CN110174482B - UPLC analysis method for simultaneously determining citicoline sodium and nine related substances - Google Patents
UPLC analysis method for simultaneously determining citicoline sodium and nine related substances Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical analytical chemistry, in particular to a UPLC (ultra Performance liquid chromatography) analysis method for simultaneously determining citicoline sodium and nine related substances. The method comprises the following steps: performing chromatographic analysis by adopting a reverse phase chromatographic column, performing gradient elution on a sample solution of the citicoline sodium by adopting the hydrophilic octadecylsilane chemically bonded silica as a filling agent, adopting a phosphate buffer solution as a mobile phase A and adopting an organic solvent as a mobile phase B, and determining the purity of the citicoline sodium and the content of nine impurities according to an area normalization method. The technical scheme provided by the invention can effectively separate the impurities of the citicoline sodium, so that the quality of the citicoline sodium can be accurately controlled, the detection advantages of a plurality of impurities of the citicoline sodium are displayed, and an accurate and efficient detection method can be provided for the determination of the purity and the impurity content of the citicoline sodium.
Description
Technical Field
The invention relates to the field of pharmaceutical analytical chemistry, in particular to a UPLC (ultra performance liquid chromatography) analysis method for simultaneously measuring citicoline sodium and nine related substances.
Background
Citicoline sodium (Citicoline sodium) is chemically known as choline cytosine nucleoside diphosphate monosodium salt, and the CAS number of the Citicoline sodium salt is as follows: 33818-15-4 with molecular formula C 14 H 25 N 4 NaO 11 P 2 The molecular weight is: 510.31, having the chemical structure:
citicoline sodium is mainly used for treating acute craniocerebral trauma and conscious disturbance after brain surgery. Citicoline is an intermediate in the biosynthesis of cell membrane-structured phospholipids. Exogenous administration of citicoline can repair neuronal cell membrane rapidly by increasing synthesis of phospholipid, promote synthesis of acetylcholine and dopamine, stabilize neurotransmitter system, and promote energy metabolism of brain. Citicoline can reduce cerebral vascular resistance, increase cerebral blood flow to promote brain metabolism, improve cerebral circulation, enhance the function of a brain stem ascending net activation system, enhance the function of a vertebral system, and improve motor paralysis, so the medicinal composition has certain effects of promoting the recovery of cerebral functions and promoting recovery.
In 1956 Geiger found in animal experiments that citicoline was able to restore brain damage. Kennedy's research in 1957 confirmed that it was crucial in the synthesis of brain phospholipids, and was developed and produced by the pharmaceutical company Wutian Japan in 1961 and registered in China in 1988. At present, the preparation of the variety is available in the market in the forms of tablets, capsules and injections.
At present, citicoline sodium is generally produced by a synthesis method, and the effective separation of citicoline sodium and impurities thereof is realized, so that the method has great significance for measuring the amount of each impurity of citicoline sodium. Publication No. CN105388225A discloses a method for analyzing and detecting UDPC in a medicinal preparation containing citicoline sodium, but the method is directed to a detection sample which is a preparation and only can effectively separate two known impurities contained in citicoline sodium, namely 5' -cytidylic acid and UDPC. The method discloses an analysis method for measuring 9 related substances of citicoline sodium raw material medicines. Therefore, the method for rapidly and accurately detecting the purity of the citicoline sodium and the content of more related substances has more important practical significance.
Disclosure of Invention
In view of the above, the present invention provides a UPLC analysis method for simultaneously determining citicoline sodium and nine related substances. The invention provides an accurate and efficient detection method for the purity of citicoline sodium and the content of nine impurities thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a UPLC analysis method for simultaneously measuring citicoline sodium and nine related substances, which comprises the following steps:
performing chromatographic analysis by adopting a reversed-phase chromatographic column, performing gradient elution on a sample solution of the citicoline sodium by using the hydrophilic octadecylsilane chemically bonded silica as a filling agent, a phosphate buffer solution as a mobile phase A and an organic solvent as a mobile phase B, and determining the purity of the citicoline sodium and the content of nine impurities according to an area normalization method, wherein the elution gradient is as follows:
elution time | Phase A (%) | Phase B (%) |
0min | 95~100 | 0~5 |
5min | 95~100 | 0~5 |
7.5min | 85~95 | 5~15 |
17min | 85~95 | 5~15 |
18min | 95~100 | 0~5 |
23min | 95~100 | 0~5 |
Wherein the plurality of impurities are respectively:
impurity 1: cytidine
Impurity 2: uridine (uridine)
Impurity 3: impurity C
Impurity 4:5' -Cytidic acid
Impurity 5: UDPC (uridine diphosphate choline)
Impurity 6: cytosic acid methyl ester
Impurity 7: cytidic acid ethyl ester
Impurity 8:5' -uridylic acid
Impurity 9: impurity X
Preferably, the reverse phase chromatography column is of the type AcquityHSS T3, a chromatographic column with the filler particle diameter of 1.5-3.0 μm, the chromatographic column length of 50-150 mm and the chromatographic column diameter of 1.8-3.0 mm.
Preferably, the reversed phase column has a packing particle size of 1.8 μm, a column length of 100mm and a column diameter of 2.1 mm.
Preferably, the elution gradient is as follows:
elution time | Phase A (%) | Phase B (%) |
0min | 100 | 0 |
5min | 100 | 0 |
7.5min | 90 | 10 |
17min | 90 | 10 |
18min | 100 | 0 |
23min | 100 | 0 |
Preferably, the elution gradient is as follows:
elution time | Phase A (%) | Phase B (%) |
0min | 98 | 2 |
6.5min | 98 | 2 |
8min | 90 | 10 |
19min | 90 | 10 |
20min | 98 | 2 |
25min | 98 | 2 |
Preferably, the phosphate buffer is a mixture of an aqueous solution of potassium dihydrogen phosphate and an aqueous solution of tetrabutylammonium hydroxide.
Preferably, the concentration of the potassium dihydrogen phosphate aqueous solution is 0.01 to 0.1mol/L.
Preferably, the concentration of the potassium dihydrogen phosphate aqueous solution in the phosphate buffer is 0.01mol/L.
Preferably, the concentration of the tetrabutylammonium hydroxide aqueous solution is 0.01 to 0.1mol/L.
Preferably, the concentration of the tetrabutylammonium hydroxide aqueous solution is 0.01mol/L.
Preferably, the volume ratio of the potassium dihydrogen phosphate aqueous solution to the tetrabutylammonium hydroxide aqueous solution is 40.
Preferably, the ratio of aqueous potassium dihydrogen phosphate to aqueous tetrabutylammonium hydroxide is 50.
Preferably, the phosphate buffer has a pH of 2.5 to 5.0.
Preferably, the phosphate buffer has a pH of 3.0 to 4.5.
Preferably, the pH regulator of the phosphate buffer is one or more of phosphoric acid, formic acid, and acetic acid.
Preferably, the organic solvent is one or more of methanol, ethanol, acetonitrile, isopropanol, and tetrahydrofuran.
Preferably, the organic solvent is methanol.
Preferably, the concentration of the sample solution of citicoline sodium is 0.1-1.0 mg/mL.
Preferably, the concentration of the sample solution of citicoline sodium is 0.2mg/mL.
Preferably, the detection wavelength of the chromatographic analysis is 270 to 290nm, the column temperature is 28 to 32 ℃, and the flow rate is 0.1 to 0.3mL/min.
Preferably, the detection wavelength of the chromatographic analysis is 280nm, the column temperature is 30 ℃, and the flow rate is 0.2mL/min.
In a specific embodiment provided by the present invention, the analysis method comprises the steps of:
preparing sample into test solution containing citicoline sodium about 0.2mg/mL, detecting with high performance liquid chromatography on an ultra performance liquid chromatograph equipped with VWD detector according to type AcquityAnd T3, analyzing by using a chromatographic column with the particle size of 1.8 mu m, the length of the chromatographic column of 100mm and the diameter of the chromatographic column of 2.1mm, and performing gradient elution under a mobile phase system by using phosphate buffer solution as a mobile phase A and methanol as a mobile phase B, wherein the phosphate buffer solution is 0.01mol/L potassium dihydrogen phosphate aqueous solution and 0.01mol/L tetrabutyl ammonium hydroxide aqueous solution which are mixed in equal proportion, and then adjusting the pH value to 3.0 by using phosphoric acid, wherein the elution gradient is as follows:
elution time | Phase A (%) | Phase B (%) |
0min | 100 | 0 |
5min | 100 | 0 |
7.5min | 90 | 10 |
17min | 90 | 10 |
18min | 100 | 0 |
23min | 100 | 0 |
Detecting wavelength of 280nm, column temperature of 30 deg.C, flow rate of 0.2mL/min, injecting 1 μ L of sample solution into liquid chromatograph, recording chromatogram, and calculating citicoline sodium purity and related substances by area normalization method.
The invention provides a UPLC analysis method for simultaneously measuring citicoline sodium and nine related substances. The method comprises the following steps: and (3) performing chromatographic analysis by adopting a reverse phase chromatographic column, wherein the reverse phase chromatographic column takes hydrophilic octadecylsilane chemically bonded silica as a filling agent, phosphate buffer solution as a mobile phase A and an organic solvent as a mobile phase B, performing gradient elution on the sample solution of the citicoline sodium, and determining the purity of the citicoline sodium and the content of nine impurities according to an area normalization method. The invention has the technical effects that:
the technical scheme provided by the invention can effectively separate the citicoline sodium impurities, so that the quality of the citicoline sodium can be accurately controlled, the detection advantages of a plurality of impurities of the citicoline sodium are displayed, and the accurate and efficient detection method can be provided for the determination of the purity of the citicoline sodium and the impurity content of the citicoline sodium.
Drawings
FIG. 1 is a schematic blank result of example 1;
fig. 2 is a schematic diagram of the system suitability results of example 1, where RT =1.1min is the peak of impurity 1, RT =1.9min is the peak of citicoline sodium, RT =2.2min is the peak of impurity 9, RT =2.7min is the peak of impurity 4, RT =4.7min is the peak of impurity 2, RT =10.0min is the peak of impurity 6, RT =12.5min is the peak of impurity 5, RT =13.2min is the peak of impurity 3, RT =13.9min is the peak of impurity 7, and RT =16.6min is the peak of impurity 8;
fig. 3 is a graph showing the detection results of the sample of example 1, wherein RT =1.9min is a peak of citicoline sodium, RT =1.1min is a peak of impurity 1, RT =2.7min is a peak of impurity 4, RT =10.0min is a peak of impurity 6, RT =13.2min is a peak of impurity 3, and the others are unknown impurity peaks;
FIG. 4 is a schematic diagram showing the results of localized detection of impurity 1 in example 1;
FIG. 5 is a schematic diagram showing the results of localized detection of impurity 2 in example 1;
FIG. 6 is a schematic diagram showing the results of localized detection of the impurity 3 in example 1;
FIG. 7 is a schematic diagram showing the results of localized detection of the impurity 4 in example 1;
FIG. 8 is a schematic diagram showing the results of the localized detection of impurity 5 in example 1;
FIG. 9 is a schematic diagram showing the results of localized detection of the impurity 6 in example 1;
FIG. 10 is a schematic diagram showing the results of the detection of the localization of the impurity 7 in example 1;
FIG. 11 is a schematic diagram showing the results of localized detection of the impurity 8 in example 1;
FIG. 12 is a schematic view showing the results of localized detection of the foreign matter 9 in example 1;
fig. 13 is a graphical representation of the system suitability results of example 2, where RT =1.0min is the peak for impurity 1, RT =1.8min is the peak for citicoline sodium, RT =1.9min is the peak for impurity 9, RT =2.4min is the peak for impurity 4, RT =3.6min is the peak for impurity 2, RT =8.7min is the peak for impurity 6, RT =12.2min is the peak for impurity 5, RT =13.1min is the peak for impurity 3, RT =13.8min is the peak for impurity 7, and RT =16.4min is the peak for impurity 8;
fig. 14 is a schematic diagram of the system applicability result of comparative example 1, in which RT =1.5min is the peak of impurity 1, RT =2.0min is the peak of impurity 2, RT =4.2min is the peak of citicoline sodium and impurity 9, RT =6.7min is the peak of impurity 4, RT =8.3min is the peak of impurity 5, RT =14.1min is the peaks of impurity 6 and impurity 8, RT =16.5min is the peak of impurity 3, and RT =18.2min is the peak of impurity 7.
Detailed Description
The invention discloses a UPLC analysis method for simultaneously measuring citicoline sodium and nine related substances, which can be realized by appropriately improving process parameters by taking the contents of the method as reference by a person skilled in the art. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and modifications, or appropriate variations and combinations of the methods and applications described herein may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The reagent or the instrument used in the UPLC analysis method for simultaneously measuring the citicoline sodium and the nine related substances can be purchased from the market.
The invention is further illustrated by the following examples:
example 1
High performance liquid chromatograph: waters H-class-VWD detector;
mobile phase: phase A: phosphate buffer (phosphate buffer is 0.01mol/L potassium dihydrogen phosphate aqueous solution and 0.01mol/L tetrabutyl ammonium hydroxide aqueous solution mixed in equal proportion, and pH is adjusted to 3.0 with phosphoric acid)
Phase B: methanol;
the elution gradient was as follows:
TABLE 1 elution gradient procedure
Detection wavelength: 280nm;
flow rate: 0.2mL/min;
column temperature: 30 ℃;
sample injection amount: 1 mu L of the solution;
blank solution: and (5) purifying the water.
Preparing a sample solution: accurately weighing about 10mg of sample, placing the sample in a 50mL measuring flask, adding purified water to dilute to the scale, and shaking up.
Preparing a system applicability solution: precisely weighing about 5mg of citicoline sodium sample and 5mg of each impurity, placing the sample and each impurity in a 50mL measuring flask, adding purified water to dilute to a scale mark, and shaking up.
Impurity localization solution: accurately weighing 5mg of each impurity, respectively placing the impurities into 50mL measuring flasks, adding purified water to dilute to the scales, and shaking up.
And (3) detection results: blank results are shown in FIG. 1, system suitability results are shown in FIG. 2, sample results are shown in FIG. 3, and impurity localization results are shown in FIGS. 4-12.
Example 2
A high performance liquid chromatograph: waters H-class-VWD detector;
mobile phase: phase A: phosphate buffer (phosphate buffer is 0.01mol/L potassium dihydrogen phosphate aqueous solution and 0.01mol/L tetrabutyl ammonium hydroxide aqueous solution mixed in equal proportion, and pH is adjusted to 4.5 with phosphoric acid)
Phase B: methanol;
the elution gradient was as follows:
TABLE 2 elution gradient procedure
Detection wavelength: 280nm;
flow rate: 0.2mL/min;
column temperature: 30 ℃;
sample introduction amount: 1 mu L of the solution;
blank solution: and (4) purifying the water.
Preparing a sample solution: accurately weighing about 10mg of sample, placing the sample in a 50mL measuring flask, adding purified water to dilute to the mark, and shaking up.
Preparing a system applicability solution: precisely weighing about 5mg of citicoline sodium sample and 5mg of each impurity, placing the sample and each impurity in a 50mL measuring flask, adding purified water to dilute to a scale mark, and shaking up.
Impurity localization solution: accurately weighing 5mg of each impurity, respectively placing the impurities into a 50mL measuring flask, adding purified water to dilute to a scale, and shaking up.
And (3) detection results: system applicability results referring to figure 13, citicoline sodium is not completely separated from impurity 9.
Comparative example 1
High performance liquid chromatograph: waters H-class-VWD detector;
mobile phase: phase A: phosphate buffer (phosphate buffer is 0.01mol/L potassium dihydrogen phosphate aqueous solution and 0.01mol/L tetrabutyl ammonium hydroxide aqueous solution mixed in equal proportion, and pH is adjusted to 4.5 with phosphoric acid)
Phase B: acetonitrile;
the elution gradient was as follows:
TABLE 3 elution gradient procedure
Detection wavelength: 280nm;
flow rate: 0.2mL/min;
column temperature: 30 ℃;
sample introduction amount: 1 mu L of the solution;
blank solution: and (4) purifying the water.
Preparing a sample solution: accurately weighing about 10mg of sample, placing the sample in a 50mL measuring flask, adding purified water to dilute to the mark, and shaking up.
Preparing a system applicability solution: precisely weighing about 5mg of citicoline sodium sample and 5mg of each impurity, placing the samples in a 50mL measuring flask, adding purified water to dilute the samples to a scale, and shaking up.
Impurity localization solution: accurately weighing 5mg of each impurity, respectively placing the impurities into a 50mL measuring flask, adding purified water to dilute to a scale, and shaking up.
And (3) detection results: the system applicability results are shown in figure 14, wherein citicoline sodium is not separated from impurity 9, and impurity 6 is not separated from impurity 8.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.
Claims (2)
1. A UPLC analysis method for simultaneously determining citicoline sodium and nine related substances is characterized in that a reversed phase chromatographic column is adopted for chromatographic analysis, the reversed phase chromatographic column takes hydrophilic octadecylsilane chemically bonded silica as a filling agent, phosphate buffer solution as a mobile phase A, the phosphate buffer solution is a 0.01mol/L potassium dihydrogen phosphate aqueous solution and a 0.01mol/L tetrabutylammonium hydroxide aqueous solution which are mixed in equal proportion, phosphoric acid is used for adjusting the pH value to 3.0, methanol is used as a mobile phase B, gradient elution is carried out on a sample solution of the citicoline sodium, the purity of the citicoline sodium and the contents of nine impurities are determined according to an area normalization method, and the elution gradient is shown in the following table:
;
A chromatographic column: acquity uplcsst T3, 2.1 x 100mm, 1.8 μm;
detection wavelength: 280nm;
flow rate: 0.2mL/min;
column temperature: 30 ℃;
sample introduction amount: 1 μ L.
2. The UPLC analytical method according to claim 1, wherein the concentration of the sample solution of citicoline sodium is 0.1 to 1.0mg/mL.
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