CN114646698B - Method for detecting sodium valproate and related substances thereof in sodium valproate injection - Google Patents
Method for detecting sodium valproate and related substances thereof in sodium valproate injection Download PDFInfo
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- CN114646698B CN114646698B CN202011522863.7A CN202011522863A CN114646698B CN 114646698 B CN114646698 B CN 114646698B CN 202011522863 A CN202011522863 A CN 202011522863A CN 114646698 B CN114646698 B CN 114646698B
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- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 105
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 81
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 81
- 238000002347 injection Methods 0.000 title claims abstract description 75
- 239000007924 injection Substances 0.000 title claims abstract description 75
- 239000000126 substance Substances 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 40
- 238000001514 detection method Methods 0.000 claims abstract description 61
- 238000004817 gas chromatography Methods 0.000 claims abstract description 33
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 10
- QUMITRDILMWWBC-UHFFFAOYSA-N nitroterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 QUMITRDILMWWBC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 10
- 238000003908 quality control method Methods 0.000 claims abstract description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 147
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 52
- 239000000243 solution Substances 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 14
- 229960000604 valproic acid Drugs 0.000 claims description 14
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000001307 helium Substances 0.000 claims description 8
- 229910052734 helium Inorganic materials 0.000 claims description 8
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- -1 2-propylpentanoic acid amine Chemical class 0.000 claims description 5
- OVBFMEVBMNZIBR-UHFFFAOYSA-N 2-methylvaleric acid Chemical compound CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- WUWPVNVBYOKSSZ-UHFFFAOYSA-N 2-ethyl-2-methyl valeric ccid Chemical compound CCCC(C)(CC)C(O)=O WUWPVNVBYOKSSZ-UHFFFAOYSA-N 0.000 claims description 3
- ODPKTGAWWHZBOY-UHFFFAOYSA-N 2-propan-2-ylpentanoic acid Chemical compound CCCC(C(C)C)C(O)=O ODPKTGAWWHZBOY-UHFFFAOYSA-N 0.000 claims description 3
- BAZMYXGARXYAEQ-UHFFFAOYSA-N alpha-ethyl valeric acid Chemical compound CCCC(CC)C(O)=O BAZMYXGARXYAEQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000009834 vaporization Methods 0.000 claims 2
- 230000008016 vaporization Effects 0.000 claims 2
- 238000000926 separation method Methods 0.000 abstract description 20
- 239000000945 filler Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 description 96
- 239000012488 sample solution Substances 0.000 description 33
- 239000000523 sample Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 21
- 238000007865 diluting Methods 0.000 description 19
- 239000007789 gas Substances 0.000 description 14
- 238000005259 measurement Methods 0.000 description 11
- 238000011084 recovery Methods 0.000 description 10
- 238000007689 inspection Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 7
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002309 gasification Methods 0.000 description 5
- 239000012159 carrier gas Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003513 alkali Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 239000000834 fixative Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 238000004451 qualitative analysis Methods 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000036572 Myoclonic epilepsy Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
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- 239000012895 dilution Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000447 pesticide residue Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for detecting sodium valproate and related substances in sodium valproate injection, which comprises the following steps: and carrying out gas chromatography detection on the sodium valproate injection, wherein the filler in a chromatographic column adopted in the gas chromatography detection is nitro terephthalic acid modified polyethylene glycol, the length of the chromatographic column is 20-40 mm, the inner diameter of the chromatographic column is 0.2-0.4 mm, and the film thickness of the chromatographic column is 0.4-0.6 mu m. The detection method provided by the invention has the advantages of good linear relation between sodium valproate injection and related substances, good accuracy and precision, strong specificity, high stability, good separation degree and good repeatability, can meet the detection requirements of sodium valproate injection related substances, and can be used for quality control of sodium valproate injection.
Description
Technical Field
The invention relates to the field of medicine. In particular, the invention relates to a method for detecting sodium valproate and related substances thereof in sodium valproate injection.
Background
Sodium valproate injection is a nitrogen-free broad-spectrum antiepileptic. The product has different degrees of antagonism on convulsions caused by various methods. Is effective on various types of epilepsy of human, such as various small-onset and myoclonus epilepsy, limited-onset and large-onset epilepsy and mixed-type epilepsy. The mechanism of action of sodium valproate is associated with the inhibition of voltage sensitive sodium ion channels. The effect of inhibiting the overdischarge and abnormal discharge diffusion of focal neurons is achieved by inhibiting the metabolism of gamma-aminobutyric acid and increasing the accumulation of gamma-aminobutyric acid in the brain.
The related substances are starting materials, intermediates, side reaction products, degradation impurities and the like which are brought in the drug synthesis production process, and the quality and the safety of the drug can be controlled by detecting the related substances. At present, the domestic and foreign pharmacopoeias do not record a detection method of related substances of sodium valproate injection, and the detection method of related substances in bulk drugs is not completely expressed.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides a method for detecting sodium valproate and related substances in sodium valproate injection and a quality control method of sodium valproate injection.
In one aspect of the invention, the invention provides a method for detecting related substances in sodium valproate injection. According to an embodiment of the invention, the method comprises: carrying out gas chromatography detection on the sodium valproate injection, wherein the related substances comprise at least one of the following substances: n-pentanoic acid (impurity a for short), 2 RS) -2-ethyl pentanoic acid (impurity B for short), 2 RS) -2- (1-methylethyl) pentanoic acid (impurity C for short), 2-dipropyl pentanoic acid (impurity D for short), 2-propylpentanoic acid amine (impurity F for short), 2 RS) -2-ethyl-2-methyl pentanoic acid (impurity K for short) and (2 RS) -2-methyl pentanoic acid (impurity L for short), wherein the packing in the chromatographic column used for the gas chromatography detection is nitro terephthalic acid modified polyethylene glycol; the chromatographic column has length of 20-40 mm, inner diameter of 0.2-0.4 mm and film thickness of 0.4-0.6 μm.
When the inventor adopts a gas chromatography to detect the sodium valproate injection, the size of the filler in the chromatographic column and the size of the chromatographic column can obviously influence the separation effect of all related substances in the sodium valproate injection, and if the selection is improper, the related substances can not be separated, so that the purpose of accurate separation and detection can not be realized, and the specific content is further more difficult to determine. Furthermore, the inventor finds that sodium valproate and related substances thereof in sodium valproate injection can be effectively separated and detected by taking polyethylene glycol modified by nitroterephthalic acid as a filler and controlling the size of a chromatographic column through intensive research analysis and optimized screening. Further, the content of sodium valproate and related substances thereof can be calculated from the obtained gas chromatogram. Therefore, the sodium valproate injection and related substances obtained by the detection method provided by the embodiment of the invention have good linear relation, good accuracy and precision, strong specificity, high stability and good separation degree. The detection method has good repeatability, can meet the detection requirements of related substances of the sodium valproate injection, and can be used for quality control of the sodium valproate injection.
According to the embodiment of the invention, the detection method of sodium valproate and related substances in the sodium valproate injection can also have the following additional technical characteristics:
according to an embodiment of the present invention, the column temperature used for the gas chromatography detection is as follows: the temperature is initially 95 to 105 ℃ and maintained for 1.5 to 2.5min; then heating to 140-160 ℃ at the speed of 8-12 ℃/min, and maintaining for 0min; then heating to 180-200 ℃ at the speed of 1-3 ℃/min, and maintaining for 4-6 min. The inventor obtains the above-mentioned preferred heating program through a large number of experiments, from this, can isolate sodium valproate and its related substance effectively, the separation degree of main peak and impurity peak is greater than 1.5, from this, has guaranteed the accuracy of the detection result.
According to the embodiment of the invention, the temperature of the gasification chamber used for gas chromatography detection is 215-225 ℃, and the temperature of the detector is 215-225 ℃. Therefore, sodium valproate and related substances thereof can be effectively separated, the separation degree of a main peak and an impurity peak is more than 1.5, and the accuracy of a detection result is ensured.
According to the embodiment of the invention, the carrier adopted in the gas chromatography detection is helium, the flow rate is 6-10 mL/min, and the sample injection volume is 0.5-1.5 mu L. Therefore, sodium valproate and related substances thereof can be effectively separated, the separation degree of a main peak and an impurity peak is more than 1.5, and the accuracy of a detection result is ensured.
According to the embodiment of the invention, the sodium valproate injection is subjected to the following treatment in advance: mixing the sodium valproate injection with water and dilute sulfuric acid to obtain a mixed solution; extracting the mixed solution with n-heptane, collecting the extracting solution, fixing the volume, and performing gas chromatography detection on the obtained liquid to be detected. Sodium valproate and related substances thereof in the sodium valproate injection can be effectively separated by adopting n-heptane, so that the subsequent gas chromatographic detection is facilitated, and qualitative and quantitative analysis is realized.
According to an embodiment of the present invention, the number of times of extraction is 2 to 4, and the amount of n-heptane added per time is 3 to 5ml based on 1ml of the valproic acid injection. Thus, the extraction efficiency can be effectively improved.
In still another aspect of the present invention, the present invention provides a quality control method for sodium valproate injection. According to an embodiment of the invention, the method comprises: carrying out gas chromatography detection on the sodium valproate injection to obtain a detection result; based on the detection result and a threshold value, determining whether the quality of the sodium valproate injection reaches the standard or not, wherein the filling material in a chromatographic column adopted by the gas chromatography detection is polyethylene glycol modified by nitroterephthalic acid; the related substances comprise at least one of the following: n-pentanoic acid, (2 RS) -2-ethylpentanoic acid, (2 RS) -2- (1-methylethyl) pentanoic acid, 2-dipropylpentanoic acid, 2-propylpentanoic acid amine, (2 RS) -2-ethyl-2-methylpentanoic acid and (2 RS) -2-methylpentanoic acid; the length of the chromatographic column is 20-40 mm, the inner diameter is 0.2-0.4 mm, and the film thickness is 0.4-0.6 mu m. Therefore, by adopting the method provided by the embodiment of the invention, whether the sodium valproate injection meets the requirements or not can be accurately judged, so that the quality can be effectively controlled.
According to an embodiment of the present invention, the column temperature used for the gas chromatography detection is as follows: the temperature is initially 95 to 105 ℃ and maintained for 1.5 to 2.5min; then heating to 140-160 ℃ at the speed of 8-12 ℃/min, and maintaining for 0min; then heating to 180-200 ℃ at the speed of 1-3 ℃/min, and maintaining for 4-6 min. Therefore, sodium valproate and related substances thereof can be effectively separated, and the accuracy of a detection result is ensured.
According to the embodiment of the invention, the temperature of the gasification chamber used for gas chromatography detection is 215-225 ℃, and the temperature of the detector is 215-225 ℃. Therefore, sodium valproate and related substances thereof can be effectively separated, and the accuracy of a detection result is ensured.
According to the embodiment of the invention, the carrier adopted in the gas chromatography detection is helium, the flow rate is 6-10 mL/min, and the sample injection volume is 0.5-1.5 mu L. Therefore, sodium valproate and related substances thereof can be effectively separated, and the accuracy of a detection result is ensured.
According to the embodiment of the invention, the sodium valproate injection is subjected to the following treatment in advance: mixing the sodium valproate injection with water and dilute sulfuric acid to obtain a mixed solution; extracting the mixed solution with n-heptane, collecting the extracting solution, fixing the volume, and performing gas chromatography detection on the obtained liquid to be detected. Sodium valproate and related substances thereof in the sodium valproate injection can be effectively separated by adopting n-heptane, so that the subsequent gas chromatographic detection is facilitated, and qualitative and quantitative analysis is realized.
According to an embodiment of the present invention, the number of times of extraction is 2 to 4, and the amount of n-heptane added per time is 3 to 5ml based on 1ml of the valproic acid injection. Thus, the extraction efficiency can be effectively improved.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
drawings
FIG. 1 shows a sample chromatogram of sodium valproate injection according to one embodiment of the present invention;
FIG. 2 shows a graph of the chromatographic peak localization of sodium valproate injection and related substances according to one embodiment of the present invention;
FIG. 3 shows a linear plot of impurity A according to one embodiment of the invention;
FIG. 4 shows a linear plot of impurity L according to one embodiment of the invention;
FIG. 5 shows a linear plot of impurity B according to one embodiment of the invention;
FIG. 6 shows a linear plot of impurity C according to one embodiment of the invention;
FIG. 7 shows a linear plot of impurity K according to one embodiment of the invention;
FIG. 8 shows a linear plot of impurity F according to one embodiment of the invention;
FIG. 9 shows a linear plot of impurity D according to one embodiment of the invention;
fig. 10 shows a linear plot of sodium valproate in accordance with one embodiment of the present invention.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
In this example, a method for detecting a substance related to sodium valproate injection in the gas phase was carried out as follows. The method comprises the following operation steps:
1. medicine and reagent
Sodium valproate injection (Siemens and De Tian pharmaceutical Co., ltd.) (2 RS) -2-ethyl-2-methyl valeric acid (impurity K, source: TRC), (2 RS) -2- (1-methylethyl) valeric acid (impurity C, source: TRC), n-valeric acid (impurity A, source: allatin), (2 RS) -2-ethyl valeric acid (impurity B, source: TRC), 2-dipropyl valeric acid (impurity D, source: TLC), 2-propyl valeric acid amine (impurity F, source: TRC), (2 RS) -2-methyl valeric acid (impurity L, source: allatin), n-heptane (GC (pesticide residue grade), CNW), sulfuric acid (AR, nanj chemical Co., ltd.), hydrochloric acid (AR, nanj chemical Co., ltd.), ultrapure water (AR, general-Reagent), 30% hydrogen peroxide solution (AR, national group chemical Co., ltd.), ultrapure water (self-made, lipore).
2. Step (a)
(1) Preparing a solution:
precisely transferring 5.0ml of sodium valproate injection, adding 5ml of water, diluting 5ml of dilute sulfuric acid (5.7 ml of sulfuric acid is taken, and diluted to 100ml by adding water) into a separating funnel, shaking, extracting 3 times with n-heptane for 20ml each time, combining n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly to obtain a sample solution.
Taking a sample solution from 1.0ml to 100ml in a volumetric flask, and fixing the volume to a scale by using n-heptane to serve as a control solution.
And respectively taking solutions of 5 mug/ml of the impurity A, the impurity L, the impurity B, the impurity C, the impurity F, the impurity D and the impurity K, and adding n-heptane to dilute the solutions until the solutions contain the impurity A, the impurity B, the impurity C, the impurity L, the impurity D and the impurity F, and the impurity K is 7.5 mug/ml as mixed solutions of impurity reference substances.
(2) The sample solution, the control solution and the impurity control mixed solution are respectively injected into a gas chromatograph, the chromatogram is recorded, the peak area is calculated according to the 1% self-control method, and the chromatographic conditions are as follows:
chromatographic column: the polyethylene glycol modified by nitroterephthalic acid is an Agilent DB-FFAP (30 m×0.32mm×0.5 μm) capillary chromatographic column of the fixative.
Column temperature: initial 100deg.C for 2min, and heating to 150deg.C at 10deg.C/min for 0min; then the temperature is raised to 190 ℃ at 2 ℃ per minute and maintained for 5 minutes.
Gasification chamber temperature: 220 ℃; detector temperature: 220 ℃; carrier gas: high purity helium gas; sample introduction without diversion; constant flow rate mode: the flow rate is 8ml/min; sample injection volume: 1 μl.
The sample solution is shown in FIG. 1. It can be seen that the detection method of the invention can effectively realize the separation of sodium valproate and related substances thereof.
Example 2 methodological verification
2.1 specificity
The impurity reference substance (impurity A, B, C, D, K, F, L) was measured in an appropriate amount (see the preparation method of example 1), and the sample solution was added to prepare a mixed solution containing about 4.3mg/ml valproic acid, A, B, C, D, F, L. Mu.g/ml impurity and 7.5. Mu.g/ml impurity K per 1 ml. The solution and n-heptane were taken and fed separately, the gas chromatography detection conditions were as in example 1, and the chromatogram was as shown in FIG. 2.
The test results show that: under the chromatographic condition, the baseline is stable, the solvent has no interference to the determination of the product, the valproic acid main peak theoretical plate number is 148619, the separation degree of each impurity in the mixed control sample is good, each impurity can be detected, and the specificity is good.
2.2 destructive testing
In order to examine whether degradation products possibly generated by sodium valproate injection can be detected under the selected chromatographic conditions, the sodium valproate injection is destroyed by severe conditions such as high temperature, acid, alkali, oxidation, illumination and the like, a sample after the destruction is prepared into a sample solution according to the method of example 1, 1 μl of each solution is precisely measured respectively, and the sample solution is injected into a gas chromatograph to record a chromatogram, and the specific method is shown in table 1.
TABLE 1 results of failure test
The sodium valproate injection does not generate new impurities under the conditions of alkali, acid, oxidation and illumination, the product is less influenced by the conditions of acid and alkali, oxidation and illumination, the original impurities can be detected after various conditions are destroyed, the separation degree of each degradation product and a main peak is good, the measurement and recovery amount of related substances is good, and the conservation of materials is good, so the chromatographic condition can be used for measuring the related substances of the product.
2.3 determination of quantitative limit and detection limit
Samples with certain concentrations are prepared by respectively taking the impurity control and the sodium valproate injection, 1 μl is injected after stepwise dilution, and the measurement is carried out by the signal to noise ratio S/N=3 and S/N=10, and the results are shown in Table 2.
TABLE 2 limit of detection and quantitative limit results
2.4 sample solution stability test
Precisely transferring 5.0ml of sodium valproate injection, adding 5ml of water, adding 5ml of dilute sulfuric acid (obtained by diluting 5.7ml of sulfuric acid to 100ml of water), adding 5ml of dilute sulfuric acid into a separating funnel, shaking, extracting 3 times with n-heptane, 20ml each time, combining n-heptane extract, transferring into a 100ml measuring flask, fixing the volume to scale with n-heptane, and shaking uniformly to obtain a sample solution.
Precisely transferring the sample solution from 1.0ml to 100ml in a volumetric flask, fixing the volume to the scale with n-heptane, and shaking to obtain the control solution.
Sample injection is carried out at 0h, 2h, 4h, 6h, 8h, 12h and 24h after preparation respectively to examine the contents of each impurity and main component in the sample solution, and the contents are counted by 1% of self-control. The results are shown in Table 3.
TABLE 3 sample solution stability test
The results show that: the sample solution has no new impurity generation within 14 hours, the RSD value of each impurity is good, the RSD of the main peak area is 1.8%, the RSD value of the reference solution peak area is 2.2%, and the stability of the sample solution and the reference solution within 24 hours is good.
2.5 linearity
Impurity linear solution: weighing appropriate amounts of impurity A, impurity B, impurity C, impurity L, impurity K, impurity D and impurity F respectively, precisely weighing, dissolving with solvent (n-heptane), and gradually diluting into a series of mixed solutions with concentration of 80%, 100%, 120% and 200% relative to the limit of the impurity (the limit of the impurity K is 0.15% (the concentration is about 7.5 mug/ml), and the concentration of other impurities is 0.1% (the concentration is about 5 mug/ml)); and (3) gradually diluting each impurity solution to a quantitative concentration-limiting solution, and taking the solution as an initial point of linear regression.
Precisely transferring 5.0ml of sodium valproate injection, adding 5ml of water, adding 5ml of dilute sulfuric acid (obtained by diluting 5.7ml of sulfuric acid with water to 100 ml) into a separating funnel, shaking, extracting 3 times with n-heptane, 20ml each time, combining n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly. As a test solution.
Linear valproic acid solution: the sample solution is diluted step by step to prepare a series of mixed solutions which are equivalent to 50%, 80%, 100%, 120% and 150% of the self-control.
1 μl of each of the above series of concentration solutions was precisely measured and analyzed, the chromatogram was recorded, and linear regression was performed with each of the peak areas (A) as the ordinate and the concentration (C: μg/ml) of each solution as the abscissa, and the measurement results were shown in Table 4 and FIGS. 3 to 10.
Table 4 results of linear investigation
2.6 sample injection precision test
Taking 100% linear solution under linear item, continuously sampling and measuring for 6 times, and examining the change condition of peak area and retention time. The results are shown in Table 5.
TABLE 5 sample injection precision test results
The result shows that the sample injection precision is good.
2.7 stability of Mixed control solution
Mixed control solutions were taken and assayed at 0, 2, 4, 6, 8, 12, 24 hours after formulation. The results are shown in Table 6.
TABLE 6 stability test results of impurity control solutions
The results show that the impurity control solution is stable in 24 hours at room temperature after preparation.
2.8 repeatability test
Test solution: taking 5.0ml of sodium valproate injection, adding 5ml of water, diluting with dilute sulfuric acid (5.7 ml of sulfuric acid is obtained by diluting with water to 100 ml), adding 5ml of dilute sulfuric acid into a separating funnel, shaking, extracting with n-heptane for 3 times, 20ml each time, mixing n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly to obtain the final product.
Control solution: precisely measuring the sample solution in a volumetric flask with volume of 1ml to 100ml, and diluting the solvent to the scale.
Six samples and control solutions are prepared in parallel, and the content of each impurity in the sample is calculated according to the peak area by a 1% self-control method. The measurement results are shown in Table 7.
TABLE 7 repeatability test results
The method has good repeatability.
2.9 recovery test
Precisely transferring 5.0ml of sodium valproate injection, adding 5ml of water and 5ml of dilute sulfuric acid into a separating funnel, shaking, measuring an impurity reference substance stock solution in the separating funnel, preparing 80%, 100% and 120% solutions containing each impurity relative to the limit (the limit of impurity K is 0.15% and the limit of other impurities is 0.1%), extracting 3 times with n-heptane, 20ml each time, combining n-heptane extract, transferring into a 100ml measuring flask, diluting n-heptane to scale, shaking uniformly; triplicate samples were prepared for each limit. 1. Mu.l of each sample was measured precisely, and the sample was injected into a gas chromatograph to measure the recovery rate. The results are shown in tables 8 to 14.
TABLE 8 results of impurity A recovery test
TABLE 9 results of impurity L recovery test
TABLE 10 results of impurity B recovery test
TABLE 11 results of impurity C recovery test
TABLE 12 results of impurity K recovery test
TABLE 13 results of impurity F recovery test
TABLE 14 results of impurity D recovery test
2.10 intermediate precision test
Test solution: taking 5.0ml of sodium valproate injection, adding 5ml of water, diluting with dilute sulfuric acid (5.7 ml of sulfuric acid is obtained by diluting with water to 100 ml), adding 5ml of dilute sulfuric acid into a separating funnel, shaking, extracting with n-heptane for 3 times, 20ml each time, mixing n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly to obtain the final product.
Control solution: precisely measuring the sample solution in a volumetric flask with volume of 1ml to 100ml, and diluting the solvent to the scale.
Six samples and control solutions were prepared in parallel, and the contents of the impurities in the samples were calculated in terms of peak area by a 1% self-control method, and the results are shown in Table 15.
Table 15 results of intermediate precision test
The test results show that: the method has good intermediate precision.
2.11 durability inspection
The invention further discusses the tolerance degree of the detection method when the chromatographic condition is slightly changed, and carries out a durability test, wherein the test sample solution is taken as a mixed control solution and a sample solution, the investigation items comprise initial column temperature, sample inlet temperature, detector temperature and chromatographic column replacement, and the durability of the method is investigated by taking the number of peaks of the mixed control solution, the number of theoretical plates of the main component in the sample solution with the separation degree of a main peak and an adjacent peak and the impurity detection content as investigation indexes.
2.11.1 variation of extraction times investigation
The preparation method comprises the following steps: taking 5.0ml of sodium valproate injection, adding 5ml of water, diluting with dilute sulfuric acid (5.7 ml of sulfuric acid is obtained by diluting with water to 100 ml), adding 5ml of dilute sulfuric acid into a separating funnel, shaking, extracting with n-heptane for 3 times, 20ml each time, mixing n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly to obtain the final product. And (5) examining impurity detection conditions when the extraction is performed 2 times, 3 times and 4 times.
The experimental results show that: the detection results of related substances of the sodium valproate injection after 2, 3 and 4 times of extraction are not obviously changed. The measurement results are shown in Table 16.
Table 16 durability inspection (variation of extraction number inspection)
2.11.2 extraction Using variation in n-heptane volume
The preparation method comprises the following steps: taking 5.0ml of sodium valproate injection, adding 5ml of water, diluting with dilute sulfuric acid (5.7 ml of sulfuric acid is obtained by diluting with water to 100 ml), adding 5ml of dilute sulfuric acid into a separating funnel, shaking, extracting with n-heptane for 3 times, 20ml each time, mixing n-heptane extract, transferring into a 100ml measuring flask, fixing volume to scale with n-heptane, and shaking uniformly to obtain the final product. The detection of impurities was examined when n-heptane was used in the extraction at 15ml, 20ml, and 25 ml.
The experimental results show that: the detection results of related substances of the sodium valproate injection are not obviously changed when the volumes of n-heptane used for extraction are 15ml, 20ml and 25 ml. The measurement results are shown in Table 17.
Table 17 durability test (extraction using n-heptane volume)
2.11.3 changes in column temperature
Other gas chromatography conditions were the same as described above, and the degree of separation of the main peak from the adjacent peaks, the number of theoretical plates of the main component in the sample solution, the retention time of the main component and the change in impurity detection were examined at column temperatures of 95 ℃, 100 ℃ and 105 ℃. The experimental results show that: when the column temperature is changed within the range of 95-105 ℃, the influence on each parameter is not great. The measurement results are shown in Table 18.
Watch 18 durability inspection (column temperature)
2.11.4 variation of sample inlet temperature
Other gas chromatography conditions were the same as described above, and the degree of separation of the main peak from the adjacent peak, the number of theoretical plates of the main component in the sample solution, the retention time of the main component and the change in impurity detection were examined at the inlet temperatures of 215 ℃, 220 ℃ and 225 ℃. The experimental results show that: when the sample inlet is changed within the range of 215-225 ℃, the influence on each parameter is not great. The measurement results are shown in Table 19.
Table 19 durability inspection (sample inlet temperature)
2.11.5 detector temperature variation
Other gas chromatography conditions were the same as described above, and the degree of separation of the main peak from the adjacent peaks, the number of theoretical plates of the main component in the sample solution, the retention time of the main component and the change in impurity detection were examined at the detector temperatures of 215 ℃, 220 ℃ and 225 ℃. The experimental results show that: the detector has little effect on each parameter when changing in the range of 215-225 ℃. The measurement results are shown in Table 20.
Table 20 durability inspection (detector temperature)
2.11.6 chromatographic column variation
Other gas chromatography conditions were the same as described above, and the degree of separation between the main peak and the adjacent peak, the number of theoretical plates of the main component in the sample solution, the retention time of the main component, and the change in impurity detection were examined. The experimental results show that: different chromatographic columns are used, so that the influence on each parameter is not great. The measurement results are shown in Table 21.
Table 21 durability inspection (different chromatographic columns)
2.12 determination of methods for determining substances
The method is verified by the methodology, and the preliminary sketching method is suitable for the inspection of related substances of the product.
Taking 5ml of the product, placing in a separating funnel, adding 5ml of water, adding 5ml of dilute sulfuric acid, shaking, extracting with n-heptane for 3 times, 20ml each time, combining n-heptane solutions, placing in a 100ml measuring flask, diluting with n-heptane to scale, shaking uniformly, taking the sample solution as a sample solution, precisely measuring 1ml, placing in a 100ml measuring flask, diluting with n-heptane to scale, shaking uniformly, and taking the sample solution as a control solution. And taking a proper amount of valproic acid system applicability solution containing the impurity I, and quantitatively diluting with n-heptane to prepare a solution containing 5mg per 1ml serving as the system applicability solution. According to the gas chromatography (rule 0521 of four universities of 2015 edition of Chinese pharmacopoeia), a capillary chromatographic column (Agilent DB-FFAP30m×0.32mm×0.5 μm) using polyethylene glycol modified by nitroterephthalic acid as a fixing solution is tested, the initial temperature is 100 ℃, the temperature is maintained for 2 minutes, the temperature is raised to 150 ℃ at a rate of 10 ℃ per minute, and then the temperature is raised to 190 ℃ at a rate of 2 ℃ per minute, and the temperature is maintained for 5 minutes; the temperature of the sample inlet is 220 ℃; the detector temperature is 220 ℃; the flow rate is 1ml per minute; the carrier gas is helium. Taking 0.5 mu l of system applicability solution, injecting the solution into a gas chromatograph, recording a chromatogram, wherein the relative retention time of the impurity I is about 0.95, and the separation degree of the impurity I and valproic acid is not less than 2.0; precisely measuring 0.5 μl of control solution and sample solution, injecting into gas chromatograph, and recording chromatogram. The chromatogram of the sample solution contains impurity peaks, the area of each impurity peak is not more than 0.15 times (0.15%) of the main peak area of the control solution, the area of each other single impurity peak is not more than 0.1 times (0.1%) of the main peak area of the control solution, the sum of the areas of each impurity peak is not more than 0.3 times (0.3%) of the main peak area of the control solution, and the chromatographic peak which is less than 0.03 times of the main peak area of the control solution is ignored.
The impurity content was calculated according to the following formula:
(1) Single impurity content (%) =a Single impurity /A Control
A Single impurity : area of impurity peak in sample solution
A Control : valproic acid peak area in self-control
(2) Total (S) Impurity content (%) =a Total impurities /A Control
A Total impurities : sum of impurity peak areas in sample solution
The pilot samples were tested using this method and the results are shown in table 22.
Table 22 shows the examination results of the related substances
Comparative example 1
In this comparative example, sodium valproate and its related substances in sodium valproate injection were detected as follows:
1. solution preparation
As in example 1.
2. The sample solution, the control solution and the impurity control mixed solution are respectively injected into a gas chromatograph, the chromatogram is recorded, the peak area is calculated according to the 1% self-control method, and the chromatographic conditions are as follows:
chromatographic column: the polyethylene glycol modified by nitroterephthalic acid is an Agilent DB-FFAP (30 m×0.32mm×0.5 μm) capillary chromatographic column of the fixative.
Column temperature: the temperature rise program is shown in Table 23 below.
Gasification chamber temperature: 220 ℃; detector temperature: 220 ℃; carrier gas: high purity helium gas; sample introduction without diversion; constant flow rate mode: the flow rate is 8ml/min; sample injection volume: 1 μl.
The test results are shown in Table 24. It can be seen that by adopting the column temperature rising and temperature rising procedure, the separation degree R of the impurity C and the impurity K is less than 1.5, and the baseline separation is not achieved, so that the accurate determination of the impurity K cannot be realized.
TABLE 23 influence of different temperature increasing programs
| Method | Rate (. Degree. C/min) | Temperature (. Degree. C.) | Holding time (min) |
| Initial value | / | 80 | 5 |
| Gradient 1 | 7 | 150 | 0 |
| Gradient 2 | 3 | 190 | 30 |
Table 24 results of comparative example 1
Comparative example 2
In this comparative example, sodium valproate and its related substances in sodium valproate injection were detected as follows:
1. solution preparation
As in example 1.
2. The sample solution, the control solution and the impurity control mixed solution are respectively injected into a gas chromatograph, the chromatogram is recorded, the peak area is calculated according to the 1% self-control method, and the chromatographic conditions are as follows:
chromatographic column: the polyethylene glycol modified by nitroterephthalic acid is an Agilent DB-FFAP (30 m×0.53mm×1.0 μm) capillary chromatographic column of the fixing solution.
Column temperature: initial 100deg.C for 2min, and heating to 150deg.C at 10deg.C/min for 0min; then the temperature is raised to 190 ℃ at 2 ℃ per minute and maintained for 5 minutes.
Gasification chamber temperature: 220 ℃; detector temperature: 220 ℃; carrier gas: high purity helium gas; sample introduction without diversion; constant flow rate mode: the flow rate is 8ml/min; sample injection volume: 1 μl.
The results of the measurements are shown in Table 25. It can be seen that with the above-sized column, the separation degree R of impurity C and impurity K is less than 1.5, and the baseline separation is not achieved.
Table 25 results of comparative example 2
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (11)
1. A method for detecting related substances in sodium valproate injection, which is characterized by comprising the following steps:
carrying out gas chromatography detection on the sodium valproate injection, wherein the related substances comprise: n-pentanoic acid, (2 RS) -2-ethylpentanoic acid, (2 RS) -2- (1-methylethyl) pentanoic acid, 2-dipropylpentanoic acid, 2-propylpentanoic acid amine, (2 RS) -2-ethyl-2-methylpentanoic acid and (2 RS) -2-methylpentanoic acid,
wherein, the filling material in the chromatographic column used in the gas chromatography detection is polyethylene glycol modified by nitroterephthalic acid;
the length of the chromatographic column is 30mm, the inner diameter is 0.32mm, and the film thickness is 0.5 mu m;
the column temperature used for the gas chromatography detection is as follows: initial 100 ℃ and maintaining for 2min; then heating to 150 ℃ at a speed of 10 ℃/min, and maintaining for 0min; then the temperature is raised to 190 ℃ at a speed of 2 ℃/min and maintained for 5min.
2. The method of claim 1, wherein the gas chromatography detection employs a vaporization chamber temperature of 215-225 ℃ and a detector temperature of 215-225 ℃.
3. The method of claim 1, wherein the carrier used for the gas chromatography detection is helium, the flow rate is 6-10 ml/min, and the sample injection volume is 0.5-1.5 μl.
4. The method according to claim 1, wherein the sodium valproate injection is subjected to the following treatment in advance:
mixing the sodium valproate injection with water and dilute sulfuric acid to obtain a mixed solution;
extracting the mixed solution with n-heptane, collecting the extracting solution, fixing the volume, and performing gas chromatography detection on the obtained liquid to be detected.
5. The method according to claim 4, wherein the number of times of extraction is 2-4, and the amount of n-heptane added is 3-5 ml each time based on 1ml of the valproic acid injection.
6. The quality control method of the sodium valproate injection is characterized by comprising the following steps of:
carrying out gas chromatography detection on the sodium valproate injection to obtain a detection result;
based on the detection result and a threshold value, determining whether the quality of the sodium valproate injection reaches the standard,
wherein, the filling material in the chromatographic column used in the gas chromatography detection is polyethylene glycol modified by nitroterephthalic acid;
related substances include: n-pentanoic acid, (2 RS) -2-ethylpentanoic acid, (2 RS) -2- (1-methylethyl) pentanoic acid, 2-dipropylpentanoic acid, 2-propylpentanoic acid amine, (2 RS) -2-ethyl-2-methylpentanoic acid and (2 RS) -2-methylpentanoic acid;
the length of the chromatographic column is 30mm, the inner diameter is 0.32mm, and the film thickness is 0.5 mu m;
the column temperature used for the gas chromatography detection is as follows: initial 100 ℃ and maintaining for 2min; then heating to 150 ℃ at a speed of 10 ℃/min, and maintaining for 0min; then the temperature is raised to 190 ℃ at a speed of 2 ℃/min and maintained for 5min.
7. The method of claim 6, wherein the gas chromatography detection employs a vaporization chamber temperature of 215-225 ℃ and a detector temperature of 215-225 ℃.
8. The method of claim 6, wherein the carrier used for gas chromatography detection is helium, the flow rate is 6-10 mL/min, and the sample injection volume is 0.5-1.5 μL.
9. The method according to claim 6, wherein the sodium valproate injection is subjected to the following treatment in advance:
mixing the sodium valproate injection with water and dilute sulfuric acid to obtain a mixed solution;
extracting the mixed solution with n-heptane, collecting the extracting solution, fixing the volume, and performing gas chromatography detection on the obtained liquid to be detected.
10. The method according to claim 9, wherein the number of extractions is 2-4.
11. The method according to claim 9, wherein the n-heptane is added in an amount of 3-5 ml based on 1ml of the valproic acid injection.
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