CN112305114A - High performance liquid chromatography method for determining sorbic acid content in difluprednate eye emulsion - Google Patents
High performance liquid chromatography method for determining sorbic acid content in difluprednate eye emulsion Download PDFInfo
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- CN112305114A CN112305114A CN202011182793.5A CN202011182793A CN112305114A CN 112305114 A CN112305114 A CN 112305114A CN 202011182793 A CN202011182793 A CN 202011182793A CN 112305114 A CN112305114 A CN 112305114A
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Abstract
The invention provides a high performance liquid chromatography method for determining sorbic acid content in difluprednate ophthalmic emulsion, which comprises the following steps: (1) preparation of control solutions: dissolving sorbic acid reference substance in a diluent to prepare a reference substance solution; (2) preparation of sample solution: taking difluprednate eye emulsion, adding a diluent to dissolve the difluprednate eye emulsion to prepare a sample solution; (3) injecting the reference solution and the sample solution into a high performance liquid chromatograph for detection respectively. The method has strong specificity, high precision and high recovery rate, is an effective method for detecting the sorbic acid content in the difluprednate eye emulsion, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of chemical analysis, and particularly relates to a high performance liquid chromatography method for determining sorbic acid content in difluprednate ophthalmic emulsion.
Background
Difluprednate ophthalmic emulsion is a sterile, external anti-inflammatory corticosteroid for use. Its chemical name is 6-3,9 difluoro-11, 17, 21-trihydroxypregnene-1, 4-diene-3, 20-dione 21-acetic acid 17-butyrate (CAS number 23674-86-4). 0.5mg (0.05%) of difluprednate as active ingredient per ml of emulsion; inactive ingredients: boric acid, castor oil, glycerin, polysorbate 80, water for injection, sodium acetate, disodium edetate, sodium hydroxide, and sorbic acid as preservative.
Sorbic acid is a chemical additive that prevents or delays the deterioration of foods, pharmaceuticals, etc. due to chemical changes or microbial growth. Sorbic acid is added to the difluprednate ophthalmic emulsion to prevent the growth of bacteria and corrosive substances in the ophthalmic emulsion, thereby increasing the application time of the ophthalmic solution. However, sorbic acid can cause certain damage to the ocular surface, so that effective and accurate monitoring of the sorbic acid content in the difluprednate ophthalmic emulsion is very necessary.
However, at present, no related method for detecting the content of sorbic acid in the difluprednate ophthalmic emulsion is reported. The existing literature reports a method for detecting the sorbic acid content in other products, but the method cannot be applied to the detection of the sorbic acid content in the difluprednate ophthalmic emulsion due to different components in different products.
Disclosure of Invention
The invention aims to provide a high performance liquid chromatography method for determining the sorbic acid content in difluprednate ophthalmic emulsion. The method comprises the following steps:
(1) preparation of control solutions: dissolving sorbic acid reference substance in a solvent to prepare a reference substance solution;
(2) preparation of sample solution: taking an emulsion for eye to be detected with difluprednate, and adding a solvent to dissolve the emulsion to prepare a sample solution;
(3) injecting the reference substance solution and the sample solution into a high performance liquid chromatograph for detection respectively, wherein the chromatographic conditions are as follows:
a chromatographic column: a C18 chromatography column;
mobile phase: the mobile phase A is an ammonium acetate solution, the mobile phase B is methanol, and the volume ratio of the mobile phase A to the mobile phase B is (75-85): (15-25) isocratic elution, preferably 80:20 isocratic elution;
(4) and calculating the content of sorbic acid in the difluprednate ophthalmic emulsion according to the detection result.
Further, the solvent in the step (1) and the step (2) is methanol.
Further, the concentration of the ammonium acetate solution in the step (3) is 0.01-0.03 mol/L, preferably 0.02 mol/L.
Further, the specification of the chromatographic column in the step (3) is 4.6mm in inner diameter, 250mm in length and 5 μm in filler particle size; a preferred column model is ACE 5C 18 column.
Further, the isocratic elution time in the step (3) is 10 to 15 minutes, preferably 12 minutes.
Further, the chromatographic conditions further comprise: the detection wavelength was 254 nm.
Further, the chromatographic conditions further comprise: the column temperature is 25-35 ℃, the sample tray temperature is 5 ℃, and the flow rate is 0.5-1.5 mL/min. Preferably, the column temperature is 30 ℃ and the flow rate is 1.0 mL/min.
Furthermore, the sample amount of the control solution and the sample solution is 5-15 μ L, preferably 10 μ L.
The test result shows that the method has strong specificity, high precision and high recovery rate, is an effective method for detecting the sorbic acid content in the difluprednate eye emulsion, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a high performance liquid chromatogram of a control solution.
FIG. 2 is a high performance liquid chromatogram of a sample solution.
FIG. 3 is a curve fitted to the results of HPLC testing for sorbic acid content.
FIG. 4 is a high performance liquid chromatogram of a sample after acid degradation.
FIG. 5 is a high performance liquid chromatogram of a sample after base degradation.
FIG. 6 is a high performance liquid chromatogram of a sample after oxidative degradation.
FIG. 7 is a high performance liquid chromatogram of a sample after high temperature degradation.
FIG. 8 is a high performance liquid chromatogram of a sample after photodegradation.
Detailed Description
The raw materials used in the invention are all known products and are obtained by purchasing commercial products.
Example 1 method for determining sorbic acid content in difluprednate ophthalmic emulsion
(1) Preparation of control solutions: weighing 25mg of sorbic acid reference substance, precisely weighing the sorbic acid reference substance into a 25mL volumetric flask, fully dissolving the sorbic acid reference substance with methanol, fixing the volume to a scale, shaking up to obtain a reference substance stock solution with the concentration of 1000 mu g/mL, precisely weighing 1.0mL to 25mL volumetric flask of the reference substance stock solution, adding methanol to dilute the reference substance stock solution to the scale, and uniformly mixing; and then taking the solution in a 2.0-25 mL volumetric flask, adding methanol to dilute to a scale, and mixing uniformly to obtain a reference solution with the concentration of 3.2 mu g/mL.
(2) Preparation of sample solution: accurately transferring 1.0mL to 25mL volumetric flasks of the difluprednate ophthalmic emulsion, adding methanol to dilute to a scale, and uniformly mixing; and then 2.0mL of the solution is taken out to be placed in a 25mL volumetric flask, methanol is added to dilute the solution to a scale mark, and the solution is uniformly mixed to obtain a sample solution with the concentration of 3.2 mu g/mL.
(3) Respectively injecting the reference substance solution and the sample solution into a high performance liquid chromatograph for detection in a sample injection amount of 10 mu L, wherein the detection conditions are as follows: a chromatographic column: ACE 5C 18 chromatography column (4.6mm 250mm, 5 μm);
mobile phase: the mobile phase A is 0.02mol/L ammonium acetate solution, the mobile phase B is methanol, and the volume ratio of the mobile phase A to the mobile phase B is 80:20 isocratic elution;
the detection wavelength is 254nm, the flow rate is 1.0mL/min, the column temperature is 30 ℃, and the sample tray temperature is 5 ℃.
(4) Calculating the sorbic acid content according to the result, wherein the calculation formula of the sorbic acid content is as follows:
wherein, the appl is the peak area of the measured sample solution;
astd is the average of peak areas of the control solutions measured repeatedly 5 times;
wstd is the mass (mg) of sorbic acid in the standard solution;
dstd is the dilution multiple of the standard solution;
dspl is the dilution multiple of the sample solution;
l is the labeled amount of sorbic acid in the sample solution, in mg;
p is the purity of the standard sorbic acid (mg/mg).
The chromatogram of the control solution is shown in FIG. 1, the chromatogram of the sample solution is shown in FIG. 2, and the diluent and the active ingredient do not interfere at the sorbic acid peak position.
Experimental example 1 Linear examination of the detection method of the present invention
1. Preparation of Linear solutions
(1) Preparation of linear stock solution: accurately weighing 25.0mg of sorbic acid reference substance into a 25mL volumetric flask, fully dissolving the sorbic acid reference substance by using a diluent and fixing the volume; then, the solution was transferred into a volumetric flask of 1.0mL to 25mL, and the volume was fixed with a diluent and mixed well to obtain a 40. mu.g/mL solution.
(2) Preparation of a linear solution: as shown in table 1.
TABLE 1 preparation of Linear solutions
2. The experimental method comprises the following steps:
the linear solution was subjected to HPLC analysis under the same conditions as in example 1, and then the results were subjected to linear fitting.
3. The experimental results are as follows:
the linear fitting curve is shown in FIG. 3, the correlation coefficient R of the obtained fitting equation reaches 0.9999, and the Y-axis intercept is-0.6% of the 100% response value, which shows that the sorbic acid has good linearity in the concentration range of 2.50ug/ml to 3.75 ug/ml.
Experimental example 2 investigation of specificity of the detection method of the present invention
1. Preparation of forced degradation sample solution
After the samples were subjected to forced degradation and destruction by acid, alkali, oxidation, high temperature and light, the samples were prepared into forced degradation sample solutions according to the preparation method of the sample solutions of example 1. Specific forced degradation conditions are shown in table 2.
TABLE 2 forced degradation conditions
| Strength of | Time of day | Temperature of | |
| Acid(s) | 1N HCl | 0.5h | 60℃ |
| Alkali | 1N NaOH | 1.0h | 60℃ |
| Oxidation by oxygen | 30％H2O2 | 1.0h | 60℃ |
| High temperature | NA | 5 days | 60℃ |
| Illumination of light | Ultraviolet light irradiation | 5 days | At room temperature |
2. The experimental method comprises the following steps:
the forcedly degraded sample solutions were subjected to HPLC detection under the same conditions as in example 1.
3. Results of the experiment
The liquid chromatogram of the sample after acid degradation is shown in FIG. 4; the liquid chromatogram of the sample after alkali degradation is shown in FIG. 5; the liquid chromatogram of the sample after oxidative degradation is shown in FIG. 6; the liquid chromatogram of the sample after high-temperature degradation is shown in FIG. 7; the liquid chromatogram of the sample after light degradation is shown in FIG. 7.
As can be seen from the figure, the chromatographic peak of sorbic acid can still be normally detected, and the sample is stable to acid, alkali, oxidation and high temperature and does not generate an interference peak; sensitive to light, but the chromatographic peaks produced by photodegradation are well separated from the sorbic acid.
And (4) conclusion: the detection method has good specificity for detecting sorbic acid in the difluprednate ophthalmic emulsion.
Experimental example 3 examination of the precision of the detection method of the present invention
The results of repeated measurements of 6 sample solutions using the method of example 1 are shown in Table 3.
TABLE 36 content results of repeated measurements of sample solutions
As can be seen, the RSD of the 6 samples for repeatedly measuring the sorbic acid content is 0.8 percent, and the method is proved to have good repeatability and high precision for detecting the sorbic acid in the difluprednate ophthalmic emulsion.
Experimental example 4 accuracy examination of the detection method of the present invention
1. Preparing gradient solutions with different concentration levels:
(1) preparation of sorbic acid stock solution: weighing a 25mg to 25mL volumetric flask of a sorbic acid standard substance, diluting to a constant volume by using a diluent, and uniformly mixing; taking the solution in a volumetric flask with the volume of 1-25 mL, diluting with a diluent, and uniformly mixing;
(2) preparation of placebo stock solution: transferring a placebo (which refers to difluprednate ophthalmic emulsion containing no sorbic acid) into a volumetric flask of 1-25 mL, diluting to a constant volume by using a diluent, and uniformly mixing;
(3) preparing gradient solutions with different concentration levels: sorbic acid stock solution and placebo stock solution are transferred into a 25mL volumetric flask according to the table 4, and diluent is added to the volumetric flask to fix the volume to the scale, so as to prepare detection solutions of three concentration levels.
TABLE 4 preparation of gradient solutions for three concentration levels
Three concentration levels were performed in triplicate.
2. Experimental methods and results: the prepared gradient solution was subjected to HPLC test under the same conditions as in example 1, and the results are shown in Table 5.
TABLE 5 detection recovery of gradient solutions at different concentration levels
The recovery rate of the content of sorbic acid in the difluprednate ophthalmic emulsion detected by the method is 98.0-102.0%, which shows that the method has high recovery rate and good accuracy. Experimental example 5 stability examination of control solution and sample solution
The sample solution and the control solution in example 1 were stabilized at 5 ℃ for 48h, and the control solution and the sample solution were tested at different time points using the chromatographic conditions in example 1, respectively, and the results are shown in table 6:
TABLE 6 stability of control and sample solutions
It can be seen that the sample solution and the reference solution prepared by the method are stored at 5 ℃ and normal temperature, the property of the solutions is not changed greatly, which shows that the sample solution and the reference solution prepared by the method can keep stable for 48 hours under the condition that the temperature of the sample plate in the detection method is 5 ℃, and the detection result is not influenced.
In conclusion, the invention provides the high performance liquid chromatography method for determining the sorbic acid content in the difluprednate ophthalmic emulsion, which has strong specificity, high precision and high recovery rate, is an effective method for detecting the sorbic acid content in the difluprednate ophthalmic emulsion, and has good application prospect.
Claims (10)
1. A high performance liquid chromatography method for determining the sorbic acid content of difluprednate ophthalmic emulsion is characterized by comprising the following steps of:
(1) preparation of control solutions: dissolving sorbic acid reference substance in a solvent to prepare a reference substance solution;
(2) preparation of sample solution: taking an emulsion for eye to be detected with difluprednate, and adding a solvent to dissolve the emulsion to prepare a sample solution;
(3) injecting the reference substance solution and the sample solution into a high performance liquid chromatograph for detection respectively, wherein the chromatographic conditions are as follows:
a chromatographic column: a C18 chromatography column;
mobile phase: the mobile phase A is an ammonium acetate solution, the mobile phase B is methanol, and the volume ratio of the mobile phase A to the mobile phase B is (75-85): (15-25) isocratic elution;
(4) and calculating the content of sorbic acid in the difluprednate ophthalmic emulsion according to the detection result.
2. The method of claim 1, wherein: the solvent in the step (1) and the step (2) is methanol.
3. The method of claim 1, wherein the concentration of the ammonium acetate solution in the step (3) is 0.01 to 0.03mol/L, preferably 0.02 mol/L.
4. The method of claim 1, wherein the volume ratio of mobile phase a to mobile phase B eluted isocratically in step (3) is 80: 20.
5. The method of claim 1, wherein: the specification of the chromatographic column in the step (3) is 4.6mm in inner diameter, 250mm in length and 5 microns in filler particle size; a preferred column model is ACE 5C 18 column.
6. The method of claim 1, wherein: the isocratic elution time in the step (3) is 10-15 minutes, and preferably 12 minutes.
7. The method according to any one of claims 1 to 5, characterized in that: the chromatographic conditions further comprise: the detection wavelength was 254 nm.
8. The method of any one of claims 1-5, wherein the chromatographic conditions further comprise: the column temperature is 25-35 ℃, the sample tray temperature is 5 ℃, and the flow rate is 0.5-1.5 mL/min.
9. The method of claim 7, wherein the column temperature is 30 ℃ and the flow rate is 1.0 mL/min.
10. The method of any one of claims 1-5, wherein: the sample injection amount of the reference substance solution and the sample solution is 5-15 mu L, and preferably 10 mu L.
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| WO2017133464A1 (en) * | 2016-02-03 | 2017-08-10 | 中国药科大学 | Amidated arylbenzofuran derivatives and pharmaceutical use thereof |
| CN107976496A (en) * | 2017-11-22 | 2018-05-01 | 苏州市金茂日用化学品有限公司 | Benzoic acid, sorbic acid, salicylic acid and the method for Phenoxyethanol separation and content analysis in a kind of toothpaste |
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