CN112964813A - Method for measuring residual quantity of organic solvent in fasudil hydrochloride - Google Patents
Method for measuring residual quantity of organic solvent in fasudil hydrochloride Download PDFInfo
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Abstract
The invention discloses a method for measuring the residual quantity of organic solvent in fasudil hydrochloride, which comprises the following steps: step 1, accurately weighing a proper amount of absolute methanol, diethyl ether and dichloromethane, and preparing a standard solution by using distilled water; step 2, precisely weighing the sample into a volumetric flask, adding distilled water to a scale, and shaking up; step 3, setting the column temperature, the gasification chamber temperature, the pre-column pressure, the split ratio and the headspace condition of a gas chromatograph by adopting a 6% cyanopropylbenzene-94% dimethyl siloxane capillary column; step 4, operating system applicability, namely sucking a standard solution into a headspace bottle, sealing, continuously injecting samples, recording a spectrogram, and comparing the relative standard deviation of the peak area of the solvent in the spectrogram to be not more than 10%; step 5, after the applicability operation of the system is qualified, precisely weighing the sample solution in the step 2, injecting the sample, detecting according to the chromatographic conditions in the step 3, and recording a chromatogram; and 6, calculating the content of each solvent by taking the peak area obtained by the control solution in the step 4 as a control.
Description
Technical Field
The invention belongs to the field of medicine quality control, and particularly relates to a method for measuring the residual quantity of an organic solvent in fasudil hydrochloride.
Background
Fasudil hydrochloride is a novel drug with wide pharmacological action, the molecular structure of the fasudil hydrochloride is a 5-isoquinoline cyclic amide derivative (shown in figure 1), the fasudil hydrochloride is an RHO kinase inhibitor, the activity of myosin light chain phosphatase is increased to expand blood vessels, the tension of endothelial cells is reduced, the microcirculation of brain tissues is improved, the stealing blood of the brain is not generated and aggravated, meanwhile, inflammatory factors can be antagonized, nerves are protected against apoptosis, and nerve regeneration is promoted. In the production process of fasudil hydrochloride, residues of methanol, ether and dichloromethane can be generated, and the residual quantity of fasudil hydrochloride needs to be measured and controlled in order to control the quality of the medicine.
Before 2015, in the quality standard YBH01832010 of fasudil hydrochloride, a capillary direct injection method is used as a detection method, and the detection method is found to be poor in detection repeatability and poor in chromatographic peak type.
After the issuance of the Chinese pharmacopoeia 2015 edition, according to the determination requirement of the fasudil hydrochloride residual solvent in the second part of the Chinese pharmacopoeia 2015 edition, the sample is directly injected by a sample injection method, a diluent [ N, N-dimethylformamide-water (1:9) ] is used as a solvent, and bonded/crosslinked polyethylene glycol is used as a stationary liquid for determination, so that the content of the residual methanol in the organic solvent is not more than 0.3%, the content of the diethyl ether is not more than 0.5%, and the content of the dichloromethane is not more than 0.06%; when the symmetry of a chromatographic peak is evaluated, the value of a tailing factor T is 0.95-1.05, the content of impurities is usually lower than 0.5%, the Relative Standard Deviation (RSD) of the peak area is less than 10%, the content of impurities is 0.5-2%, and the RSD of the peak area is less than 5%. We have carried out experiments on the method and find that the detection reproducibility is poor, the chromatographic peak generates a tailing phenomenon, and the theoretical plate number is low.
Disclosure of Invention
Aiming at the problems of poor reproducibility and good chromatographic peak tailing in the determination of the residual quantity of the organic solvent in fasudil hydrochloride in the prior art, the invention aims to provide a method for determining the residual quantity of the organic solvent in fasudil hydrochloride.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a method for measuring the residual quantity of organic solvent in fasudil hydrochloride comprises the following steps:
step 1, preparing a standard solution: accurately weighing anhydrous methanol, diethyl ether and appropriate amount of dichloromethane, and preparing into standard solution of methanol, diethyl ether with dichloromethane content of 30 μ g/mL, 50 μ g/mL and 6 μ g/mL respectively with distilled water;
step 3, setting the column temperature, the gasification chamber temperature, the pre-column pressure, the split ratio and the headspace condition of a gas chromatograph by adopting a 6% cyanopropylbenzene-94% dimethyl siloxane capillary column;
step 4, operating the system in a suitable manner, sucking the standard solution into a headspace bottle, sealing, continuously injecting samples, recording a spectrogram, and comparing the relative standard deviation of the peak area of the solvent in the spectrogram with no more than 10%;
step 5, after the applicability operation of the system is qualified, precisely weighing the sample solution in the step 2, injecting the sample, detecting according to the chromatographic conditions in the step 3, and recording a chromatogram;
and 6, calculating, namely calculating the content of each solvent by taking the peak area obtained by the control solution in the step 4 as a control.
As a preferred technical scheme of the application, in the step 3, the temperature of the gasification chamber of the gas chromatograph is 200-250 ℃.
As a preferred technical scheme of the application, in the step 3, the headspace conditions are that the headspace equilibrium temperature is 80 ℃, the equilibrium time is 45min, the sample injection needle temperature is 85 ℃, the transmission line temperature is 120 ℃, and the sample injection time is 0.03 min.
As a preferred technical scheme of the application, in the step 3, the specification of the capillary column is DB-62430m multiplied by 0.32mm multiplied by 1.8 μm capillary column.
As a preferred technical scheme of the present application, in step 3, the column temperature is 80 ℃, the gasification chamber temperature is 200 ℃, the column pressure is 10.36psi, and the split ratio is 7: 1.
advantageous effects
Compared with the prior art, the method for measuring the residual amount of the organic solvent in the fasudil hydrochloride has the following beneficial effects:
(1) from the experimental time, the time ratio of the method to the prior art is 4: 3; in terms of accuracy, the sensitivity is high by adopting a headspace sampling method, the interference of DMF is avoided, and the data ratio is at least 45: 2.
(2) In the aspect of experimental expense, the method has small influence on the performance of the column, prolongs the service life of the chromatographic column, and simultaneously has lower cost of the used solvent;
(3) from the perspective of environmental pollution, the method is more environment-friendly by using water as a solvent, and the method does not need high-temperature column baking and has lower energy consumption.
Drawings
FIG. 1 shows the structural formula of fasudil hydrochloride;
FIG. 2 is chromatograms of a control solution 2(a), a test solution 2(b) and a blank solvent 2(c) in example 1, respectively; wherein the peak sequences are methanol, diethyl ether and dichloromethane respectively.
Detailed Description
The present invention will be described in further detail with reference to examples. The reagents or instruments used are not indicated by manufacturers, and are regarded as conventional products which can be purchased in the market.
Example 1:
adopting a headspace sampling method to sample, and respectively measuring three batches of fasudil hydrochloride with different batches of numbers, wherein the method comprises the following steps:
the instrument used an Agilent 6890N gas chromatograph with FID, chemical workstation and Perkin Elmer Turbomatrix HS40 headspace sampler. The gas chromatographic conditions were DB-624 (stationary phase 6% cyanopropylbenzene, 94% dimethylsiloxane) 30m × 0.32mm × 1.8 μm capillary column, column temperature 80 deg.C, vaporizer temperature 200 deg.C, column head pressure 10.36psi, split ratio 7: 1. the headspace conditions were headspace equilibration temperature of 80 deg.C, equilibration time of 45min, injection needle temperature of 85 deg.C, transfer line temperature of 120 deg.C, and injection time of 0.03 min.
The preparation method of the standard solution comprises the following steps: a proper amount of absolute methanol, ether and dichloromethane are precisely weighed and prepared into standard sample solutions containing 30 mu g/mL, 50 mu g/mL and 6 mu g/mL of methanol, ether and dichloromethane respectively by using distilled water. Sucking 2.0mL of standard sample stock solution into a 22mL headspace bottle, and sealing; the preparation method of the sample solution comprises the following steps: accurately weighing a sample in a volumetric flask of 0.10g to 10mL, adding distilled water to the scale, shaking up, sucking the solution in a headspace flask of 2.0mL to 22mL, and sealing to obtain a sample solution.
1. System suitability test
The three components of the control solution were completely separated with a separation of methanol, 19.0 between ether, 20.8 between ether and dichloroethane (fig. 2), and the blank solution was not sensitive to detection.
2. Precision and repeatability test
Continuously feeding the reference solution for 6 times, and calculating to obtain RSD of peak areas of methanol, ether and dichloroethane; taking 6 parts of the same batch of sample solution, and sampling to determine RSD of peak areas of methanol, ether and dichloroethane.
Table 1 precision and repeatability of each component (n ═ 6)
| Organic solvent | Reference solution RSD | Test solution RSD |
| Methanol | 0.50％ | 1.8％ |
| Ether (A) | 1.11％ | 3.4％ |
| Methylene dichloride | 1.60％ | 5.4％ |
3. Linearity
An appropriate amount of methanol, ether and dichloromethane was precisely weighed, and control stock solutions containing 30. mu.g/mL, 50. mu.g/mL and 6. mu.g/mL of each of methanol, ether and dichloromethane were prepared with distilled water. Precisely measuring 1.0 mL, 2.0mL, 4.0 mL and 5.0mL of the reference stock solution into a 10mL volumetric flask, and adding water to a constant volume. And respectively sucking the serial solutions and a reference substance stock solution from 2.0mL to 22mL in a headspace bottle, carrying out sample injection measurement, and recording a chromatogram. The results of linear regression with peak area A as ordinate and concentration c (. mu.g/mL) as abscissa are shown in Table 2.
Table 2 regression equation for each component (n ═ 5)
As can be seen from table 2, the components are in good linear relationship within their respective concentration ranges.
4. Minimum detected concentration
The concentration of the standard use solution was gradually decreased, the measurement was performed until the signal-to-noise ratio was close to 3:1, and the lowest detection concentration was calculated, and the results are shown in table 3.
TABLE 3 minimum assay concentration of each component
| Organic solvent | Methanol | Ether (A) | Methylene dichloride |
| Minimum assay concentration (μ g/mL) | 0.08 | 0.0007 | 0.07 |
5. Recovery test
Preparing a stock solution of a standard solution containing 300 mu g/mL of methanol, 500 mu g/mL of diethyl ether and 60 mu g/mL of dichloromethane, precisely weighing 9 fasudil hydrochloride (batch No. 100501) with known solvent residue in 0.10g to 10mL volumetric flasks, adding the standard solutions of 0.8, 1.0 and 1.2mL according to 3 levels of 80%, 100% and 120% of various solvent residue limit indexes, repeating the steps for 3 times at each level, measuring and calculating the standard addition recovery rate. The results are shown in Table 4.
TABLE 4 recovery of each component normalized
6. Sample assay
The solvent residues in fasudil hydrochloride of three different batches are respectively measured according to the headspace sampling method, and the measurement results are shown in table 5.
TABLE 5 determination of solvent residue in fasudil hydrochloride
As can be seen from Table 5, the residual amounts of the solvents all meet the requirements of the Chinese pharmacopoeia 2015 edition.
From the experimental time, in the direct injection method, during gasification, the initial temperature is maintained at 45 ℃ for 2min, the temperature is raised to 120 ℃ at the rate of 40 ℃ per minute and then maintained for 5min, which is 8.875min in total, so that the headspace injection method can save the gasification time for 8-9min at least on each sample, and the experimental efficiency is improved, and the time ratio of the two is 4: 3. In terms of accuracy, the sensitivity is high by adopting a headspace sampling method, the interference of DMF is avoided, and the data ratio is at least 45: 2.
From the aspect of experimental cost, a solution direct injection method takes N, N-dimethylformamide-water (1:9) as a solvent, firstly, although a polyethylene glycol chromatographic column can tolerate trace water, the performance of the column can be affected by excessive use of the polyethylene glycol chromatographic column, the service life of the chromatographic column is reduced, the price of one capillary chromatographic column is generally different from 2000-6000 yuan, the service life of the chromatographic column is reduced, which means that the experimental cost is greatly increased, and a headspace injection method avoids the problem, reduces the requirement on the daily maintenance work of an instrument and also prolongs the service time of some key parts of the instrument; secondly, N-dimethylformamide-water (1:9) is taken as a solvent by a direct sample injection method,
and the headspace sampling method uses water as a solvent, the price ratio of 1L of DMF to 1L of water is 9:1, and the adoption of water as the solvent is obviously more economical.
From the perspective of environmental pollution, water is more environmentally friendly, and the ratio of the pollution of DMF to the environment to the pollution of water is 9:1 (the ratio of the treatment cost of DMF to water is 9: 1). In terms of energy saving, the headspace sampling method avoids energy consumption of heating to 45 ℃, 120 ℃ and even 250 ℃ in the gasification process of the direct sampling method, and is more energy-saving and environment-friendly. In particular, when DMF is present in the solvent, the column must be baked at high temperature, the maximum temperature must be raised to at least 200 ℃ and the column temperature must be maintained at only 50 ℃ using water as the solvent, with an energy consumption ratio of about 4: 1.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept and the scope of the appended claims is intended to be protected.
Claims (5)
1. A method for measuring the residual quantity of organic solvent in fasudil hydrochloride is characterized by comprising the following specific steps:
step 1, preparing a standard solution: accurately weighing anhydrous methanol, diethyl ether and appropriate amount of dichloromethane, and preparing into standard solution of methanol, diethyl ether with dichloromethane content of 30 μ g/mL, 50 μ g/mL and 6 μ g/mL respectively with distilled water;
step 2, preparation of a sample solution: accurately weighing a sample in a volumetric flask of 0.10g to 10mL, adding distilled water to scale, shaking up, sucking the solution in a headspace flask of 2.0mL to 22mL, and sealing to obtain a sample solution;
step 3, setting the column temperature, the gasification chamber temperature, the pre-column pressure, the split ratio and the headspace condition of a gas chromatograph by adopting a 6% cyanopropylbenzene-94% dimethyl siloxane capillary column;
step 4, operating the system in a suitable manner, sucking the standard solution into a headspace bottle, sealing, continuously injecting samples, recording a spectrogram, and comparing the relative standard deviation of the peak area of the solvent in the spectrogram with no more than 10%;
step 5, after the applicability operation of the system is qualified, precisely weighing the sample solution in the step 2, injecting the sample, detecting according to the chromatographic conditions in the step 3, and recording a chromatogram;
and 6, calculating, namely calculating the content of each solvent by taking the peak area obtained by the control solution in the step 4 as a control.
2. The method for measuring the residual amount of the organic solvent in fasudil hydrochloride according to claim 1, wherein the temperature of the gasification chamber of the gas chromatograph in the step 3 is 200-250 ℃.
3. The method for measuring the residual quantity of the organic solvent in the fasudil hydrochloride according to claim 1, wherein in the step 3, the headspace conditions are headspace equilibrium temperature of 80 ℃, equilibrium time of 45min, injection needle temperature of 85 ℃, transmission line temperature of 120 ℃ and injection time of 0.03 min.
4. The method for measuring the residual amount of organic solvents in fasudil hydrochloride according to claim 1, wherein the capillary column specification in step 3 is DB-62430m x 0.32mm x 1.8 μm capillary column.
5. The method for determining the residual amount of the organic solvent in fasudil hydrochloride according to claim 1, wherein in the step 3, the column temperature is 80 ℃, the gasification chamber temperature is 200 ℃, the pre-column pressure is 10.36psi, and the split ratio is 7: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114236003A (en) * | 2021-12-15 | 2022-03-25 | 精晶药业股份有限公司 | Detection method of volatile impurities in calcium pantothenate |
| CN114264736A (en) * | 2021-12-02 | 2022-04-01 | 乳源东阳光药业有限公司 | Method for detecting 1, 2-dichloroethane solvent residue in sultopride hydrochloride |
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