CN113567595A - Method for detecting ether impurities in medicine - Google Patents
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Abstract
The application belongs to the technical field of drug analysis. The application provides a method for detecting ether impurities in a medicine, which comprises the following steps: dissolving a sample with an organic solvent, adding an extraction reagent, oscillating to obtain a sample solution, and respectively injecting the sample solution and a reference substance solution into a liquid chromatograph to perform detection by an external standard method; the liquid chromatographic column is: a chromatographic column with octyl silane bonded silica gel as a filler; the mobile phase of the liquid phase is: the mobile phase A is selected from water or salt solution, and the mobile phase B is selected from acetonitrile or methanol. The method is based on the chemical properties of the main drug and the components to be detected, can be used for quantitative detection of ether impurities in the drug, and the specificity, linearity, accuracy, sensitivity, durability and stability of the method meet the detection requirements.
Description
Technical Field
The application belongs to the technical field of drug analysis, and particularly relates to a method for detecting ether impurities in a drug.
Background
In the process of drug production, the purity of the drug may be changed by the starting materials, intermediates and degradation impurities, which further affects the curative effect of the drug, and the residue of related substances and impurities also seriously affects the safety of the drug. Therefore, quantitative control of ether impurities in drugs is of great interest in order to assess and control DNA reactive (mutagenic) impurities in drug assays to limit potential carcinogenic risks.
Vortioxetine hydrobromide, having a chemical name of 1- [2- (2, 4-dimethyl-thiophenyl) phenyl-piperazine hydrobromide, is a novel adult antidepressant. According to the synthesis process of the medicine, the vortioxetine hydrobromide can generate ether impurities such as bis (2-diphenylphosphinophenyl) ether in the preparation process of the medicine. The limit of bis (2-diphenylphosphinophenyl) ether does not exceed 1000ppm, starting from an acceptable intake of vortioxetine hydrobromide. However, the research on related substances or impurities of vortioxetine hydrobromide lacks a determination method for ether compounds.
Disclosure of Invention
In view of this, the application provides a method for detecting ether impurities in a drug, which can be used for quantitative detection of ether impurities in a drug, and the method has good accuracy, sensitivity and stability.
The specific technical scheme of the application is as follows:
the application provides a method for detecting ether impurities in a medicine, which comprises the following steps:
dissolving a sample with an organic solvent, adding an extraction reagent, oscillating to obtain a sample solution, and respectively injecting the sample solution and a reference substance solution into a liquid chromatograph to perform detection by an external standard method;
the chromatographic column of the liquid phase is as follows: a chromatographic column with octyl silane bonded silica gel as a filler;
the mobile phase of the liquid phase is as follows: the mobile phase A is selected from water or salt solution, and the mobile phase B is selected from acetonitrile or methanol;
the organic solvent is selected from methanol and/or acetonitrile;
the extraction reagent comprises a first solvent and a second solvent, wherein the first solvent is selected from one or more of a sodium chloride solution, a sodium sulfate solution, a sodium carbonate solution, a sodium bicarbonate solution and a sodium dihydrogen phosphate solution, and the second solvent is selected from one or more of cyclohexane, n-hexane, n-heptane, isooctane and toluene;
the drug comprises vortioxetine hydrobromide, and the ether impurities comprise bis (2-diphenylphosphinophenyl) ether.
Preferably, the concentration of the first solvent is 0.2-0.4 g/mL, more preferably 0.3g/mL, and the volume ratio of the first solvent to the second solvent is 1: 1-3, more preferably 1: 1.
Preferably, the volume ratio of the organic solvent, the first solvent and the second solvent is 0.1:1: 1.
Preferably, the organic solvent is selected from methanol, the first solvent is selected from sodium sulfate, and the second solvent is selected from cyclohexane;
the solvent of the control solution was cyclohexane.
Preferably, the concentration of the sample solution is 0.001-0.01 g/mL, and the concentration of the control solution is 100-4000 ng/mL.
Preferably, the column of the liquid chromatography is Agilent ZORBAX Eclipse Plus C8, 5 μm, 4.6mm × 250 mm; the mobile phase A is ultrapure water, and the mobile phase B is acetonitrile.
Preferably, the column temperature of the liquid chromatogram is 30-35 ℃, more preferably 30 ℃, the flow rate is 0.8-1.2 ml/min, more preferably 1ml/min, the sample injection volume is 1-2 μ l, more preferably 2 μ l, and the detection wavelength is 233 nm.
Preferably, the elution procedure of the liquid chromatography is: 0-5.5 min, 40% of mobile phase A and 60% of mobile phase B; 6.5-14 min, mobile phase A0%, and mobile phase B100%; 14.1-21 min, 40% of mobile phase A and 60% of mobile phase B.
In summary, the present application provides a method for detecting ether impurities in a drug, comprising: dissolving a sample with an organic solvent, adding an extraction reagent, oscillating to obtain a sample solution, and respectively injecting the sample solution and a reference substance solution into a liquid chromatograph to perform detection by an external standard method; the liquid chromatographic column is: a chromatographic column with octyl silane bonded silica gel as a filler; the mobile phase of the liquid phase is: the mobile phase A is selected from water or salt solution, and the mobile phase B is selected from acetonitrile or methanol. The method is based on the chemical properties of the main drug and the components to be detected, can be used for quantitative detection of ether impurities in the drug, and the specificity, linearity, accuracy, sensitivity, durability and stability of the method meet the detection requirements.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive exercise.
FIG. 1 is a chromatogram of example 1 of the present application;
FIG. 2 is a chromatogram of example 3 of the present application;
FIG. 3 is a chromatogram of example 4 of the present application;
FIG. 4 is a chromatogram of example 5 of the present application;
FIG. 5 is a chromatogram of example 6 of the present application;
FIG. 6 is a chromatogram of example 7 of the present application;
FIG. 7 is a chromatogram of example 8 of the present application;
FIG. 8 is a chromatogram of example 9 of the present application;
FIG. 9 is a chromatogram of example 10 of the present application;
FIG. 10 is a chromatogram of example 11 of the present application;
FIG. 11 is a chromatogram of example 12 of the present application;
FIG. 12 is a linear regression curve of a test example of the present application;
wherein, the single spectrogram displays the superposed spectrogram of the control solution and/or the standard solution under different concentrations, and the shadow peak shape is the spectrogram under the conditions of the current embodiment.
Detailed Description
In order to make the objects, features and advantages of the present application more obvious and understandable, the technical solutions in the embodiments of the present application are clearly and completely described, and it is obvious that the embodiments described below are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
The raw materials and reagents used in the examples of the present application are commercially available or self-made. Reagents and methods not specifically described in the examples are all conventional in the art.
Solution preparation in the examples of the present application:
sodium sulfate solution: weighing 30g of anhydrous sodium sulfate, adding 100ml of ultrapure water, ultrasonically dissolving, and shaking up to obtain the product.
Example 1
1. The liquid chromatography column is Agilent ZORBAX Eclipse Plus C8, 5 μm, 4.6mm × 250 mm; the mobile phase A is ultrapure water, and the mobile phase B is acetonitrile; the column temperature was 35 ℃; the flow rate is 1.0 ml/min; the sample injection volume is 2 mul; the detection wavelength was 233 nm.
The elution procedure for liquid chromatography was: 0-5.5 min, 40% of mobile phase A and 60% of mobile phase B; 6.5-14 min, mobile phase A0%, and mobile phase B100%; 14.1-21 min, 40% of mobile phase A and 60% of mobile phase B.
2. Test solution: precisely weighing about 0.01g of bulk drug powder of the vortioxetine hydrobromide into a 10mL centrifuge tube, adding 0.5mL of methanol for dissolving, adding 5mL of sodium sulfate solution, uniformly mixing by oscillation, precisely adding 5mL of cyclohexane, carrying out vortex oscillation for 5min, centrifuging, and taking supernatant to obtain the vortioxetine hydrobromide.
3. Control solution: about 5mg of bis (2-diphenylphosphinophenyl) ether standard substance is precisely weighed, placed in a 10mL volumetric flask, and added with a proper amount of cyclohexane for ultrasonic dissolution. And then performing gradient dilution by using cyclohexane as a solvent to obtain a standard curve solution with the concentration of 100-4000 ng/mL.
4. Adding a standard solution: precisely weighing about 10mg of raw material powder of vortioxetine hydrobromide, placing the raw material powder into different 10mL centrifuge tubes, adding 0.5mL of methanol for dissolving, adding 5mL of sodium sulfate solution for uniformly mixing by oscillation, precisely adding 5mL of reference solution with the concentration of 2000 ng/mL for extraction, carrying out vortex oscillation for 5min, centrifuging, and taking supernatant to obtain the vortioxetine hydrobromide.
And (3) sampling and detecting the added standard solution, wherein the target peak in the chromatogram is good in shape and other impurity peaks are not detected as shown in figure 1.
Example 2
Referring to the test method of example 1, the only difference is that the sodium sulfate solution and cyclohexane in steps 2 to 4 are replaced with acetonitrile. And (4) sampling and detecting the added standard solution, and no obvious target peak is found after full scanning.
Example 3
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2 to 4 is replaced with cyclohexane. The standard solution is taken for sample loading detection, as shown in figure 2, a peak exists at 2.78min, but the separation degree of a target peak and a hetero peak is poor, and the interference is serious.
Example 4
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced by cyclohexane, and the mobile phase A is replaced by n-hexane and the mobile phase B is replaced by isopropanol in step 1. And (3) sampling and detecting the added standard solution, wherein the peak shape of the target peak is better, but the impurity peak is not completely removed, the recovery rate is 78.2%, and the component to be detected can be partially degraded as shown in figure 3.
Example 5
Referring to the test method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced with isopropanol. The spiked solution was tested on the sample and as shown in FIG. 4, the baseline for the peak shape was poor and the recovery of the assay was about 118% with possible interference.
Example 6
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced by isopropanol, and the mobile phase a is replaced by n-hexane and the mobile phase B is replaced by isopropanol in step 1. When the spiked solution is sampled for detection, as shown in FIG. 5, the baseline of the peak shape is unstable, and the recovery rate of the spiked solution is high, which may be caused by the fluctuation of the baseline or the failure of the target peak to separate from the adjacent interfering peak.
Example 7
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2 to 4 is replaced with water. And (3) sampling and detecting the standard solution, and as shown in figure 6, although the recovery rate of the target peak in the figure is 84.6%, a large peak is interfered before the target peak, and the separation degree is not satisfactory.
Example 8
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced by water, and the mobile phase A is replaced by n-hexane and the mobile phase B is replaced by isopropanol in step 1. The spiked solution was tested and as shown in FIG. 7, the peak area at 4.6min in the spiked solution was disproportionate, the recovery rate was poor (37.9%), and it was likely that the target was oxidized.
Example 9
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced by water, a small amount of 0.1mg/ml antioxidant is added before the sample solution is loaded, and mobile phase A is replaced by n-hexane and mobile phase B is replaced by isopropanol in step 1. The loaded standard solution was tested, and as shown in FIG. 8, the linearity of the two peaks was not significant, and the recovery rate of the loaded standard solution was low (38.3%).
Example 10
Referring to the detection method of example 1, the only difference is that the sodium sulfate solution in steps 2-4 is replaced by water, 1ml of 30% hydrogen peroxide is added before the sample solution is loaded, and mobile phase a is replaced by n-hexane and mobile phase B is replaced by isopropanol in step 1. The spiked solution was tested on the sample, as shown in FIG. 9, only one peak of 6.5 appeared with obvious linearity, but the recovery rate of the spiked solution was high (140.6%), possibly mixing with interfering impurities.
Example 11
With reference to the test method of example 1, the only difference was that the column in step 1 was replaced with ZORBAX extended C18 (150mm 4.6mm 5 μm). The labeled solution is sampled and detected, and as shown in figure 10, linear peaks exist at 1.692min and 4.833min, but the recovery rate is higher, and the target peak possibly wraps the impurity peak.
Example 12
Referring to the detection method of example 1, the only difference is that the elution procedure in step 1 is adjusted to: 0-7 min, mobile phase A60%, and mobile phase B40%; 8-13 min, 95% of mobile phase A and 5% of mobile phase B; 13.1-20 min, mobile phase A60% and mobile phase B40%. The sample is taken out from the standard solution for detection, as shown in figure 11, the baseline of the peak shape is floated, meanwhile, the recovery rate is 73.76 percent, and the recovery rate is lower and is not in accordance with the requirement.
Test example
Methodological verification was performed according to the detection method of example 1:
1. linearity and range
And (4) taking a standard curve solution, and carrying out sample injection detection according to an analysis method. As shown in fig. 12, the results show that: the concentration of the bis (2-diphenylphosphinophenyl) ether in the range of 202.13ng/ml to 4042.56ng/ml is equivalent to 101.065ppm to 2021.28ppm of the concentration of a test sample, the r value of a correlation coefficient is 0.9995, the ratio of the absolute value of y-axis intercept to the response value of a 100% limit concentration solution is 7.4%, and the peak area and the concentration have a good linear relation.
2. Detection limit and quantification limit
And respectively taking 100 ng/mL and 200ng/mL reference substance solutions, respectively and continuously injecting samples for 3 times and 6 times according to an analysis method, and recording chromatograms. The results show that: the concentration of bis (2-diphenylphosphinophenyl) ether in the detection limiting solution was 101.06ng/ml, which corresponds to a test sample concentration of 50.530ppm and a minimum S/N value of 5.2. The concentration of the bis (2-diphenylphosphinophenyl) ether in the quantitative limiting solution is 202.13ng/ml, which is about equal to the concentration of a test sample of 101.065ppm, the minimum value of S/N is 28.1, the peak area RSD value of the bis (2-diphenylphosphinophenyl) ether in the 6-needle quantitative limiting solution is 4.9 percent, and the results all meet the requirements.
3. Accuracy of
And taking the added standard solution, carrying out sample injection detection according to an analysis method, repeatedly measuring for 3 times, recording a chromatogram, and calculating the recovery rate of the bis (2-diphenylphosphinophenyl) ether in the added standard solution. The results show that: the recovery rate range of the bis (2-diphenylphosphinophenyl) ether in the standard solution with 100% limit concentration is 93.5% -102.8%, the RSD value of the recovery rate is 3.0%, and the accuracy of the method meets the requirement.
4. Durability
The initial temperature of the chromatographic column fluctuates within the range of 30-35 ℃, and the flow rate fluctuates within the range of 0.8-1.2 ml/min as the durability condition of the method. The added standard solution is taken for analysis under different durability conditions, and the result shows that the correlation coefficient r value of the standard curve solution is between 0.9993 and 0.9995 under the condition of fluctuation range; the recovery rates of the bis (2-diphenylphosphinophenyl) ether in the 100% limit concentration reference solution and the 100% limit concentration standard solution are respectively 102.6-103.0% and 97.4-97.8%, and the method has good durability.
5. Stability of
Respectively taking the sample solution and the standard solution, performing sample injection analysis at different times according to an analysis method, and recording the chromatogram. The results are shown in tables 1 and 2 below, which show that: standing in dark room temperature for different time, wherein the test solution is not detected and is stable for at least 51 h; the detection concentration of the bis (2-diphenylphosphinophenyl) ether in the standard solution with 100% of limit concentration is equivalent to the absolute value range of the change rate of the detection concentration of initial (0 h) of 0.6-7.8%, the standard solution with 100% of limit concentration is stable within at least 51 hours.
TABLE 1 stability results for test solutions
| Time (h) | Detection concentration (ng/ml) | Relative initial detection concentration change rate absolute value (%) |
| 0 | Not detected out | |
| 4 | Not detected out | |
| 10 | Not detected out | |
| 14 | Not detected out | NA |
| 22 | Not detected out | NA |
| 37 | Not detected out | NA |
| 51 | Not detected out | NA |
TABLE stability results for 2100% Limit strength spiked solutions
| Time (h) | Detection concentration (ng/ml) | Relative initial detection concentration change rate absolute value (%) |
| 0 | 1974.67 | |
| 4 | 1985.86 | 0.6 |
| 10 | 2022.69 | 2.4 |
| 14 | 2018.40 | 2.2 |
| 22 | 2017.05 | 2.1 |
| 37 | 2066.61 | 4.7 |
| 51 | 2128.43 | 7.8 |
The above embodiments are only used for illustrating the technical solutions of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions in the embodiments of the present application.
Claims (8)
1. A method for detecting ether impurities in a drug is characterized by comprising the following steps:
dissolving a sample with an organic solvent, adding an extraction reagent, oscillating to obtain a sample solution, and respectively injecting the sample solution and a reference substance solution into a liquid chromatograph to perform detection by an external standard method;
the chromatographic column of the liquid phase is as follows: a chromatographic column with octyl silane bonded silica gel as a filler;
the mobile phase of the liquid phase is as follows: the mobile phase A is selected from water or salt solution, and the mobile phase B is selected from acetonitrile or methanol;
the organic solvent is selected from methanol and/or acetonitrile;
the extraction reagent comprises a first solvent and a second solvent, wherein the first solvent is selected from one or more of a sodium chloride solution, a sodium sulfate solution, a sodium carbonate solution, a sodium bicarbonate solution and a sodium dihydrogen phosphate solution, and the second solvent is selected from one or more of cyclohexane, n-hexane, n-heptane, isooctane and toluene;
the drug comprises vortioxetine hydrobromide, and the ether impurities comprise bis (2-diphenylphosphinophenyl) ether.
2. The detection method according to claim 1, wherein the concentration of the first solvent is 0.2 to 0.4g/mL, and the volume ratio of the first solvent to the second solvent is 1:1 to 3.
3. The detection method according to claim 1, wherein a volume ratio of the organic solvent, the first solvent, and the second solvent is 0.1:1: 1.
4. The detection method according to claim 1, wherein the organic solvent is selected from methanol, the first solvent is selected from sodium sulfate, and the second solvent is selected from cyclohexane;
the solvent of the control solution was cyclohexane.
5. The detection method according to claim 1, wherein the concentration of the sample solution is 0.001 to 0.01g/mL, and the concentration of the control solution is 100 to 4000 ng/mL.
6. The detection method according to claim 1, wherein the chromatographic column of the liquid chromatography is Agilent ZORBAX Eclipse Plus C8, 5 μm, 4.6mm x 250 mm; the mobile phase A is ultrapure water, and the mobile phase B is acetonitrile.
7. The detection method according to claim 1, wherein the column temperature of the liquid chromatography is 30 to 35 ℃, the flow rate is 0.8 to 1.2ml/min, the sample injection volume is 1 to 2 μ l, and the detection wavelength is 233 nm.
8. The detection method according to claim 1, wherein the elution procedure of the liquid chromatography is: 0-5.5 min, 40% of mobile phase A and 60% of mobile phase B; 6.5-14 min, mobile phase A0%, and mobile phase B100%; 14.1-21 min, 40% of mobile phase A and 60% of mobile phase B.
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