CN113447584A - Detection and analysis method for high piperazine in fasudil hydrochloride injection - Google Patents
Detection and analysis method for high piperazine in fasudil hydrochloride injection Download PDFInfo
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- CN113447584A CN113447584A CN202110716124.XA CN202110716124A CN113447584A CN 113447584 A CN113447584 A CN 113447584A CN 202110716124 A CN202110716124 A CN 202110716124A CN 113447584 A CN113447584 A CN 113447584A
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Abstract
The invention belongs to the technical field of substance detection, and provides a detection and analysis method for high piperazine in fasudil hydrochloride injection. According to the detection and analysis method, fasudil hydrochloride injection to be detected is diluted to obtain a test sample solution; and carrying out ion chromatography analysis on the test solution to obtain the content of high piperazine in the fasudil hydrochloride injection to be detected. The detection and analysis method provided by the invention has no interference peak and is high in stability and accuracy. The data of the examples show that: the mass concentration of the high piperazine is in a good linear relation with the ion chromatographic peak area within the range of 1.54-9.23 mu g/mL, r is 0.9991, the normalized average recovery rate is 96.86%, and the relative standard deviation of the measurement result is 1.2% (3 concentrations n is 9). The detection and analysis method provided by the invention is accurate, simple, convenient and quick, and can be used for quickly determining the high piperazine in fasudil hydrochloride injection in actual production.
Description
Technical Field
The invention relates to the technical field of substance detection, in particular to a detection and analysis method for high piperazine in fasudil hydrochloride injection.
Background
Fasudil hydrochloride is an isoquinoline sulfonamide drug developed by Asahi Kasei corporation in Japan in the 80 th century, is a protein kinase RHO inhibitor, and can improve brain tissue microcirculation without generating and aggravating cerebral hemorrhage by blocking the final stage of vasoconstriction process, namely increasing the activity of myosin hydrogen chain phosphatase, dilating blood vessels (inhibiting vasospasm), reducing the tension of endothelial cells and exerting efficacy. The compound preparation is mainly used for improving and preventing cerebral spasm after subarachnoid hemorrhage and cerebral ischemia symptoms caused by the cerebral spasm after the subarachnoid hemorrhage, and can also protect nerves against apoptosis and promote nerve regeneration.
Fasudil hydrochloride is used as an efficient vasodilator, can effectively relieve cerebral vasospasm, and is a novel drug with wide pharmacological action. The homopiperazine is a raw material used in a fasudil hydrochloride synthesis process, and is also a degradation impurity of fasudil hydrochloride, and the homopiperazine cannot be detected by a chromatographic system under the relevant substance examination item of the second fasudil hydrochloride injection in 2020 edition of Chinese pharmacopoeia, namely the homopiperazine impurity is not controlled by the existing standard.
In the prior art, a gas chromatography is reported to be used for detecting the content of high piperazine in fasudil hydrochloride, but the problems of poor stability and accuracy exist, so that the result cannot reflect the real content of high piperazine, and the quality of fasudil hydrochloride cannot be controlled.
Disclosure of Invention
In view of the above, the present invention aims to provide a detection and analysis method for piperazine in fasudil hydrochloride injection. The detection and analysis method provided by the invention has no interference peak and is high in stability and accuracy.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a detection and analysis method for high piperazine in fasudil hydrochloride injection, which comprises the following steps:
diluting fasudil hydrochloride injection to be detected to obtain a test solution;
carrying out ion chromatographic analysis on the test solution to be tested to measure the content of high piperazine in the fasudil hydrochloride injection to be tested;
the parameters of the ion chromatography include:
cation exchange column: dionex IonPac CS12A, 4 mm. times.250 mm;
protection of the column: dionex IonPac CG12A, 4 mm. times.50 mm;
eluent: 40mmol/L methane sulfonic acid solution and acetonitrile according to the volume ratio of 80: 20 of a mixed solution;
a detector: a conductance detector;
the detection mode is as follows: inhibiting conductance detection;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
sample introduction amount: 25 μ L.
Preferably, the diluted reagent is a 40mmol/L methane sulfonic acid solution.
Preferably, after the dilution, the obtained dilution system is further subjected to filtration.
Preferably, after the ion chromatography, the method further comprises: and calculating the peak area of the obtained homopiperazine according to an external standard method to obtain the content of the homopiperazine in the fasudil hydrochloride injection to be detected.
The invention provides a detection and analysis method for high piperazine in fasudil hydrochloride injection, which comprises the following steps: diluting fasudil hydrochloride injection to be detected to obtain a test solution; carrying out ion chromatographic analysis on the test solution to be tested to measure the content of high piperazine in the fasudil hydrochloride injection to be tested; the parameters of the ion chromatography include: cation exchange column: dionex IonPac CS12A, 4 mm. times.250 mm; protection of the column: dionex IonPac CG12A, 4 mm. times.50 mm; eluent: 40mmol/L methane sulfonic acid solution and acetonitrile according to the volume ratio of 80: 20 of a mixed solution; a detector: a conductance detector; the detection mode is as follows: inhibiting conductance detection; flow rate: 1.0 mL/min; column temperature: 30 ℃; sample introduction amount: 25 μ L. In the detection and analysis method provided by the invention, 40mmol/L methane sulfonic acid solution and acetonitrile are mixed according to the volume ratio of 80: the mixed solution of 20 is eluent, has no interference peak, good peak shape, high stability and high accuracy. The data of the examples show that: the mass concentration of the high piperazine is in a good linear relation with the ion chromatographic peak area within the range of 1.54-9.23 mu g/mL, r is 0.9991, the normalized average recovery rate is 96.86%, and the relative standard deviation of the measurement result is 1.2% (3 concentrations n is 9). The detection and analysis method provided by the invention is accurate, simple, convenient and quick, and can be used for quickly determining the high piperazine in fasudil hydrochloride injection in actual production.
Drawings
FIG. 1 is a chromatogram of a blank solvent (40mmol/L methanesulfonic acid solution);
FIG. 2 is a chromatogram of a test solution;
FIG. 3 is an enlarged view of a chromatogram of a test solution;
FIG. 4 is a chromatogram of a homopiperazine control;
FIG. 5 is a chromatogram of a homopiperazine control stock solution;
FIG. 6 is a chromatogram of a system suitability solution;
FIG. 7 is an enlarged view of a chromatogram of a system suitability solution;
FIG. 8 is a chromatogram of a sensitive solution;
FIG. 9 is an enlarged view of a chromatogram of a sensitive solution;
FIG. 10 is a graph of high piperazine linearity versus range results.
Detailed Description
The invention provides a detection and analysis method for high piperazine in fasudil hydrochloride injection, which comprises the following steps:
diluting fasudil hydrochloride injection to be detected to obtain a test solution;
and carrying out ion chromatography analysis on the test solution to obtain the content of high piperazine in the fasudil hydrochloride injection to be detected.
In the present invention, the samples used in the present invention are all commercially available products unless otherwise specified.
The fasudil hydrochloride injection to be detected is diluted to obtain the upper computer test sample solution.
In the present invention, the diluted reagent is preferably a 40mmol/L methane sulfonic acid solution. The dosage of the diluted reagent is not specifically limited, and a person skilled in the art can dilute homopiperazine in fasudil hydrochloride injection to be detected to a target concentration range according to a conventional technical means; the target concentration range is preferably a concentration range in which a high piperazine concentration-peak area standard curve is established when ion chromatography is performed.
After said dilution, the present invention preferably further comprises filtering the resulting diluted system. In the present invention, the filtration membrane for filtration is preferably a 0.22 μm membrane.
After a test solution is obtained, the method carries out ion chromatography analysis on the test solution to obtain the content of high piperazine in the fasudil hydrochloride injection to be detected.
In the present invention, the parameters of the ion chromatography include:
cation exchange column: dionex IonPac CS12A, 4 mm. times.250 mm;
protection of the column: dionex IonPac CG12A, 4 mm. times.50 mm;
eluent: 40mmol/L methane sulfonic acid solution and acetonitrile according to the volume ratio of 80: 20 of a mixed solution;
a detector: a conductance detector;
the detection mode is as follows: inhibiting conductance detection;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
sample introduction amount: 25 μ L.
In the present invention, the ion chromatography apparatus is preferably a Thermo ICS-2100 ion chromatograph.
After the ion chromatography, the present invention preferably further comprises: and calculating the peak area of the obtained homopiperazine according to an external standard method, and measuring the content of the homopiperazine in the fasudil hydrochloride injection to be measured. In the present invention, the operation of the external standard method preferably includes: respectively detecting the test sample solution and the high piperazine standard sample solution with known concentration to obtain peak areas of the test sample solution and the high piperazine standard sample solution with known concentration; and then obtaining the content of the high piperazine in the test solution based on the relation between the peak area and the concentration of the high piperazine standard sample solution with known concentration.
The following examples are provided to illustrate the detection and analysis method of piperazine in fasudil hydrochloride injection of the present invention in detail, but they should not be construed as limiting the scope of the present invention.
The following examples used instruments and materials:
thermo ICS-2100 ion chromatograph;
MettlerXS-105DU electronic balance;
PURELAB FLEX water machine (ELGA, uk);
methanesulfonic acid (analytical grade, national pharmaceutical group chemical reagents, Ltd., lot number: 20181031);
acetonitrile (chromatographically pure, DIKMA, batch: R141555);
high piperazine control: shanxi Nuo pharmaceutical Co., Ltd provides (Shenzhen Excellent Biotech Co., Ltd., batch No. 20180321, content: 98.63%);
fasudil hydrochloride injection: shanxi Nuo pharmaceutical Co., Ltd. (size: 2 mL: 30mg, lot numbers: 17052611, 17052711, 17052811).
Preparation of the solution
Test solution: precisely measuring 10mL of fasudil hydrochloride injection (batch number: 17052711) to be measured, placing the fasudil hydrochloride injection into a 25mL measuring flask, diluting the fasudil hydrochloride injection to a scale with 40mmol/L methane sulfonic acid solution, and shaking up to obtain the fasudil hydrochloride injection.
High piperazine control stock solution: accurately weighing 12mg of homopiperazine reference substance, placing the reference substance in a 100mL measuring flask, adding 40mmol/L methane sulfonic acid solution to dissolve and dilute the reference substance to scale, and shaking up to obtain the product.
High piperazine control solution: precisely measuring 5mL of high piperazine reference substance stock solution, placing into a 100mL measuring flask, dissolving and diluting with 40mmol/L methanesulfonic acid solution to obtain a solution containing 6 μ g of high piperazine reference substance per 1mL, and shaking up to obtain the final product.
System applicability solution: dissolving fasudil hydrochloride injection to be detected and homopiperazine reference substance with 40mmol/L methanesulfonic acid solution, diluting to prepare mixed solution containing 6mg of fasudil hydrochloride to be detected and 6 mu g of homopiperazine in every 1mL, and shaking up to obtain the fasudil hydrochloride injection.
Sensitivity solution: precisely measuring 3mL of high piperazine reference substance solution, placing the solution in a 10mL measuring flask, adding 4mL of fasudil hydrochloride injection to be measured, diluting the solution to scale with 40mmol/L methane sulfonic acid solution, and shaking up to obtain the fasudil hydrochloride injection.
Conditions for ion chromatography
Cation exchange column: dionex IonPac CS12A (4 mm. times.250 mm);
protection of the column: dionex IonPac CG12A (4 mm. times.50 mm);
eluent: 40mmol/L methanesulfonic acid solution-acetonitrile (volume ratio 80: 20);
a detector: a conductance detector;
the detection mode is as follows: inhibiting conductance detection;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
sample introduction amount: 25 μ L.
The separation degree of the high piperazine peak and the fasudil peak in the system applicability solution meets the requirement. The signal-to-noise ratio of the high piperazine peak in the sensitive solution should be greater than 10.
Specificity test
And (3) respectively injecting 25 mu L of a hollow white solvent (40mmol/L methane sulfonic acid solution), a high piperazine reference substance stock solution, a high piperazine reference substance solution, a system applicability solution, a test sample solution and a sensitivity solution in the preparation part of the solution into a Thermo ICS-2100 ion chromatograph, performing ion chromatographic analysis according to the ion chromatographic analysis conditions, and recording a chromatogram, wherein the result is shown in figures 1-9. As can be seen from FIGS. 1-9: the blank solvent does not interfere the detection of the homopiperazine in the fasudil hydrochloride injection, and the separation degree of the homopiperazine peak and the fasudil hydrochloride peak meets the requirement.
Linearity and range
Precisely measuring 1.5 mL, 2.0 mL, 3.0 mL, 5.0 mL, 7.0 mL and 9.0mL of the reference substance stock solution of the homopiperazine 'solution preparation', respectively placing the reference substance stock solution of the homopiperazine 'solution preparation' into a 100mL measuring flask, adding 40mmol/L methane sulfonic acid solution to dilute the reference substance stock solution to a scale, shaking up the reference substance stock solution, carrying out ion chromatographic analysis according to the 'condition of ion chromatographic analysis', and carrying out linear regression on the peak area (A) by using the concentration (C) to obtain the regression equation of the homopiperazine as shown in FIG. 10. The regression equation of homopiperazine is specifically: a is 0.0379C-0.0235 and r is 0.9991(n is 6). As can be seen from fig. 10 and the regression equation: the homopiperazine is in good linear relation in the concentration range of 1.54-9.23 mu g/mL.
Accuracy test
Accurately weighing 12mg of high piperazine reference substance, placing the high piperazine reference substance in a 200mL measuring flask, diluting with 40mmol/L methane sulfonic acid solution to a constant volume to a scale, and taking the diluted solution as reference substance stock solution; precisely measuring 5mL of the reference substance stock solution, placing the reference substance stock solution into a 50mL measuring flask, and diluting with 40mmol/L methanesulfonic acid solution to a constant volume to scale to obtain a high piperazine reference substance solution.
Precisely measuring 3 parts of each of 4mL, 5mL and 6mL of high piperazine reference substance stock solutions, respectively placing the high piperazine reference substance stock solutions into 50mL measuring bottles, respectively adding 20.0mL of fasudil hydrochloride injection (batch number: 17052711) to be measured, diluting the solution to a scale with a solvent of 40mmol/L methanesulfonic acid solution, shaking up the solution to obtain solutions with concentrations of 80%, 100% and 120%, performing ion chromatographic analysis according to the conditions of the ion chromatographic analysis, recording chromatograms, and calculating the recovery rate, wherein the results are shown in Table 1.
TABLE 1 high piperazine accuracy test results
As can be seen from table 1: the average recovery rate is 96.86%, and the RSD is 1.2%, which shows that the detection and analysis method provided by the invention has good accuracy.
Stability test
Accurately weighing a proper amount of high piperazine reference substances, putting the high piperazine reference substances into a 100mL measuring flask, diluting the high piperazine reference substances to a scale with a 40mmol/L methane sulfonic acid solution, and shaking up; precisely measuring 5mL, placing in a 100mL measuring flask, diluting to scale with 40mmol/L methanesulfonic acid solution, and shaking up. Samples were taken at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours after the preparation, and the results of the ion chromatography analysis were shown in Table 2, according to the "conditions for ion chromatography".
TABLE 2 high piperazine stability test results
As can be seen from table 2: RSD of the high piperazine peak area was 1.4%, indicating that the high piperazine control solution was stable within 12 hours.
Precision test
The high piperazine control solution in the "preparation of solution" was taken, and subjected to ion chromatography according to the "conditions of ion chromatography", 6 portions were continuously injected, and chromatograms were recorded, with the results shown in table 3.
TABLE 3 high piperazine repeatability test results
As can be seen from table 3: the RSD of the calculated peak area is 1.0 percent, which shows that the repeatability of the detection analysis method provided by the invention is good.
Quantitative limit and detection limit
3mL and 1mL of homopiperazine reference substance solution in the 'solution preparation' are precisely measured, the solution is respectively placed in 10mL measuring bottles, 4.0mL of fasudil hydrochloride injection (batch number: 17052711) to be detected is respectively added, 40mmol/L methane sulfonic acid solution is used for diluting to a scale, and the lowest quantitative concentration is 1.8 mu g/mL and the minimum detection concentration is 0.6 mu g/mL.
Durability test
Ion chromatography was carried out under the "conditions for ion chromatography" by changing the flow rate (+ -10%), the column temperature (35 ℃), and the acetonitrile ratio in the mobile phase [40mmol/L methanesulfonic acid solution-acetonitrile (volume ratio 85: 15) and 40mmol/L methanesulfonic acid solution-acetonitrile (volume ratio 75: 25) ], respectively, and the results are shown in Table 4.
TABLE 4 high piperazine durability test results
As can be seen from table 4: the areas of the high piperazine peaks in the reference solution have no significant difference; the separation degrees of the high piperazine peak and the fasudil peak in the system applicability solution meet the requirements, and the detection and analysis method provided by the invention is good in durability.
Sample assay
The fasudil hydrochloride injection test solution (batch numbers: 17052611, 17052711 and 17052811) in the solution preparation is precisely measured, and the ion chromatographic analysis is carried out according to the ion chromatographic analysis conditions, and the result is as follows: no homopiperazine was detected in any of 3 samples.
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 decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (4)
1. A detection and analysis method for high piperazine in fasudil hydrochloride injection comprises the following steps:
diluting fasudil hydrochloride injection to be detected to obtain a test solution;
carrying out ion chromatographic analysis on the test solution to be tested to measure the content of high piperazine in the fasudil hydrochloride injection to be tested;
the parameters of the ion chromatography include:
cation exchange column: dionex IonPac CS12A, 4 mm. times.250 mm;
protection of the column: dionex IonPac CG12A, 4 mm. times.50 mm;
eluent: 40mmol/L methane sulfonic acid solution and acetonitrile according to the volume ratio of 80: 20 of a mixed solution;
a detector: a conductance detector;
the detection mode is as follows: inhibiting conductance detection;
flow rate: 1.0 mL/min;
column temperature: 30 ℃;
sample introduction amount: 25 μ L.
2. The assay of claim 1, wherein the diluted reagent is 40mmol/L methane sulfonic acid solution.
3. The assay of claim 1, further comprising, after said diluting, filtering the resulting diluted system.
4. The detection analysis method of claim 1, further comprising, after the ion chromatography: and calculating the peak area of the obtained homopiperazine according to an external standard method to obtain the content of the homopiperazine in the fasudil hydrochloride injection to be detected.
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