CN116953111A - Method for detecting content and dissolution rate of valproimide - Google Patents
Method for detecting content and dissolution rate of valproimide Download PDFInfo
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- 210000004498 neuroglial cell Anatomy 0.000 description 1
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
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- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
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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
-
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
- G01N30/86—Signal analysis
-
- 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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
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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)
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- Pathology (AREA)
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Abstract
The invention provides a method for detecting the content and dissolution rate of valproimide, and relates to the technical field of analysis and detection. According to the invention, a valproamide sample to be detected, methanol and water are mixed, and the obtained sample liquid to be detected is subjected to high performance liquid chromatography detection to obtain a detection result of the content of valproamide. The detection method provided by the invention has good linear relation of valproimide concentration within the range of 0.3994-1.5984 mg/mL, the sampling precision RSD is 0.6%, the total average recovery rate of high, medium and low concentration sample solutions is 100.63%, the repeatability test RSD is 0.3%, and the repeatability of the detection method is good; the stability of the sample liquid to be tested is excellent within 12 hours; the valproamide has the quantitative limit of 64.09 mug/mL and the detection limit of 7.74 mug/mL, and the detection method provided by the invention has the advantages of simple operation, strong specificity, high sensitivity, and high accuracy and precision of detection results.
Description
Technical Field
The invention relates to the technical field of analysis and detection, in particular to a method for detecting the content and dissolution rate of valproimide.
Background
Valpromide (Valpromide) is a novel antiepileptic drug with broad spectrum, strong action, quick effect and low toxicity. Animal experiment research shows that valproimide has 2 times of anti-penta-tetrazaconvulsion effect as sodium valproate, and has good curative effect in clinical trial on various types of epilepsy, and is also suitable for epileptic tonic clonic attacks, absence attacks, infantile spasticity and the like. The action mechanism of valproimide is probably that by inhibiting gamma-aminobutyric acid (GABA) degrading enzyme system in brain to different degrees, the GABA concentration in brain is increased, and meanwhile, the activity of glutamate dehydrogenase is increased, so that GABA synthesis in brain is increased. On the other hand, preventing the reuptake of GABA by axons and glial cells can also increase GABA concentration in the synaptic cleft. Increase postsynaptic inhibition by GABA. Studies have shown that valproimide can prevent the spread of abnormal discharge in epileptic lesions. Few people take valproamide medicines, and the medicines have inappetence, nausea, dizziness, headache, hypodynamia and rash, disappear by themselves after more than one week, and even pancreatitis and acute liver necrosis are caused after long-term taking. Can cause purpura, hemorrhage and prolonged bleeding time due to thrombocytopenia, and can be checked regularly.
The current legal quality standard of valproimide raw materials and preparations is national standard chemical standard landmark rise national standard second book, and the content measurement method is nitrogen measurement method, but the content measurement method is not strong in specificity.
In addition, the dissolution test of valproimide tablet can reflect the in vivo bioavailability of the oral solid preparation from a certain degree. However, there is no check item for dissolution in the current legal quality standards. In order to better evaluate the effectiveness of the valproamide tablet, it is necessary to establish a dissolution method which is convenient to operate and to examine the dissolution curve of the valproamide tablet.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for detecting the content and dissolution rate of valproic acid amide, which has strong specificity to the detection result of the content of valproic acid amide, and can realize accurate and high-sensitivity detection of the content of valproic acid amide.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for detecting the content of valproimide, which comprises the following steps:
mixing a valproimide sample to be detected, methanol and water to obtain a sample liquid to be detected;
and carrying out high performance liquid chromatography detection on the sample liquid to be detected to obtain a detection result of the content of valproimide.
Preferably, the volume ratio of the methanol to the water is 5-15: 85-95.
Preferably, the ratio of the mass of the valproimide sample to be tested to the total volume of methanol and water is 1g: 900-1100 mL.
Preferably, the conditions for high performance liquid chromatography detection include: the chromatographic column is a chromatographic column with octadecyl bonded silica gel as a stationary phase; the mobile phase is methanol aqueous solution, and the volume fraction of methanol in the methanol aqueous solution is 49.5-60.5%; the detection wavelength is 205nm, the flow rate of the mobile phase is 0.5-1.5 mL/min, and the sample injection amount is 10-30 mu L.
Preferably, the content of the valproimide is calculated by an external standard method.
The invention provides a method for detecting the dissolution rate of valproimide, which comprises the following steps:
dissolving a valproimide sample to be detected in water to obtain a solution;
and (3) performing high performance liquid chromatography detection on the dissolution liquid to obtain a detection result of the dissolution rate of valproimide.
Preferably, the ratio of the mass of the valproimide sample to be measured to the volume of water is 1g: 2250-2750 mL.
Preferably, the dissolution is carried out under stirring conditions, and the stirring speed is 48-52 r/min and the stirring time is 44-46 min.
Preferably, the conditions for high performance liquid chromatography detection include: the chromatographic column is a chromatographic column with octadecyl bonded silica gel as a stationary phase; the mobile phase is methanol aqueous solution, and the volume fraction of methanol in the methanol aqueous solution is 49.5-60.5%; the detection wavelength is 205nm, the flow rate of the mobile phase is 0.5-1.5 mL/min, and the sample injection amount is 10-30 mu L.
Preferably, the dissolution rate of the valproimide is calculated by an external standard method.
The invention provides a method for detecting the content of valproimide, which comprises the following steps: mixing a valproimide sample to be detected, methanol and water to obtain a sample liquid to be detected; and carrying out high performance liquid chromatography detection on the sample liquid to be detected to obtain a detection result of the content of valproimide. The detection method provided by the invention has the advantages of simple operation, strong specificity, high sensitivity, high accuracy of detection results, high accuracy and no interference in blank. As shown in the test results of the examples, the valproimide concentration is in the range of 0.3996-1.5984 mg/mL, and the correlation coefficient R 2 =0.9999, the linear range of the detection method is wide; the sample injection precision RSD is 0.6%, and the precision of the detection method is high; the total average recovery rate of the high-concentration sample solution, the medium-concentration sample solution and the low-concentration sample solution is 100.63%, the repeatability test RSD is 0.3%, and the repeatability of the detection method is good; the stability of the sample liquid to be tested is excellent within 12 hours; the quantitative limit of valproimide is 64.09 mug/mL, the detection limit is 7.74 mug/mL, the quantitative limit and the detection limit are low, and the sensitivity of the detection method is high.
The invention provides a method for detecting the dissolution rate of valproimide, which comprises the following steps: dissolving a valproimide sample to be detected in water to obtain a solution; and (3) performing high performance liquid chromatography detection on the dissolution liquid to obtain a detection result of the dissolution rate of valproimide. No dissolution test item in the current legal quality standard of valproimide tabletFor the purpose of this, the dissolution test can reflect the in vivo bioavailability of the oral solid preparation from a certain degree. The method for detecting the dissolution rate is simple and convenient to operate, high in specificity, high in sensitivity, high in accuracy of detection results, high in accuracy and free of interference, and the method for detecting the dissolution curve of the valproimide by using the dissolution rate method is established, so that the effectiveness of a valproimide sample (such as a valproimide tablet) to be detected can be better evaluated, and the blank of detection of the dissolution rate of the valproimide is made up. As shown in the test results of the examples, the valproimide concentration is in the range of 0.01629-0.8145 mg/mL, and the correlation coefficient R 2 =0.9997, the linear range of the detection method is wide; the sample injection precision RSD is 0.64%, and the precision of the detection method is high; the total average recovery rate of the high-concentration sample solution, the medium-concentration sample solution and the low-concentration sample solution is 100.38 percent, the average dissolution rate of the repeatability test is 92.47-95.79 percent, and the repeatability of the detection method is good; the dissolution liquid has excellent stability within 24 hours; the quantitative limit of valproimide is 64.09 mug/mL, the detection limit is 7.74 mug/mL, the quantitative limit and the detection limit are low, and the sensitivity of the detection method is high.
Drawings
FIG. 1 is a valproimide content determination-ultraviolet spectrum;
FIG. 2 is a valproimide content determination-blank solvent HPLC profile;
FIG. 3 is a linear relationship between valproimide concentration and peak area;
FIG. 4 is a graph showing valproimide content measurement versus minimum detection limit;
FIG. 5 is a HPLC profile of valproimide tablet dissolution rate measurement-control solution;
FIG. 6 is a HPLC chart of valproimide tablet dissolution rate measurement-test solution;
FIG. 7 is a cumulative dissolution profile of valproimide tablet in different dissolution media and rotational speeds;
FIG. 8 is a linear relationship between valproimide concentration and peak area;
FIG. 9 is an HPLC profile of hollow white adjuvant in valproimide tablet;
FIG. 10 is an HPLC chart of the valeramide tablet dissolution test-valproimide limit of detection.
Detailed Description
The invention provides a method for detecting the content of valproimide, which comprises the following steps:
mixing a valproimide sample to be detected, methanol and water to obtain a sample liquid to be detected;
and carrying out high performance liquid chromatography detection on the sample liquid to be detected to obtain a detection result of the content of valproimide.
The raw materials adopted by the invention are all commercial products unless specified.
The method comprises the steps of mixing a valproimide sample to be detected, methanol and water to obtain a sample liquid to be detected.
In the invention, the valproamide sample to be tested preferably comprises valproamide tablets and/or valproamide raw materials. In the present invention, the volume ratio of methanol to water is preferably 5 to 15:85 to 95, more preferably 8 to 12:88 to 92, more preferably 10:90. In the present invention, the ratio of the mass of the valproimide sample to be measured to the total volume of methanol and water is preferably 1g:900 to 1100mL, more preferably 1g:950 to 1050mL, more preferably 1g:1000mL.
In the present invention, the mixing is preferably performed by dissolving the valproimide sample to be measured in methanol and then diluting with water.
After obtaining a sample liquid to be detected, the invention carries out high performance liquid chromatography detection on the sample liquid to be detected to obtain a detection result of the content of valproimide.
In the present invention, the conditions for the detection by high performance liquid chromatography include: the chromatographic column is preferably a chromatographic column with octadecyl bonded silica gel as a stationary phase, and particularly preferably comprises a Takara Shuzo CAPCELLPAK chromatographic column, a Welch Xtime chromatographic column or an Agilent ZORBAX chromatographic column; the column temperature is preferably 29.5-30.5 ℃, more preferably 30 ℃; the mobile phase is preferably an aqueous methanol solution, and the volume fraction of methanol in the aqueous methanol solution is preferably 49.5-60.5%, more preferably 50-58%, and even more preferably 55%; the detection wavelength is preferably 205nm, the flow rate of the mobile phase is preferably 0.5-1.5 mL/min, more preferably 0.8-1.2 mL/min, and even more preferably 1mL/min; the amount of the sample to be introduced is preferably 10 to 30. Mu.L, more preferably 15 to 25. Mu.L, and still more preferably 20. Mu.L.
In the present invention, the content of valproic acid amide is preferably calculated by an external standard method, more preferably by an external standard method calculated by the peak area of valproic acid amide. In the invention, the reference substance solution adopted by the external standard method is preferably valproamide reference substance solution, and the concentration of the reference substance solution is preferably 0.9-1.1 mg/mL, more preferably 1mg/mL.
The invention provides a method for detecting the dissolution rate of valproimide, which comprises the following steps:
dissolving a valproimide sample to be detected in water to obtain a solution;
and (3) performing high performance liquid chromatography detection on the dissolution liquid to obtain a detection result of the dissolution rate of valproimide.
In the invention, the ratio of the mass of the valproimide sample to be detected to the volume of water is preferably 1g:2250 to 2750mL, more preferably 1g:2300 to 2700mL, more preferably 1g: 2400-2600 mL.
In the present invention, the dissolution is preferably performed under stirring conditions, and the stirring speed is preferably 48 to 52r/min, more preferably 49 to 51r/min, and still more preferably 50r/min; the stirring time is preferably 44 to 46 minutes, more preferably 45 minutes.
After the dissolution, the present invention preferably further comprises filtering the dissolution solution obtained by the dissolution, and the obtained filtrate is the dissolution solution. In the present invention, the filtration is preferably 0.45 μm membrane filtration.
After the dissolution liquid is obtained, the invention carries out high performance liquid chromatography detection on the dissolution liquid to obtain the detection result of the dissolution rate of the valproimide.
In the present invention, the conditions for the detection by high performance liquid chromatography include: the chromatographic column is preferably a chromatographic column with octadecyl bonded silica gel as a stationary phase, and particularly preferably comprises a Takara (R) CAPCELLPAK chromatographic column, a WelchXtime chromatographic column or an AgilentZORBAX chromatographic column; the column temperature is preferably 36-38 ℃, more preferably 37 ℃; the mobile phase is preferably an aqueous methanol solution, and the volume fraction of methanol in the aqueous methanol solution is preferably 49.5-60.5%, more preferably 50-58%, and even more preferably 55%; the detection wavelength is preferably 205nm, the flow rate of the mobile phase is preferably 0.5-1.5 mL/min, more preferably 0.8-1.2 mL/min, and even more preferably 1mL/min; the amount of the sample to be introduced is preferably 10 to 30. Mu.L, more preferably 15 to 25. Mu.L, and still more preferably 20. Mu.L.
In the present invention, the dissolution rate of valproimide is preferably calculated by an external standard method, more preferably by the peak area of valproimide. In the invention, the reference substance solution adopted by the external standard method is preferably valproamide reference substance solution, and the concentration of the reference substance solution is preferably 0.2-0.4 mg/mL, and particularly preferably 0.2mg/mL or 0.4mg/mL.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, the following instruments and reagents were used: the HPLC instrument is a Dionex Ultimate3000 high performance liquid chromatograph (DAD ultraviolet detector); the dissolution adopts a Fux FADT-801RC full-automatic dissolution instrument and a Fux FADT-800RC full-automatic dissolution instrument; methanol is a chromatographic pure reagent, and is Burdock & Jackson; the other reagents are analytically pure reagents and the water is purified water. The valproimide reference substance purity is 99.89%. HPLC detection conditions: the chromatographic column is a senior hall CAPCELL PAK chromatographic column (250 mm×4.6mm×5 μm); the column temperature is 30+/-0.5 ℃, the mobile phase is methanol-water (methanol: water volume ratio=55:45), the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 205nm, and the sample injection amount is 20 mu L.
Example 1
1. Solution preparation
Test solution: the valproimide tablet (50 mg) is precisely weighed, placed in a 50mL volumetric flask, added with 30mL of methanol, and subjected to ultrasonic treatment at room temperature until the valproimide tablet is dissolved (the temperature of the solution rises in the ultrasonic treatment process), cooled to room temperature, diluted to a scale by adding water, and uniformly shaken to obtain a sample solution.
Control solution: accurately weighing valproimide reference substance 50mg, placing in a 50mL volumetric flask, adding 30mL of methanol, performing ultrasonic treatment to dissolve, cooling to room temperature, adding water to dilute to scale, and shaking uniformly to obtain a sample solution.
2. Selection of chromatographic columns
The HPLC detection of the sample solution is performed by selecting different chromatographic columns, and the chromatograms are recorded, and the types of the chromatographic columns and the influence of the chromatographic columns on the detection results are shown in Table 1.
Table 1 selection results for chromatographic columns
| Chromatographic column | Valproimide retention time (min) | Number of theoretical plates |
| Innovation hall CAPCELL PAK (250 mm. Times.4.6mm.times.5μm) | 16.177 | 16179 |
| Welch Xtimate(250mm×4.6mm×5μm) | 15.867 | 14789 |
| Agilent ZORBAX(250mm×4.6mm×5μm) | 15.007 | 6767 |
System applicability requirements: the theoretical plate number is not lower than 2000 according to valproamide peak calculation, and as can be seen from table 1, the C18 chromatographic columns of different brands can meet the detection requirement of valproamide content, and the separation degree of valproamide peak and adjacent impurity peak meets the requirement.
3. Selection of detection wavelength
FIG. 1 is a graph of ultraviolet light spectrum of valproimide from DAD graph of sample solution, and as can be seen from FIG. 1, valproimide has maximum absorption at 193.4nm wavelength, and 205nm is selected as content detection wavelength of valproimide in order to avoid solvent interference and ensure proper response value considering 193nm as terminal absorption.
Example 2
1. Blank solvent interference test
The blank solvent (methanol: water volume ratio=1:9) was subjected to HPLC detection, and the results are shown in fig. 2. As can be seen from fig. 2, the blank solvent did not interfere with the determination of valproimide content.
2. Test of Linear relation
1000.1mg of valproimide reference substance is precisely weighed, placed in a 100mL measuring flask, added with 60mL of methanol for ultrasonic treatment until the valproimide reference substance is dissolved, cooled to room temperature, diluted to a scale by adding water, and uniformly shaken to be used as a linear stock solution. Precisely measuring 2mL, 3mL, 4mL, 5mL, 6mL, 7mL and 8mL of linear stock solution, respectively placing the linear stock solution in a 50mL volumetric flask, adding water to dilute the linear stock solution to a scale, and shaking the linear stock solution to obtain linear solution 1-7.
The solutions were subjected to HPLC detection, chromatograms were recorded, the valproimide concentration (x) was taken as the abscissa, the valproimide peak area (y) was taken as the ordinate, and a standard curve was drawn, and the linear relation test results were shown in FIG. 3 and Table 2. From fig. 3 and table 2, a linear regression equation is derived: y=3173.8x+96.557, r 2 ＝0.9996。
TABLE 2 test results of the linear relationship between valproimide concentration and peak area
| Linear solution | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Concentration (μg/mL) | 0.3996 | 0.5994 | 0.7992 | 0.9990 | 1.1988 | 1.3986 | 1.5984 |
| Peak area | 1326.25 | 2011.14 | 2643.39 | 3315.00 | 3896.87 | 4530.21 | 5147.59 |
As can be seen from FIG. 2 and Table 2, the valproimide concentration was in the range of 0.3994 to 1.5984mg/mL, the peak area and the concentration were well-linearly related, and the linear range was broad.
3. Sample injection precision test
The linear solution 4 was subjected to HPLC detection, sample was continuously introduced 6 times, and the chromatogram was recorded, and the results are shown in Table 3.
Table 3 content determination sample injection precision test results (n=6)
As shown in Table 3, the sample injection precision of the method for detecting the valproimide content provided by the invention is good.
4. Recovery test
Valproimide tablets (batch number: 191101) 60mg (high), 50mg (medium) and 40mg (low) (3 parts each) are respectively placed in 50mL volumetric flasks, 30mL of methanol is added for ultrasonic treatment until the valproimide tablets are dissolved, the mixture is cooled to room temperature, water is added and diluted to a scale, and the valproimide tablets are uniformly shaken to be used as a high-concentration test solution, a medium-concentration test solution and a low-concentration test solution.
The linear solution 4 was used as a control solution.
HPLC detection is carried out on the sample solution and the reference solution, chromatograms are recorded, the content of valproimide is calculated according to an external standard method by using the peak area of valproimide, and then the recovery rate is calculated, and the result is shown in Table 4.
TABLE 4 recovery test results for content determination method
As can be seen from Table 4, the method for detecting the valproimide content provided by the invention has good recovery rate.
5. Solution stability test
The linear solution 4 was sampled and assayed at 0, 2, 4, 6, 8 and 12 hours, respectively, and the results are shown in Table 5.
TABLE 5 assay solution stability test results
As is clear from Table 5, the linear solution was measured after 12 hours of standing, and the peak area was not substantially changed, indicating that the solution was excellent in stability within 12 hours.
6. Repeatability test
Valproimide tablets (batch number: 191101) were taken at 50mg (6 parts) and placed in 50mL volumetric flasks, respectively, 30mL of methanol was added to sonicate until dissolved, water was added and diluted to scale, and shaking was performed to give test solutions.
The linear solution 4 was used as a control solution.
The sample solution and the reference solution were subjected to HPLC detection, the chromatograms were recorded, the content of valproimide was calculated as the peak area of valproimide by the external standard method, and the recovery rate was calculated, and the results are shown in Table 6.
TABLE 6 content determination repeatability test results
As is clear from Table 6, the method for detecting valproimide content provided by the invention has good repeatability.
7. Limit of quantification and limit of detection
Valproamide reference 50mg was taken, and each reference dilution was subjected to HPLC detection by stepwise dilution, and a chromatogram was recorded. The limit S/n=10 is set, the detection limit S/n=3, and the lowest detection limit result is shown in fig. 4. The valproimide was quantified at 64.09. Mu.g/mL and detected at 7.74. Mu.g/mL.
Example 3
Comparison of results of high performance liquid chromatography and nitrogen determination
High performance liquid chromatography: test and control solutions were prepared as in example 1, and valproimide lot numbers were 191110, 191111 and 191112, respectively. HPLC detection was performed, and the content of valproic acid amide was calculated as the peak area of valproic acid amide by the external standard method, and the results are shown in Table 7.
Nitrogen determination: the content of valproimide in the second volume of the national standard is measured by adopting a nitrogen determination method by valproimide in the standard of original quality of chemicals of national drug Standard, and the specific method is as follows: valproimide tablet 0.3g is taken, precisely weighed and measured according to nitrogen measurement method (second appendix VIIID first method of China pharmacopoeia 2000 edition). Each 1mL of sulfuric acid titration (0.05 mol/L) corresponds to 14.32mg of C 8 H 17 NO, valproimide lot numbers 191110, 191111 and 191112, respectively, and valproimide content measurements are shown in table 7.
TABLE 7 comparison of results of high Performance liquid chromatography and Nitrogen determination for valproic acid amide content of various batches of valproic acid amide samples
| Lot number | High performance liquid chromatography (%) | Nitrogen determination method (%) |
| 191110 | 98.9 | 99.0 |
| 191111 | 99.7 | 99.9 |
| 191112 | 98.6 | 99.0 |
As can be seen from Table 7, the detection method provided by the invention has no obvious difference from the detection result of valproimide content by the nitrogen fixation method.
Example 4
1. Selection of dissolution method
Valproimide tablet is common tablet and is prepared through paddle process. Since the response value of valproimide measured by high performance liquid chromatography is not high, the volume of the solvent is assumed to be 500mL.
2. Method for detecting dissolved solution
Dissolution liquid: valproimide tablet 1 (batch No. 191107, specification 0.2 g/tablet) was placed in 500mL of water, stirred at 50r/min, stirred for 45min, then sampled with a 0.45 μm filter membrane, and the resulting filtrate was subjected to HPLC testing.
Control dissolution: taking 100mg of valproimide reference substance, placing the valproimide reference substance into a 100mL volumetric flask, adding a proper amount of methanol to dissolve, diluting to a scale with a dissolution medium, and shaking uniformly; precisely weighing 20mL, placing in a 50mL volumetric flask, adding a dissolution medium to dilute to a scale, shaking uniformly, and performing HPLC test on the obtained solution.
The HPLC spectrum of the control solution is shown in FIG. 5, and the HPLC spectrum of the dissolution solution is shown in FIG. 6.
3. Selection of dissolution medium and rotational speed
Selecting (1) water and rotating speed of 50r/min; (2) water and rotating speed of 75r/min; (3) the screening was carried out at a pH=1.2 in aqueous hydrochloric acid at a rotation speed of 50r/min,3 cases.
Valproamide tablet samples (batch No. 201006, specification 0.2 g/tablet) were selected, the above dissolution medium was used as solvent (500 mL), and stirred at 37.+ -. 0.5 ℃ at the above rotation speed, sampled for 5, 10, 15, 20, 30, 45 and 60min, and the solution was filtered through 5mL of 0.45 μm filter membrane (and 5mL of dissolution medium of the same temperature was immediately replenished), and HPLC measurement was performed, and the measurement results are shown in Table 8 and FIG. 7.
TABLE 8 cumulative dissolution results for valproimide tablet samples in different dissolution media and rotational speeds
As can be seen from fig. 7 and table 8, the dissolution rate of 45min Shi Bingwu amide can reach 85% or more under three conditions of 50r/min water-rotation speed of the dissolution medium, 75r/min water-rotation speed of the dissolution medium and 50r/min hydrochloric acid aqueous solution with ph=1.2.
4. Test of Linear relation
Taking 1016.28mg of valproimide reference substance, placing the valproimide reference substance into a 100mL volumetric flask, adding 20mL of a proper amount of methanol for dissolution, diluting to a scale with a dissolution medium (water), and shaking uniformly; precisely measuring 20mL, placing in a 50mL volumetric flask, adding a dissolution medium, diluting to a scale, and shaking uniformly; precisely measuring 2.0mL, 3.0mL, 4.0mL, 5.0mL, 6.0mL, 7.0mL and 8.0mL, respectively placing into 50mL volumetric flasks, adding a dissolution medium (water) to dilute to a scale, and shaking uniformly to obtain linear solutions 1-7. The linear solutions 1 to 7 were subjected to HPLC, and the chromatograms were recorded, and the peak areas (y) of valproimide were plotted on the ordinate with the concentration (x) of valproimide as the abscissa, and the results are shown in Table 9 and FIG. 8.
TABLE 9 test results of the linear relationship between valproimide concentration and peak area
| Linear solution | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Concentration (mg/mL) | 0.1622 | 0.2434 | 0.3245 | 0.4056 | 0.4868 | 0.5679 | 0.6490 |
| Average peak area | 551.31 | 817.00 | 1104.53 | 1348.23 | 1628.37 | 1898.12 | 2145.44 |
As can be seen from table 9 and fig. 8, the dissolution linear regression equations are respectively: y=3287.4x+22.487, r 2 Valproimide concentration was in the range of 0.01629-0.8145 mg/mL with good peak area to concentration linearity.
5. Auxiliary material interference test
Mixing adjuvants with the prescription amount of valproimide tablet (with specification of 0.2 g/tablet), placing in 100mL volumetric flask, adding methanol 10mL, stirring to dissolve, diluting with dissolution medium (water) to scale, shaking, filtering with 0.45 μm filter membrane, and collecting filtrate for HPLC determination, wherein the adjuvants in valproimide tablet do not interfere with valproimide determination as shown in FIG. 9.
6. Sample injection precision test
The linear solution 4 was subjected to HPLC detection, sample was continuously introduced 6 times, and the chromatogram was recorded, and the results are shown in Table 10.
Table 10 sample injection precision test results
| Number of times | 1 | 2 | 3 | 4 | 5 | 6 | Average peak area | RSD/％ |
| Peak area | 1341.70 | 1355.09 | 1360.24 | 1355.80 | 1340.70 | 1342.04 | 1349.26 | 0.64 |
As can be seen from Table 10, the method for detecting valproimide dissolution rate provided by the invention has good sample injection precision.
7. Recovery test
About 40mg, 50mg and 60mg of valproimide reference substances are precisely weighed and respectively placed in 100mL volumetric flasks, mixed blank auxiliary materials with prescription amounts (80%, 100% and 120%) are respectively added, 10mL of methanol is added and stirred until the mixture is dissolved, the mixture is diluted to scale by a dissolution medium (water), the mixture is uniformly shaken, and a 0.45 mu m filter membrane is used for filtration, so that a high-concentration test solution (120%), a medium-concentration test solution (100%) and a low-concentration test solution (80%) are obtained. And taking the linear solution 4 as a reference substance solution. The solution was measured precisely and subjected to HPLC detection, a chromatogram was recorded, the valproimide dissolution rate was calculated by an external standard method, and the recovery rate of valproimide was calculated, and the results are shown in Table 11.
TABLE 11 dissolution test method recovery test results
As is clear from Table 11, the method for detecting valproimide dissolution rate provided by the present invention has a good recovery rate.
8. Solution stability test
The solutions prepared in the section "detection method of 2 and solution" in this example were sampled at 0, 2, 4, 8, 12 and 24 hours, respectively, and subjected to HPLC detection, and chromatograms were recorded, and the results are shown in Table 12.
TABLE 12 results of solution stability test
| Time (h) | 0 | 2 | 4 | 8 | 12 | 24 | Average peak area | RSD(％) |
| Peak area | 1204.01 | 1186.12 | 1149.38 | 1169.88 | 1195.61 | 1215.12 | 1186.68 | 2.01 |
As can be seen from Table 12, the peak area was not substantially changed when the solution was left for 24 hours, indicating that the solution had good stability within 24 hours.
9. Repeatability test
Valproimide tablet samples (batch number: 191107,6 batches of samples, each batch of samples tested 6 times, specification 0.2 g/tablet) 1 tablet were placed in 500mL of water, stirred at a rotation speed of 50r/min, stirred for 45min, then sampled with a 0.45 μm filter membrane for filtration, the obtained filtrate was used as a test solution, the test solution was subjected to HPLC detection, and a chromatogram was recorded.
Control solution: precisely weighing 100mg of valproimide reference substance, placing into a 100mL volumetric flask, adding 20mL of methanol for dissolution, and adding water for dilution to a scale; precisely measuring 20mL, placing in a 50mL volumetric flask, adding dissolution medium (water), diluting to scale, and shaking to obtain reference solution with concentration of 0.4 mg/L.
The dissolution rate of valproimide tablet was calculated as the peak area of valproimide by external standard method, and the results are shown in Table 13.
TABLE 13 dissolution reproducibility results
As is clear from Table 13, the method for detecting valproimide dissolution rate provided by the present invention was excellent in reproducibility.
10. Quantitative limit and detection limit
Taking 100mg of valproimide reference substance, gradually diluting with water as a dissolution medium, performing HPLC detection on each reference substance diluent, and recording a chromatogram. The limit S/N=10 and the limit S/N=3 were set to give valproimide with a limit of 64.09. Mu.g/mL and 7.74. Mu.g/mL, see FIG. 10.
Example 5
Dissolution rate measurement of test sample
Valproimide tablets of different lot numbers (191106, 191107 and 191108, specification 0.2 g/tablet) are placed in 500mL of water, stirred at a rotation speed of 50r/min, stirred for 45min, then sampled with a 0.45 μm filter membrane for filtration, the obtained filtrate is used as a test solution, the test solution is subjected to HPLC detection, and a chromatogram is recorded.
Control solution: precisely weighing 100mg of valproimide reference substance, placing into a 100mL volumetric flask, adding 20mL of methanol for dissolution, and adding water for dilution to a scale; precisely measuring 20mL, placing in a 50mL volumetric flask, adding a dissolution medium, diluting to a scale, and shaking uniformly to obtain a reference substance solution with the concentration of 0.4 mg/L.
The dissolution rate of valproimide tablet was calculated by external standard method with peak area of valproimide, and each sample was tested 6 times, and the results are shown in Table 14.
Table 14 results of dissolution (%) of test article
| Lot number | 1 | 2 | 3 | 4 | 5 | 6 | Average of |
| 191106 | 95.55 | 95.74 | 96.46 | 96.59 | 95.74 | 99.12 | 96.53 |
| 191107 | 89.45 | 96.86 | 97.52 | 95.96 | 98.56 | 94.54 | 95.48 |
| 191108 | 99.71 | 100.14 | 100.41 | 102.62 | 99.78 | 109.31 | 102.00 |
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The method for detecting the content of valproimide is characterized by comprising the following steps of:
mixing a valproimide sample to be detected, methanol and water to obtain a sample liquid to be detected;
and carrying out high performance liquid chromatography detection on the sample liquid to be detected to obtain a detection result of the content of valproimide.
2. The method according to claim 1, wherein the volume ratio of methanol to water is 5 to 15: 85-95.
3. The method according to claim 1, wherein the ratio of the mass of the valproimide sample to be tested to the total volume of methanol and water is 1g: 900-1100 mL.
4. The method according to claim 1, wherein the conditions for high performance liquid chromatography detection include: the chromatographic column is a chromatographic column with octadecyl bonded silica gel as a stationary phase; the mobile phase is methanol aqueous solution, and the volume fraction of methanol in the methanol aqueous solution is 49.5-60.5%; the detection wavelength is 205nm, the flow rate of the mobile phase is 0.5-1.5 mL/min, and the sample injection amount is 10-30 mu L.
5. The method according to any one of claims 1 to 4, wherein the valproimide content is calculated by an external standard method.
6. The method for detecting the dissolution rate of valproimide is characterized by comprising the following steps of:
dissolving a valproimide sample to be detected in water to obtain a solution;
and (3) performing high performance liquid chromatography detection on the dissolution liquid to obtain a detection result of the dissolution rate of valproimide.
7. The method according to claim 6, wherein the ratio of the mass of the valproimide sample to be measured to the volume of water is 1g: 2250-2750 mL.
8. The method according to claim 6, wherein the dissolution is performed under stirring conditions, and the stirring speed is 48-52 r/min and the stirring time is 44-46 min.
9. The method according to claim 6, wherein the conditions for high performance liquid chromatography detection include: the chromatographic column is a chromatographic column with octadecyl bonded silica gel as a stationary phase; the mobile phase is methanol aqueous solution, and the volume fraction of methanol in the methanol aqueous solution is 49.5-60.5%; the detection wavelength is 205nm, the flow rate of the mobile phase is 0.5-1.5 mL/min, and the sample injection amount is 10-30 mu L.
10. The method according to any one of claims 6 to 9, wherein the valproimide dissolution is calculated by an external standard method.
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