CN113203824A - Detection method of sodium valproate related substances - Google Patents
Detection method of sodium valproate related substances Download PDFInfo
- Publication number
- CN113203824A CN113203824A CN202110442454.4A CN202110442454A CN113203824A CN 113203824 A CN113203824 A CN 113203824A CN 202110442454 A CN202110442454 A CN 202110442454A CN 113203824 A CN113203824 A CN 113203824A
- Authority
- CN
- China
- Prior art keywords
- temperature
- sodium valproate
- detection method
- rate
- detector
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000126 substance Substances 0.000 title claims abstract description 50
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 46
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 46
- 238000001514 detection method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000012085 test solution Substances 0.000 claims abstract description 28
- 238000004817 gas chromatography Methods 0.000 claims abstract description 16
- 238000004458 analytical method Methods 0.000 claims abstract description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000002535 acidifier Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 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 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 abstract description 16
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 238000005220 pharmaceutical analysis Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 35
- 239000000523 sample Substances 0.000 description 18
- 238000012360 testing method Methods 0.000 description 16
- 239000007789 gas Substances 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 206010015037 epilepsy Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Landscapes
- 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)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention provides a detection method of sodium valproate related substances, and relates to the field of pharmaceutical analysis. The detection method provided by the invention is characterized in that sodium valproate is dissolved, acidified and extracted to obtain a test solution, and the test solution is subjected to gas chromatography analysis. The method can effectively separate various potential trace related substances in the sodium valproate, has the advantages of good separation degree between a main peak and adjacent impurities and between adjacent impurities, high durability, stable base line and attractive peak shape, efficiently realizes the qualitative and quantitative determination of each related substance, is suitable for the rapid quality monitoring of the sodium valproate in industrial mass production, and has important significance for the quality control of sodium valproate products.
Description
Technical Field
The invention relates to the field of drug analysis, in particular to a method for detecting a sodium valproate related substance.
Background
Epilepsy is a central nervous system disease, is second to stroke in prevalence rate, is a central nervous system disease caused by cerebral nerve overdischarge, and in onset, sudden, repeated or transient functional loss of the central nervous system of a patient occurs, according to WHO statistics, the number of epilepsy patients reaches 5000 ten thousand worldwide, and the speed of 200 ten thousand new cases per year is increased.
Epilepsy is extremely difficult to treat because the types of seizures are varied and there are different types of concurrent seizures. The quality control of antiepileptic drugs, which are used as main treatment means for epilepsy, is directly related to the medication safety of patients, and the quality of the drugs should be strictly controlled from the perspective of medication safety of people, and scientific rigor, accuracy and comprehensiveness.
Sodium valproate occupies an important position in clinical practice as one of the active ingredients against epilepsy. At present, sodium valproate is used as a raw material in the market to prepare injections, tablets, oral solutions and other dosage forms. Different methods for testing the substances of interest are specified in the respective legal standards for different dosage forms, but they all have some respective disadvantages, such as: the inspection of sodium valproate raw materials and sodium valproate related substances for injection in Chinese pharmacopoeia comprises operations such as rotary evaporation, filtration and the like in the operation process, so that the experiment is complicated and tedious, the total experiment time is long, and the industrial mass production is not facilitated. Therefore, it is necessary to develop a detection method for sodium valproate related substances closer to the development of the prior art, so as to be suitable for industrial mass production and quality control of sodium valproate.
Disclosure of Invention
The invention aims to provide a method for detecting a sodium valproate related substance.
The technical scheme adopted by the invention is as follows:
a method for detecting a sodium valproate related substance comprises the following steps: dissolving, acidifying and extracting sodium valproate to obtain a test solution, and carrying out gas chromatography analysis on the test solution; the gas chromatography conditions included:
adopting a polyethylene glycol polar capillary chromatographic column, and injecting samples without shunting;
the flow rate is 1mL/min to 4 mL/min;
the initial temperature is 45-60 ℃, the temperature is maintained for 5-10 min, the temperature is increased to 125-140 ℃ at the rate of 6-10 ℃ per minute, the temperature is increased to 170-200 ℃ at the rate of 2-5 ℃ per minute, and the temperature is maintained for 5-20 min.
Further, detecting by using an FID detector; the temperature of the sample inlet is 200-230 ℃, the temperature of the detector is 200-230 ℃, and the temperature of the detector is not lower than the temperature of the sample inlet.
Furthermore, a capillary column with nitroterephthalic acid modified polyethylene glycol as stationary liquid is adopted, and the sample injection volume is 1 mu L.
Further, the gas chromatography conditions were:
adopting a polyethylene glycol polar capillary chromatographic column, and injecting samples without shunting;
the flow rate is 1.5mL/min to 3 mL/min;
the initial temperature is 50-60 ℃, the temperature is maintained for 6-8 minutes, the temperature is raised to 128-135 ℃ at the rate of 8-10 ℃ per minute, the temperature is raised to 180-190 ℃ at the rate of 2-4 ℃ per minute, and the temperature is maintained for 5-15 minutes;
the sample injection volume is 1 mu L; the temperature of the sample inlet is 200-220 ℃, the temperature of the detector is 210-230 ℃, and the temperature of the detector is not lower than the temperature of the sample inlet.
Further, the gas chromatography conditions were:
adopting a capillary column which adopts nitroterephthalic acid modified polyethylene glycol as stationary liquid, and injecting samples without shunting;
the flow rate is 1.5 mL/min-2.5 mL/min;
the initial temperature is 50 ℃, the temperature is maintained for 8 minutes, the temperature is increased to 130 ℃ at the rate of 8 ℃ per minute, then the temperature is increased to 190 ℃ at the rate of 3 ℃ per minute, and the temperature is maintained for 12 minutes;
the sample injection volume is 1 mu L; the injection port temperature was 220 ℃ and the detector temperature was 220 ℃.
Further, the acidifying agent used in the acidifying is selected from dilute hydrochloric acid and dilute sulfuric acid, preferably dilute sulfuric acid.
Further, the acidifying agent is dilute sulfuric acid with the concentration of 1.0-1.2mol/L, and the volume ratio of the acidifying agent to the sodium valproate solution is 0.8-1.5: 1.
further, the extractant used in the extraction is heptane.
Further, the volume ratio of the extracting agent to the acidified sodium valproate solution is 1: 0.8-2 times of extraction, and 2-5 times of extraction.
The invention provides a method for detecting sodium valproate related substances, which can effectively separate various potential trace related substances in sodium valproate, has good separation degree between a main peak and adjacent impurities and between adjacent impurities, high durability, stable base line and beautiful peak shape, efficiently realizes the qualitative and quantitative determination of each related substance, is suitable for the rapid quality monitoring of sodium valproate in industrial mass production, and has important significance for the quality control of sodium valproate products.
Drawings
The invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a gas chromatogram of comparative example 1;
FIG. 2 is a gas chromatogram of comparative example 2;
FIG. 3 is a gas chromatogram of comparative example 3;
FIG. 4 is a gas chromatogram of comparative example 4;
FIG. 5 is a gas chromatogram of comparative example 5;
FIG. 6 is a gas chromatogram of comparative example 6;
FIG. 7 is a gas chromatogram of example 1.
Detailed Description
Comparative example 1
Sodium valproate sample: synthesized according to the literature (exploration of conditions for the synthesis of sodium valproate in the Tridi laboratory [ J ]. Shandong chemical, 2012(03): 30-31.).
Test solution: taking about 0.5g of the sodium valproate sample, placing the sodium valproate sample in a centrifuge tube, adding 10mL of water, shaking to dissolve the sodium valproate sample, adding 5mL of dilute sulfuric acid, shaking uniformly, extracting with n-heptane three times, 20mL each time, combining organic layers (upper layers), placing the organic layers in a 100mL measuring flask, diluting the organic layers to a scale with n-heptane, and shaking uniformly to obtain a sample solution.
A sample solution (1.0. mu.L) was taken and subjected to gas chromatography under the following chromatographic conditions.
A chromatographic column: agilent HP-FFAP, 50M 0.320mm 0.50 μ M (capillary chromatography column with polyethylene glycol (PEG-20M) as fixative);
the split ratio is as follows: no flow diversion;
and (3) sample introduction mode: directly feeding liquid;
sample inlet temperature: 220 ℃;
detector temperature: 220 ℃, detector: FID;
flow rate: 8 mL/min;
carrier gas: nitrogen gas;
the temperature-raising program is shown in table 1.
TABLE 1 temperature program for comparative example 1
| Speed/min | Value of C | Holding time min |
| - | 80 | 5 |
| 7 | 150 | 0 |
| 3 | 190 | 2 |
The results of the test using this method are shown in table 2 and fig. 1. In FIG. 1, peaks in the order of 1-3 and 5 are related substance peaks, and 4 is a main peak. Detecting 4 related substances by the method; the baseline is severely shifted, which is not beneficial to the qualitative and quantitative determination of the related substances.
Table 2 comparative example 1 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 14.859 | 2.93 | 1.35 | / | 296126 |
| 2 | 15.254 | 4.47 | 1.17 | 2.10 | 60555 |
| 3 | 16.769 | 2.37 | 1.06 | 8.11 | 256753 |
| 4 | 18.564 | 45932.86 | 0.67 | 11.36 | 161327 |
| 5 | 20.662 | 2.14 | 1.02 | 11.48 | 208706 |
Comparative example 2
The sodium valproate sample and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The chromatographic conditions were substantially the same as in comparative example 1, except that the flow rate was changed to 2 mL/min.
The results of the test using this method are shown in table 3 and fig. 2. In FIG. 2, peaks in the order of 1 to 5 and 7 are related substance peaks, and 6 is a main peak. The method is used for detecting 6 related substances in total, wherein the separation degree between related substance peaks 3 and 4 is only 1.04, the baseline drift is realized, the tailing factor of the main peak is more than 2.0, and the method is not satisfactory. Therefore, the method is not suitable for detecting related substances in the sodium valproate.
Table 3 comparative example 2 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 23.212 | 8.45 | 1.04 | / | 371110 |
| 2 | 25.405 | 2.06 | 1.14 | 13.69 | 359782 |
| 3 | 25.699 | 2.32 | 1.03 | 1.51 | 226655 |
| 4 | 25.893 | 1.48 | 1.19 | 1.04 | 410647 |
| 5 | 26.767 | 3.89 | 1.19 | 5.73 | 553269 |
| 6 | 27.354 | 59910.10 | 2.04 | 3.80 | 434513 |
| 7 | 28.338 | 7.07 | 1.57 | 4.40 | 160795 |
Comparative example 3
The sodium valproate sample and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The flow rate was 5mL/min, and the temperature-raising program was as shown in Table 4. The remaining chromatographic conditions were the same as in comparative example 1.
TABLE 4 temperature program for comparative example 3
| Speed/min | Value of C | Holding time min |
| - | 60 | 5 |
| 5 | 160 | 0 |
| 2 | 200 | 15 |
The results of the test by this method are shown in Table 5 and FIG. 3. In FIG. 3, the peaks with the appearance order of 1-5 and 7-8 are related substance peaks, and 6 is the main peak. The method detects 7 related substances in total, wherein the separation degree between related substance peaks 4 and 5 is only 0.95, which is not satisfactory. Therefore, the method is not suitable for detecting related substances in the sodium valproate.
TABLE 5 comparative example 3 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 5.246 | 33.98 | 1.05 | / | 2471 |
| 2 | 9.484 | 39.32 | 0.86 | 15.84 | 102258 |
| 3 | 18.976 | 33.82 | 0.96 | 87.23 | 582052 |
| 4 | 22.240 | 39.48 | 0.80 | 26.29 | 354642 |
| 5 | 22.377 | 132.74 | 1.02 | 0.95 | 408509 |
| 6 | 23.016 | 58194.50 | 0.65 | 3.98 | 250971 |
| 7 | 24.646 | 43.07 | 1.01 | 8.81 | 457379 |
| 8 | 26.127 | 36.92 | 1.01 | 11.21 | 468056 |
Comparative example 4
Sodium valproate and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The flow rate was 5mL/min, and the temperature-raising program was as shown in Table 6. The remaining chromatographic conditions were the same as in comparative example 1.
TABLE 6 temperature raising procedure of comparative example 4
| Speed/min | Value of C | Holding time min |
| - | 80 | 5 |
| 9 | 150 | 20 |
| 3 | 190 | 2 |
The results of the test by this method are shown in Table 7 and FIG. 4. In FIG. 4, peaks with the appearance order of 1-6 and 8 are related substance peaks, and 7 is the main peak. The method is used for detecting 7 related substances in total, wherein the separation degree between related substance peaks 3 and 4 is only 0.55, and the tailing factor of related substance peak 8 is more than 2.0, which is not satisfactory. Therefore, the method is not suitable for detecting related substances in the sodium valproate.
TABLE 7 comparative example 4 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 16.689 | 10.53 | 0.92 | / | 108735 |
| 2 | 19.210 | 2.71 | 1.20 | 10.26 | 70138 |
| 3 | 19.663 | 1.92 | 0.76 | 1.26 | 32185 |
| 4 | 19.862 | 1.16 | 1.36 | 0.55 | 79421 |
| 5 | 20.358 | 1.34 | 1.01 | 1.79 | 88895 |
| 6 | 21.167 | 5.48 | 1.00 | 2.74 | 72467 |
| 7 | 22.249 | 62853.62 | 1.76 | 3.26 | 63395 |
| 8 | 24.043 | 9.05 | 2.04 | 3.38 | 18293 |
Comparative example 5
The sodium valproate sample and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The flow rate was 2mL/min, and the temperature-raising program was as shown in Table 8. The remaining chromatographic conditions were the same as in comparative example 1.
TABLE 8 temperature raising procedure for comparative example 5
| Speed/min | Value of C | Holding time min |
| - | 50 | 5 |
| 7 | 150 | 0 |
| 3 | 190 | 15 |
The results of the test by this method are shown in Table 9 and FIG. 5. In FIG. 5, the peaks with the appearance order of 1-5 and 7-8 are related substance peaks, and 6 is the main peak. The method detects 7 related substances in total, wherein the separation degree between related substance peaks 4 and 5 is only 1.28, which is not satisfactory. Therefore, the method is not suitable for detecting related substances in the sodium valproate.
TABLE 9 comparative example 5 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 12.209 | 37.24 | 0.90 | / | 72669 |
| 2 | 16.269 | 40.46 | 0.99 | 27.98 | 351476 |
| 3 | 26.635 | 27.30 | 1.43 | 69.51 | 316984 |
| 4 | 30.879 | 40.50 | 0.98 | 25.25 | 696397 |
| 5 | 31.069 | 132.29 | 1.02 | 1.28 | 679606 |
| 6 | 31.528 | 58697.88 | 1.50 | 2.84 | 542249 |
| 7 | 33.972 | 42.72 | 1.48 | 11.26 | 265276 |
| 8 | 36.728 | 38.06 | 1.79 | 8.66 | 153989 |
Comparative example 6
The sodium valproate sample and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The flow rate was 2mL/min, and the temperature-raising program was as shown in Table 10. The remaining chromatographic conditions were the same as in comparative example 1.
TABLE 10 temperature program for comparative example 6
| Speed/min | Value of C | Holding time min |
| - | 40 | 10 |
| 8 | 120 | 0 |
| 3 | 180 | 15 |
The results of the detection by this method are shown in table 11 and fig. 6. In FIG. 6, the peaks with the appearance order of 1 to 5 are related substance peaks, and 6 is the main peak. The method is used for detecting 5 related substances in total, wherein the separation degree between related substance peaks 4 and 5 is only 1.43, and the tailing factor of a main peak 6 is more than 2.0, so that the method is not satisfactory. Therefore, the method is not suitable for detecting related substances in the sodium valproate.
TABLE 11 comparative example 6 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 12.845 | 16.68 | 0.88 | / | 52329 |
| 2 | 16.638 | 18.89 | 0.98 | 20.18 | 192736 |
| 3 | 28.952 | 12.31 | 1.38 | 62.96 | 232172 |
| 4 | 34.630 | 18.92 | 1.01 | 24.33 | 367735 |
| 5 | 34.962 | 61.52 | 1.02 | 1.43 | 343422 |
| 6 | 35.564 | 27494.35 | 2.61 | 2.35 | 307177 |
Example 1
The sodium valproate sample and the test solution were the same as in comparative example 1.
1.0. mu.L of the test solution was taken for gas chromatography. The flow rate was 2mL/min, and the temperature-raising program was as shown in Table 12. The remaining chromatographic conditions were the same as in comparative example 1.
TABLE 12 temperature raising procedure of example 1
| Speed/min | Value of C | Holding time min |
| - | 50 | 8 |
| 8 | 130 | 0 |
| 3 | 190 | 12 |
The results of the detection by this method are shown in table 13 and fig. 7. In FIG. 7, the peaks with the appearance order of 1-5 and 7-8 are related substance peaks, and 6 is the main peak. The method can detect 7 related substances, the separation degree between each adjacent chromatographic peak is more than 1.5, the base line is stable, the peak shape is beautiful, and the method meets the analysis requirements. Therefore, the method is suitable for detecting related substances in the sodium valproate.
Table 13 example 1 test data
| Order of appearance | Retention time (min) | Peak area | Tailing factor | Degree of separation | Number of |
| 1 | 12.860 | 15.16 | 0.86 | / | 44783 |
| 2 | 16.430 | 16.14 | 0.98 | 18.27 | 194994 |
| 3 | 27.809 | 11.56 | 1.01 | 72.11 | 440217 |
| 4 | 33.001 | 17.54 | 1.04 | 27.11 | 372678 |
| 5 | 33.314 | 56.01 | 1.00 | 1.68 | 344128 |
| 6 | 34.157 | 24923.87 | 0.90 | 3.68 | 334328 |
| 7 | 37.128 | 17.53 | 1.12 | 11.76 | 300847 |
| 8 | 40.831 | 16.13 | 1.01 | 12.46 | 252931 |
Example 2
In this embodiment, the durability of the method for detecting a sodium valproate related substance provided by the present invention is tested, and the durability test conditions are as follows:
initial column temperature change: the initial column temperature of example 1 was varied by. + -. 2 ℃ from 50 ℃ i.e.48 ℃ and 52 ℃.
Change of flow rate: the flow rate of example 1 was changed to. + -. 0.2mL/min, i.e., 1.8mL/min and 2.2mL/min, based on 2.0 mL/min.
Replacing chromatographic columns of different models: the column was replaced with USE338025H (manufacturer, specification 30m 0.530mm 0.50 μm).
Test solution: the same as in example 1.
Control solution: precisely measuring 1mL of the test solution, placing the test solution in a 100mL measuring flask, diluting the test solution to the scale with n-heptane, shaking up, taking 1mL of the test solution, placing the test solution in a 20mL measuring flask, adding n-heptane to dilute the test solution to the scale, and shaking up to obtain a control solution.
In the invention, the content of related substances is calculated by adopting a principal component self-contrast method without adding a correction factor, and the calculation formula is as follows:
in the formula: a. theHetero compoundIs the peak area of related substances in the chromatogram of the test solution; a. theTo pairThe peak area of the main peak in the chromatogram of the control solution; vTo pairIs the dilution factor of the control solution(ii) a The total impurities are total related substances, and A1+ A2 … + An is the sum of peak areas of the single related substances in the test solution.
The durability test results are shown in table 14. As is clear from table 14, when the chromatographic conditions were changed, the contents of the substances concerned and the total impurity content were not more than 0.01% as much as the results of the measurement in example 1 under each of the durability conditions, and the degrees of separation of adjacent chromatographic peaks were more than 1.5. Therefore, the detection method for the sodium valproate related substance provided by the invention has high durability.
TABLE 14 durability test results
Claims (9)
1. A method for detecting a sodium valproate related substance is characterized by comprising the following steps: dissolving, acidifying and extracting sodium valproate to obtain a test solution, and carrying out gas chromatography analysis on the test solution; the gas chromatography conditions included:
adopting a polyethylene glycol polar capillary chromatographic column, and injecting samples without shunting;
the flow rate is 1mL/min to 4 mL/min;
the initial temperature is 45-60 ℃, the temperature is maintained for 5-10 min, the temperature is increased to 125-140 ℃ at the rate of 6-10 ℃ per minute, the temperature is increased to 170-200 ℃ at the rate of 2-5 ℃ per minute, and the temperature is maintained for 5-20 min.
2. The detection method according to claim 1, characterized in that the FID detector is used for detection; the temperature of the sample inlet is 200-230 ℃, the temperature of the detector is 200-230 ℃, and the temperature of the detector is not lower than the temperature of the sample inlet.
3. The detection method according to claim 1, wherein a capillary column using nitroterephthalic acid-modified polyethylene glycol as a stationary liquid is used, and the sample injection volume is 1 μ L.
4. The detection method according to claim 1, wherein the gas chromatography conditions are:
adopting a polyethylene glycol polar capillary chromatographic column, and injecting samples without shunting;
the flow rate is 1.5mL/min to 3 mL/min;
the initial temperature is 50-60 ℃, the temperature is maintained for 6-8 minutes, the temperature is raised to 128-135 ℃ at the rate of 8-10 ℃ per minute, the temperature is raised to 180-190 ℃ at the rate of 2-4 ℃ per minute, and the temperature is maintained for 5-15 minutes;
the sample injection volume is 1 mu L; the temperature of the sample inlet is 200-220 ℃, the temperature of the detector is 210-230 ℃, and the temperature of the detector is not lower than the temperature of the sample inlet.
5. The detection method according to claim 4, wherein the gas chromatography conditions are:
adopting a capillary column which adopts nitroterephthalic acid modified polyethylene glycol as stationary liquid, and injecting samples without shunting;
the flow rate is 1.5 mL/min-2.5 mL/min;
the initial temperature is 50 ℃, the temperature is maintained for 8 minutes, the temperature is increased to 130 ℃ at the rate of 8 ℃ per minute, then the temperature is increased to 190 ℃ at the rate of 3 ℃ per minute, and the temperature is maintained for 12 minutes;
the sample injection volume is 1 mu L; the injection port temperature was 220 ℃ and the detector temperature was 220 ℃.
6. The detection method according to any one of claims 1 to 5, wherein the acidifying agent is selected from dilute hydrochloric acid and dilute sulfuric acid, preferably dilute sulfuric acid.
7. The detection method according to claim 6, wherein the acidifying agent is dilute sulfuric acid with a concentration of 1.0 to 1.2mol/L, and the volume ratio of the acidifying agent to the sodium valproate solution is 0.8 to 1.5: 1.
8. the detection method according to any one of claims 1 to 5, wherein an extractant used in the extraction is heptane.
9. The detection method according to claim 8, wherein the volume ratio of the extractant to the acidified sodium valproate solution is 1: 0.8-2, and the extraction times are 2-5 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110442454.4A CN113203824A (en) | 2021-04-23 | 2021-04-23 | Detection method of sodium valproate related substances |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110442454.4A CN113203824A (en) | 2021-04-23 | 2021-04-23 | Detection method of sodium valproate related substances |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113203824A true CN113203824A (en) | 2021-08-03 |
Family
ID=77028292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110442454.4A Pending CN113203824A (en) | 2021-04-23 | 2021-04-23 | Detection method of sodium valproate related substances |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113203824A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114354803A (en) * | 2021-12-31 | 2022-04-15 | 成都倍特药业股份有限公司 | Method for detecting related substances of sodium valproate oral solution |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580831A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
| CN109580828A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | A kind of related substance-measuring method of sodium vedproate oral administration solution |
| CN111257440A (en) * | 2019-12-25 | 2020-06-09 | 四川健能制药有限公司 | GC-HS-based method for determining potential genotoxic impurities in sodium valproate |
| CN114354803A (en) * | 2021-12-31 | 2022-04-15 | 成都倍特药业股份有限公司 | Method for detecting related substances of sodium valproate oral solution |
-
2021
- 2021-04-23 CN CN202110442454.4A patent/CN113203824A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109580831A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | Method for measuring related substances of sodium valproate oral solution |
| CN109580828A (en) * | 2018-12-28 | 2019-04-05 | 四川健能制药有限公司 | A kind of related substance-measuring method of sodium vedproate oral administration solution |
| CN111257440A (en) * | 2019-12-25 | 2020-06-09 | 四川健能制药有限公司 | GC-HS-based method for determining potential genotoxic impurities in sodium valproate |
| CN114354803A (en) * | 2021-12-31 | 2022-04-15 | 成都倍特药业股份有限公司 | Method for detecting related substances of sodium valproate oral solution |
Non-Patent Citations (2)
| Title |
|---|
| 欧洲药品质量委员会: "European Pharmacopoeia 9th edition", vol. 9, 31 July 2016, 欧洲药品质量管理局, pages: 3609 - 3610 * |
| 陈爽等: "GC测定丙戊酸钠缓释片的有关物质", 中国现代应用药学, vol. 35, no. 7, 31 July 2018 (2018-07-31), pages 998 - 1000 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114354803A (en) * | 2021-12-31 | 2022-04-15 | 成都倍特药业股份有限公司 | Method for detecting related substances of sodium valproate oral solution |
| CN114354803B (en) * | 2021-12-31 | 2023-11-14 | 成都倍特得诺药业有限公司 | Method for detecting related substances of sodium valproate oral solution |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113203824A (en) | Detection method of sodium valproate related substances | |
| CN102375033A (en) | High performance liquid chromatographic analysis method of bendamustine hydrochloride and its related substances | |
| CN102706998A (en) | Quality control method for shengmai injection | |
| CN117092251A (en) | Detection method of taurine and sulfoalanine in cysteine raw material and application thereof | |
| CN104914194B (en) | A method of with Determination of menthol in gas chromatograph detection Dementholized mint oil dripping pill | |
| CN113702514A (en) | Method for determining atorvastatin calcium related impurity I | |
| CN111220730A (en) | Analysis method of related substances in irbesartan and hydrochlorothiazide compound preparation | |
| CN112946136B (en) | Method for determining content of mesylate in ozesamicin | |
| CN108548885A (en) | The method that two-dimensional liquid chromatography detects compound Nanxing pain paste | |
| CN110412164B (en) | Method for detecting related substances of mexiletine hydrochloride | |
| Al-Momani et al. | Automated flow injection spectrophotometric determination of the proton pump inhibitor omeprazole in pharmaceutical formulations | |
| CN113252803A (en) | Method for determining process and degradation impurities in sodium valproate raw material | |
| CN107976494B (en) | Construction of standard characteristic spectrum of Kangfu tincture and quality detection method thereof | |
| CN112666278A (en) | Limit detection method for strychnine in Huatuo reconstruction pills | |
| CN111208214A (en) | Method for detecting Tween content in medicinal preparation by liquid phase method | |
| CN114200050B (en) | HPLC detection method for content of related substances in p-bromoanisole | |
| CN104914174A (en) | Content determination method of gingko diterpene lactone for injection | |
| CN113125585B (en) | Method for detecting R-4-propyl-dihydrofuran-2-ketone or/and related substances thereof | |
| CN115327003B (en) | Method for detecting clopidogrel oxide related substances | |
| CN112684021B (en) | Vitamin B12Method for detecting related substances of injection | |
| CN117129599A (en) | Method for measuring impurity F content in piracetam by high performance liquid phase method | |
| CN117907456A (en) | Method for detecting pioglitazone hydrochloride and genotoxic impurities in preparation thereof by high performance liquid chromatography | |
| CN116577450A (en) | Method for simultaneously detecting blood concentration of 7 antitumor drugs | |
| CN117990846A (en) | Method for detecting R-isomer impurity in irinotecan hydrochloride injection by HPLC method | |
| CN115656356A (en) | Method for measuring 4-hydroxy-7-phenoxy isoquinoline-3-methyl formate and related substances thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |