear storing solution of each impurity.
Precision weighs each 10mg of L-aminobutanedioic acid, ornithine, puts in 10ml measuring bottles, and precision adds in the above-mentioned linear storing solution of impurity
2ml is put in 100ml measuring bottles, and solubilizer makes dissolving and is diluted to scale in right amount, shakes up, as linear test solution 1#.
Precision measures linear test solution 1#8ml, 7ml, 6ml, 5ml, 4ml, 3ml, 2.5ml, 1ml, 0.5ml, puts respectively
In 10ml measuring bottles, solubilizer is diluted to scale, shakes up, as linear test solution 2#, 3#, 4#, 5#, 6#, 7#, 8#, 9#, 10#.
Precision weighs 3- amino -2- piperidones 40mg and is placed in 100ml measuring bottles, and solubilizer dissolves and is diluted to scale, shakes
It is even, as linear test solution 11#.
Precision measures linear test solution 11#9ml, 7ml, 5ml, 3ml, 1ml, 0.5ml, puts in 10ml measuring bottles, adds respectively
Solvent is diluted to scale, shakes up, as linear test solution 12#, 13#, 14#, 15#, 16#, 17#.
2) it measures
Precision measures above-mentioned linear each 20 μ l of test solution, injects liquid chromatograph, measures the range of linearity of each substance such as
Under:
Table 2:The linear test result of L-aminobutanedioic acid condensation product
Table 3:α-linear the test result of L-aminobutanedioic acid dimer
Table 4:The linear test result of two poly arginines
Table 5:The linear test result of 3- amino -2- piperidones
Table 6:The linear test result of ornithine
Table 7:L-aminobutanedioic acid test result
Experimental result:
In the range of the μ g/ml of 0.09 μ g/ml~38.5, L-aminobutanedioic acid condensation product peak area and concentration linear relationship are good, r
Be worth is 0.9992;
In the range of the μ g/ml of 0.15 μ g/ml~20.25, α-L-aminobutanedioic acid dimer peak area and concentration linear relationship are good
Good, r values are 0.9997;
In the range of the μ g/ml of 0.15 μ g/ml~20.30, two poly arginine peak areas and concentration linear relationship are good, r values
It is 0.9997;
In the range of the μ g/ml of 0.02 μ g/ml~383.61,3- amino -2- piperidones peak area and concentration linear relationship are good
Good, r values are 0.9990;
In the range of the μ g/ml of 2.5 μ g/ml~99.88, ornithine peak area and concentration linear relationship are good, and r values are
0.9999;
In the range of the μ g/ml of 0.75 μ g/ml~99.88, L-aminobutanedioic acid peak area and concentration linear relationship are good, and r values are
0.9999;
The measure of the detection limit of embodiment 3
1), detection limit method for measuring
The configuration of detection limit solution:The linear storing solution of each impurity in embodiment 2 is subjected to echelon dilution, obtains S/N ≈ 3
When solution as detection limit solution;
2), measurement result
Precision takes 20 μ l of blank solution, injects liquid chromatograph;Precision takes above-mentioned 20 μ l of quantitative limit solution, injects liquid phase color
Spectrometer, continuous sample introduction 3 times record chromatogram, are limited using S/N ≈ 3 as detection, data statistics such as following table.
Table 8:Detection limit result of the test
Result of the test:L-aminobutanedioic acid condensation analyte detection is limited to 0.6ng, and α-L-aminobutanedioic acid dimerization analyte detection is limited to 1.0ng, and two
Poly arginine detection is limited to 3.4ng, and ornithine detection is limited to 16.7ng, and L-aminobutanedioic acid detection is limited to 5.0ng, 3- amino -2- piperazines
The detection of pyridine ketone is limited to 0.13ng.
4 quantitative limit of embodiment
1), the method for quantitative limit detection
Quantitative limit solution allocation:The linear storing solution of each impurity in embodiment 2 is subjected to echelon dilution, obtains S/N ≈ 10
When solution as quantitative limit solution;
2), test method:Precision takes 20 μ l of blank solution, injects liquid chromatograph.Precision takes above-mentioned 20 μ of quantitative limit solution
L, injects liquid chromatograph, and continuous sample introduction 6 times records chromatogram, using S/N ≈ 10 as quantitative limit, as a result see the table below.
Table 9:Quantitative limit result of the test
Result of the test:L-aminobutanedioic acid condensation product is quantitatively limited to 1.8ng, α-L-aminobutanedioic acid dimer quantitative limit 3.0ng, dimerization
Arginine is quantitatively limited to 10.2ng, and ornithine is quantitatively limited to 50.0ng, and L-aminobutanedioic acid is quantitatively limited to 15.0ng, 3- amino -2- piperazines
Pyridine ketone is quantitatively limited to 0.4ng.
Embodiment 5
1), chromatographic condition:
Chromatographic column:Amino bonded silicone filler agent, ThermoAPS-2;Flow velocity:0.8ml/min;Column temperature:30℃;Ultraviolet inspection
Survey device Detection wavelength:190nm;Sample size:10μl;Mobile phase:A phases:0.1mol/L potassium phosphate buffers-acetonitrile, volume
Than being 25:75;B phases:0.1mol/L potassium phosphate buffers-acetonitrile, volume ratio 40:60;
Mobile phase A, B are carried out by Gradient program
2), prepared by test solution:
It is each that precision weighs 3- amino -2- piperidones, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product, two poly arginines
10mg is put in 10ml volumetric flasks, and solubilizer makes dissolving and is diluted to scale in right amount, shakes up, as the linear storing solution of each impurity.
Precision measures 3- amino -2- piperidones storing solution 2ml and other each storing solution 0.75ml, puts in 10ml volumetric flasks,
Solubilizer is diluted to scale, shakes up, as reference substance solution.
Precision measures ornithine aspartate injection 1ml, puts in 50ml volumetric flasks, and solubilizer is diluted to scale, shakes up,
As not plus impurity test solution.
It is analyzed by above-mentioned condition, result is:Four kinds of impurity are complete in ornithine aspartate injection under this condition
Complete to separate, appearance time and peak area are:
Table 10:Assay result
Title | Retention time (min) | Separating degree | Content (μ g/ml) |
Solvent peak | 2.0min before | —— | |
3- amino -2- piperidones | 5.236 | - | 0.05 |
L-aminobutanedioic acid | 10.658 | 4.85 | 23.6 |
Ornithine | 22.125 | 5.56 | 36.2 |
L-aminobutanedioic acid condensation product | 27.389 | 2.35 | 0.236 |
α-L-aminobutanedioic acid dimer | 30.125 | 1.85 | 0.25 |
Two poly arginines | 42.586 | 8.25 | 0.56 |
Embodiment 6
1), chromatographic condition:
Chromatographic column:Amino bonded silicone filler agent, ThermoAPS-2;Flow velocity:1.2ml/min;Column temperature:40℃;Ultraviolet inspection
Survey device Detection wavelength:220nm;Sample size:30μl;Mobile phase:A phases:0.1mol/L potassium phosphate buffers-acetonitrile, volume
Than being 45:55;B phases:0.1mol/L potassium phosphate buffers-acetonitrile, volume ratio 60:40;
Mobile phase A, B are carried out by Gradient program
2), prepared by test solution:
It is each that precision weighs 3- amino -2- piperidones, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid condensation product, two poly arginines
10mg is put in 10ml volumetric flasks, and solubilizer makes dissolving and is diluted to scale in right amount, shakes up, as the linear storing solution of each impurity.
Precision measures 3- amino -2- piperidones storing solution 2ml and other each storing solution 0.75ml, puts in 10ml volumetric flasks,
Solubilizer is diluted to scale, shakes up, as reference substance solution.
Precision measures aspartic acid ornithine granule 1ml, puts in 50ml volumetric flasks, and solubilizer is diluted to scale, shakes up,
As not plus impurity test solution.
It is analyzed by above-mentioned condition, result is:Four kinds of impurity are complete in ornithine aspartate injection under this condition
Complete to separate, appearance time and peak area are:
Table 11:Assay result
Title | Retention time (min) | Separating degree | Content (μ g/ml) |
Solvent peak | 2.0min before | —— | |
3- amino -2- piperidones | 4.569 | - | 0.36 |
L-aminobutanedioic acid | 8.795 | 3.90 | 30.6 |
Ornithine | 19.567 | 5.28 | 56.2 |
L-aminobutanedioic acid condensation product | 24.589 | 2.07 | 5.63 |
α-L-aminobutanedioic acid dimer | 27.586 | 1.65 | 0.38 |
Two poly arginines | 39.568 | 8.45 | 0.18 |
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not limited by embodiment
System, it is other it is any without departing from the present invention Spirit Essences with made under principle change, modification, combine, replacement, simplification should be
Equivalence replacement mode, is included within protection scope of the present invention.
Claims (8)
1. a kind of analysis method for detecting aspartic acid ornithine impurity, which is characterized in that it is measured using high performance liquid chromatograph,
Chromatographic condition is:
Chromatographic column:Amino bonded silicone filler agent, ThermoAPS-2;
Flow velocity:0.8-1.2ml/min;
Column temperature:30-40℃;
UV detector Detection wavelength:190-220nm;
Sample size:10-30μl;
Mobile phase:A phases:0.1mol/L potassium phosphate buffers-acetonitrile;
B phases:0.1mol/L potassium phosphate buffers-acetonitrile;
Mobile phase A, B are carried out by Gradient program
2. a kind of analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that described
Chromatographic column specification is 4.6mm × 250mm × 5 μm.
3. a kind of analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that described
The preparation method of potassium phosphate buffer adds water 1000ml to make dissolving, with phosphorus acid for adjusting pH value to take potassium dihydrogen phosphate 13.7g
To 4.3.
A kind of 4. analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that flowing
The volume ratio of 0.1mol/L potassium phosphate buffers and acetonitrile is 25-45 in phase A:55-75;0.1mol/L phosphorus in Mobile phase B
The volume ratio of acid dihydride potassium buffer solution and acetonitrile is 40-60:40-60.
5. a kind of analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that described
The volume ratio of 0.1mol/L potassium phosphate buffers and acetonitrile is 35 in mobile phase A:65;0.1mol/L phosphoric acid in Mobile phase B
The volume ratio of potassium dihydrogen buffer solution and acetonitrile is 50:50.
A kind of 6. analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that flowing
Phase A,
B is carried out by following Gradient program:
7. a kind of analysis method for detecting aspartic acid ornithine impurity according to claim 1, which is characterized in that described
Sample size is 20 μ l, flow velocity 1.0ml/min;The column temperature:35℃;The UV detector Detection wavelength:200nm.
8. according to a kind of analysis method for detecting aspartic acid ornithine impurity of claim 1-7 any one of them, feature
It is, this method can be used for detection aspartic acid ornithine raw material and preparation or the food containing aspartic acid ornithine raw material
Contain 3- amino -2- piperidones, two poly arginines, α-L-aminobutanedioic acid dimer, L-aminobutanedioic acid in product, health products and medicine preparation
The method of condensation product impurity.
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CN111337620A (en) * | 2020-05-09 | 2020-06-26 | 费森尤斯卡比华瑞制药有限公司 | Method for detecting content of 3-amino-2-piperidone in compound amino acid injection |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108593815A (en) * | 2018-08-03 | 2018-09-28 | 安徽省金楠医疗科技有限公司 | The related substance detecting method of aspartic acid ornithine |
CN111337620A (en) * | 2020-05-09 | 2020-06-26 | 费森尤斯卡比华瑞制药有限公司 | Method for detecting content of 3-amino-2-piperidone in compound amino acid injection |
CN111337620B (en) * | 2020-05-09 | 2022-05-17 | 费森尤斯卡比华瑞制药有限公司 | Method for detecting content of 3-amino-2-piperidone in compound amino acid injection |
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