CN115389680B - High performance liquid chromatography for detecting related substances and content of tabersonine hydrochloride - Google Patents
High performance liquid chromatography for detecting related substances and content of tabersonine hydrochloride Download PDFInfo
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Abstract
The invention discloses a high performance liquid chromatography for detecting related substances and contents of tabersonine hydrochloride, belonging to the technical field of pharmaceutical analysis. Firstly, the invention provides a method for detecting tabersonine hydrochloride and related substances thereof, and provides specific chromatographic conditions. According to the chromatographic conditions provided by the invention, the separation effect of tabersonine hydrochloride and related substances thereof is good, and the test result is accurate. The detection method provided by the invention can be applied to the refining process of tabersonine hydrochloride, and provides scientific and efficient methodology basis for quality control of tabersonine hydrochloride.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and relates to a high performance liquid chromatography for detecting related substances and contents of tabersonine hydrochloride.
Background
Tabersonine hydrochloride (see formula I) has the formula: c 21 H 24 N 2 O 2 HCl, white or off-white or yellowish powder:
tabersonine has effects of lowering blood pressure, resisting tumor, lowering blood sugar, promoting urination, and can be used for treating apoplexy sequela, ischemic hypertensive encephalopathy, depression caused by cerebrovascular disease, anxiety and mood instability, and eliminating symptoms of senilism brain degeneration, such as vertigo, headache, hypomnesis, inattention, aphasia, meniere syndrome, etc.; can also be used for treating retinal hemorrhage, nervous tachycardia and other vegetative nerve functional disorders.
Meanwhile, tabersonine hydrochloride is also a raw material of vincamine and vinpocetine. Vincamine and vinpocetine are used for treating various diseases requiring increased oxygen supply to brain, such as cerebral arteriosclerosis, premature brain degeneration, alzheimer disease, cerebral embolism, cerebral thrombosis and hemorrhage sequelae, and can be used for treating mental disorder, inner ear blood flow disorder, tinnitus, giddiness, retinal circulation disorder, acute retinopathy, and retinal middle artery embolism. Vinpocetine has various pharmacological actions beneficial to brain, cardiovascular and blood circulation systems, increases cerebral blood flow, promotes the uptake and utilization of glucose and oxygen in the brain, prevents brain cells from being excited and poisoned to death, relieves cerebral anoxia damage and protects neurons.
Tabersonine hydrochloride is not loaded in pharmacopoeias of various countries, so that no legal tabersonine hydrochloride inspection method exists. The high performance liquid phase determination method of the content of tabersonine hydrochloride is also rarely reported in the literature. Patent application with publication number CN103235071A discloses a high performance liquid chromatography method for tabersonine content detection, which comprises the following steps: c18 (4.6 mm. Times.250mm, 5 μm); mobile phase: methanol: acetonitrile: 0.2M ammonium acetate (7; the column temperature is 30 ℃, and the sample injection amount is 10 mu L; flow rate: 1.0mL/min; and an ultraviolet detector with the detection wavelength of 280nm. The tabersonine has a good linear relation with the peak area in the concentration range of 10-1000 mug/mL, and the linear correlation coefficient r =1. The method for detecting the content of tabersonine by the high performance liquid chromatography has high accuracy and good repeatability, can shorten the sample analysis time, reduce the preparation cost of a mobile phase and the preparation cost of a sample, and can improve the accuracy of the analysis result of the sample. However, the method can only be used for measuring the content of the tabersonine hydrochloride and cannot effectively measure related substances in the tabersonine hydrochloride.
Therefore, it is necessary to search for a method for detecting substances related to tabersonine hydrochloride.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a high performance liquid chromatography which can scientifically, efficiently and quantitatively detect related substances and contents of tabersonine hydrochloride.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
firstly, a method for detecting tabersonine hydrochloride and related substances thereof is provided, and the method is used for measuring the tabersonine hydrochloride by using a high performance liquid chromatography and comprises the following steps of:
step 1, using octadecylsilane chemically bonded silica as a filler for a chromatographic column;
step 2, taking ammonium acetate water solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution;
step 3, sampling and testing the system applicability solution, the reference substance solution and the test substance solution;
step 4, taking the system applicability solution for chromatographic analysis, and calculating the content of the tabersonine hydrochloride related substances according to an area normalization method;
and 5, taking the reference substance solution and the test sample solution for chromatographic analysis, and calculating the content of tabersonine hydrochloride in the test sample according to an external standard method.
Further, the chromatographic conditions of the high performance liquid chromatography are set as follows:
flow rate of mobile phase: 1.0mL/min;
temperature of the column box: 30 ℃;
sample introduction amount: 5-20 μ L;
detection wavelength: 190-400nm.
Further, the particle size of the filler in the step 1 is 2.1-5.0 μm; the length of the chromatographic column is 100mm or 150mm, and the inner diameter is 4-5 μm.
Further, the concentration of the ammonium acetate aqueous solution in the step 2 is 0.01-0.1mol/L.
Further, the procedure of the gradient elution in step 2 is as follows: the volume fraction of acetonitrile is changed from 25 percent to 90 percent within 0-20 min; 20-38min, keeping the volume fraction of acetonitrile at 90%;38-40min, wherein the volume fraction of acetonitrile is changed from 90% to 25%; the volume fraction of acetonitrile is kept unchanged at 25 percent for 40-45 min. The procedure means: at 0min, acetonitrile accounts for 25%, ammonium acetate aqueous solution accounts for 75%, at 20min, acetonitrile accounts for 90%, ammonium acetate aqueous solution accounts for 10%, and so on, and 20-38min, 38-40min and 40-45min are also the same respectively.
In the gradient elution procedure, the acetonitrile ratio is low at the beginning stage, so that all components in a tabersonine hydrochloride sample are separated; then gradually increasing the acetonitrile ratio and keeping the acetonitrile ratio for a period of time to ensure that all components in the sample are completely eluted; after complete elution of the components, the acetonitrile ratio was returned to the same as in the initial phase and the instrument was allowed to re-equilibrate for a period of time.
Further, in the step 3, the diluent of each solution in the sample injection test is a mixed solution of acetonitrile and water, preferably a mixed solution of acetonitrile and water in a volume ratio of 1.
Further, the concentrations of the tabersonine hydrochloride in the system applicability solution, the reference solution and the test solution are all 0.01-2mg/mL, and preferably 0.5-1.2 mg/mL.
Further, related substances of tabersonine hydrochloride in the system applicability solution comprise impurities I, II and III, and the structures of the impurities I, II and III are as follows:
further, the related substances account for 0.2-0.5% by mass of tabersonine hydrochloride.
Secondly, the method is applied to detection of crude products, dry products and refined products of tabersonine hydrochloride, and mainly relates to the crude products, the dry products and the refined products of tabersonine hydrochloride in the refining process of the tabersonine hydrochloride.
In some embodiments, the method for detecting tabersonine hydrochloride and related substances comprises the following steps:
preparation of control solutions: taking 25mg of tabersonine hydrochloride as a reference substance, precisely weighing, putting into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking uniformly to obtain the tabersonine hydrochloride;
system applicability solution: taking 25mg of a tabersonine hydrochloride system applicability reference substance, putting the tabersonine hydrochloride system applicability reference substance into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking up to obtain the target product;
preparing a test solution: taking 25mg of a test sample, precisely weighing, placing in a 25mL measuring flask, adding a diluent for dissolving, diluting to a scale, and shaking up to obtain the test sample;
the determination method comprises the following steps: taking a reference substance solution and a test sample solution, performing sample injection test according to the chromatographic conditions, measuring the content of tabersonine hydrochloride according to an external standard method, and calculating the content of impurities I, II and III in the test sample according to an area normalization method.
According to the specific embodiment of the invention, in the quantitative detection method provided by the invention, the linear regression equation of tabersonine hydrochloride is y =3990.1x +266.59, the correlation coefficient r is 0.9994, and the linear range is 0.8-1.2mg/mL.
According to the specific embodiment of the invention, in the quantitative determination method provided by the invention, the calculation formula of the content of tabersonine hydrochloride in the test sample is as follows: content (%) = AX/AR × mR/mX × P, wherein AX is the peak area of tabersonine hydrochloride in the test solution; AR is the peak area of tabersonine hydrochloride in the reference solution; mR is the weight of tabersonine hydrochloride reference substance, and the unit is mg; mX is the weight of the sample, and the unit is mg; p is the content of tabersonine hydrochloride, and the unit is%.
Compared with the prior art, the invention has the following beneficial effects:
(1) The high performance liquid chromatography provided by the invention can accurately determine the contents of the tabersonine hydrochloride and related substances thereof in a tabersonine hydrochloride sample; by adopting the chromatographic conditions in the method, the separation of related substances (such as impurity I, impurity II and impurity III) in a tabersonine hydrochloride sample can be realized, and further the quantitative detection of the related substances can be carried out;
(2) The method provided by the invention not only realizes the rapid detection of the sample containing the tabersonine hydrochloride, but also realizes the quantitative detection of related substances, and provides scientific and efficient methodology basis for the quality control of the raw material medicine of the tabersonine hydrochloride or some compositions and pharmaceutical preparations containing the tabersonine hydrochloride.
Drawings
FIG. 1 is a solution chromatogram for suitability in the system of example 1;
FIG. 2 is a chromatogram of a blank solution of example 1;
FIG. 3 is a chromatogram of a control of tabersonine hydrochloride of example 7;
fig. 4 is a chromatogram of a solution suitable for use in the system of comparative example 1.
Detailed Description
It should be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited.
The chromatographic conditions used in the examples of the invention were: using Agilent1260 high performance liquid chromatograph, and octadecyl silane bonded silica gel as filler (YMC Triart C18, specification of 4.6 × 150mm,3.0 μm); taking 0.05mol/L ammonium acetate aqueous solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution according to the table 1; the flow rate is 1.0mL/min; the detection wavelength is 272nm; the sample injection volume is 10 mu L; column box temperature 30 ℃, diluent: acetonitrile-water (1.
TABLE 1
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 20 | 10 | 90 |
| 38 | 10 | 90 |
| 40 | 75 | 25 |
| 45 | 75 | 25 |
Preparation of the solution:
preparation of control solutions: taking 25mg of tabersonine hydrochloride as a reference substance, accurately weighing, placing into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking up to obtain the tabersonine hydrochloride liquid;
system applicability solution: taking 25mg of a tabersonine hydrochloride system applicability reference substance, putting the tabersonine hydrochloride system applicability reference substance into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking up to obtain the target product;
preparation of a test solution: taking 25mg of a test sample, precisely weighing, placing in a 25mL measuring flask, adding a diluent for dissolving, diluting to a scale, and shaking up to obtain the test sample;
the tabersonine hydrochloride reference substance refers to a pure product with the purity of more than 99.0%.
The determination method comprises the following steps:
and precisely taking the system applicability solution, the test solution and the reference solution, respectively injecting into a liquid chromatograph, and performing chromatographic analysis. And calculating the content of tabersonine hydrochloride in the test sample by using the peak area according to an external standard method, and calculating the content of impurities I, II and III in the test sample according to an area normalization method.
Example 1
Experimental materials: a tabersonine hydrochloride system applicability reference substance is prepared by the following steps:
taking a tabersonine hydrochloride reference substance (a pure product with the purity of more than 99.0 percent), sequentially adding an impurity I, an impurity II and a miscellaneous goods III (the weight ratio of the impurity I to the impurity II to the miscellaneous goods III is 1, accounting for 0.25 percent of the weight of the tabersonine hydrochloride reference substance), adding acetonitrile for complete dissolution, and carrying out spin drying and drying to obtain the tabersonine hydrochloride reference substance.
The experimental steps are as follows:
and (3) taking a blank solution (diluent) and the system applicability solution, sequentially carrying out sample injection and testing, and recording a chromatogram (fig. 1 is a system applicability solution chromatogram, and fig. 2 is a blank solution chromatogram). A blank solution in which there was no interference of spectral peaks at the retention time of each component of tabersonine hydrochloride and a system suitability solution in which the degree of separation of each component of tabersonine hydrochloride was shown in table 2 were examined. The result shows that the test method has good separation effect and is not influenced by the diluent.
TABLE 2 relative retention times and degrees of separation of the components in the solution for suitability of the System
| Components | Retention time (min) | Relative retention time | Degree of separation |
| Tabersonine impurity I | 17.221 | 0.819 | - |
| Tabersonine impurity II | 18.429 | 0.876 | 6.33 |
| Tabersonine hydrochloride | 21.026 | 1.000 | 13.69 |
| Tabersonine impurity III | 35.685 | 1.697 | 39.64 |
Example 2
Experimental materials: tabersonine hydrochloride control
The experimental steps are as follows:
using tabersonine hydrochloride as reference, preparing reference solution according to the method of the implementation method, continuously feeding sample for 5 times, and performing chromatographic analysis. The small standard deviation of the peak area of the control solution was calculated to be 0.44%, and the detailed data are shown in table 3. As a result, the reproducibility of the apparatus in this method was good.
TABLE 3 mean and relative standard deviation of control solutions
Example 3
Experimental materials: tabersonine hydrochloride test sample.
The experimental steps are as follows:
preparing a tabersonine hydrochloride test sample into test sample solutions according to the method under the implementation method, wherein six test sample solutions are prepared in parallel. And (5) sample injection test and chromatographic analysis. The tabersonine hydrochloride content of each test sample solution was calculated, and the mean and relative standard deviation were calculated, and the detailed results are shown in table 4. The results show that the test method has good repeatability.
TABLE 4 tabersonine hydrochloride reproducibility results
Example 4
Experimental materials: tabersonine hydrochloride reference substance and tabersonine hydrochloride test substance.
The experimental steps are as follows:
another operator performed the tests according to the conditions and methods of example 2, example 3 and performed the chromatographic analyses. Calculating the content of tabersonine hydrochloride in each test sample solution, and calculating the average value and the relative standard deviation; the mean values and relative standard deviations of the tabersonine hydrochloride content in a total of 12 test solutions (6 in table 4 and 6 in table 5) were calculated for both operators, and the detailed results are shown in table 5. The results show that the intermediate precision of the test method is good.
TABLE 5 intermediate precision results for tabersonine hydrochloride
Example 5
Experimental materials: tabersonine hydrochloride control.
The experimental steps are as follows:
taking tabersonine hydrochloride reference substances, and preparing 1 reference substance solution and 3 test substance solutions with the concentrations of 80%, 100% and 120% of the reference substance solution according to the implementation method. And (5) sample injection test and chromatographic analysis. The recovery rate of the tabersonine hydrochloride reference substance at each concentration is calculated by taking the reference substance solution as 100% (see table 6), and the recovery rate of each concentration is good and the accuracy is high.
TABLE 6 accuracy test results for tabersonine hydrochloride
Example 6
Experimental materials: tabersonine hydrochloride control.
The experimental steps are as follows:
taking tabersonine hydrochloride reference substances, preparing two solutions with the concentrations of 80%, 90%, 100%, 110% and 120% of the reference substance solution according to the implementation method, sequentially injecting samples for testing, and performing chromatographic analysis. And (4) plotting the function of the peak area (y) and the concentration (x) of the measured tabersonine hydrochloride, observing whether the peak area (y) is linear or not, and performing linear regression by using a least square method. The linear regression equation is y =3990.1x +266.59, and the correlation coefficient r is 0.9994. The linear relation is good, which shows that the test method has good linearity and accurate result within the range of 0.8mg/mL-1.2 mg/mL. The specific results are shown in Table 7.
TABLE 7 statistical table of peak areas of tabersonine hydrochloride at various concentrations
Example 7
Experimental materials: tabersonine hydrochloride control.
The experimental steps are as follows:
taking a tabersonine hydrochloride reference substance, preparing a reference substance solution according to the method under the implementation method item, diluting to 0.5% of the concentration of the reference substance solution, carrying out sample injection test, and carrying out chromatographic analysis, wherein the signal-to-noise ratio of a tabersonine hydrochloride peak in the solution is 77.8, the quantitative detection capability is high, and the detection capability is strong (see figure 3).
Comparative example 1
The above system applicability solution was sampled and tested according to the test method in patent application publication No. CN103235071A, and chromatogram was recorded (see FIG. 4). In the chromatogram recorded, two chromatographic peaks, except the main peak, were found, with sizes of 0.29% and 0.31%, respectively. The number of chromatographic peaks is different from the number of impurities in the specification of a tabersonine hydrochloride system applicability reference substance, and all impurities cannot be effectively detected or separated. In patent application with publication number CN103235071A, no description is given about the related substance items, and the two chromatographic peaks cannot be characterized.
The test method of the patent has more advantages than the test method of the patent application with the publication number CN103235071A in all relevant substance tests of tabersonine hydrochloride.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (7)
1. A method for detecting tabersonine hydrochloride and related substances thereof is characterized in that the method for detecting tabersonine hydrochloride and related substances thereof by using high performance liquid chromatography comprises the following steps:
preparation of control solutions: taking 25mg of tabersonine hydrochloride as a reference substance, accurately weighing, placing into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking up to obtain the tabersonine hydrochloride liquid;
system applicability solution: taking 25mg of a tabersonine hydrochloride system applicability reference substance, putting the tabersonine hydrochloride system applicability reference substance into a 25mL measuring flask, adding a diluent to dissolve, diluting to a scale, and shaking up to obtain the target product;
preparation of a test solution: taking 25mg of a test sample, precisely weighing, placing in a 25mL measuring flask, adding a diluent for dissolving, diluting to a scale, and shaking up to obtain the test sample;
the diluent is acetonitrile-water, 1 v/v,
the chromatographic column in the step (1) takes octadecylsilane chemically bonded silica as a filler;
step (2) taking ammonium acetate aqueous solution as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution; the procedure for the gradient elution was: 0-20min, the volume fraction of acetonitrile is 25% → 90%;20-38min, wherein the volume fraction of acetonitrile is 90% → 90%;38-40min, the volume fraction of acetonitrile is 90% → 25%;40-45min, the volume fraction of acetonitrile is 25% → 25%;
sampling and testing the system applicability solution, the reference substance solution and the test substance solution;
step (4) carrying out chromatographic analysis on the system applicability solution, and calculating the content of the tabersonine hydrochloride related substances according to an area normalization method;
step (5) taking the reference substance solution and the test sample solution for chromatographic analysis, calculating the content of tabersonine hydrochloride in the test sample according to an external standard method,
the related substances comprise impurities I, II and III, and the structures of the impurities I, II and III are as follows:
2. the method according to claim 1, wherein the chromatographic conditions of the high performance liquid chromatography are set as follows:
flow rate of mobile phase: 1.0mL/min;
temperature of the column box: 30 ℃;
sample introduction amount: 5-20 μ L;
detection wavelength: 190-400nm.
3. The method according to claim 1, wherein the filler in step (1) has a particle size of 2.1 to 5.0 μm; the length of the chromatographic column is 100mm or 150mm, and the inner diameter is 4-5 μm.
4. The method according to claim 1, wherein the concentration of the ammonium acetate aqueous solution in the step (2) is 0.01 to 0.1mol/L.
5. The method according to claim 1, wherein the concentrations of tabersonine hydrochloride in the system suitability solution, the control solution and the test solution in step (3) are all 0.01-2 mg/mL.
6. The method according to claim 1, wherein the related substances are 0.2-0.5% by mass of tabersonine hydrochloride.
7. Use of the method of any one of claims 1-6 for detecting crude, dry, or refined tabersonine hydrochloride.
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