CN112611809A - Method for detecting and analyzing fasudil nitrogen oxide impurity in fasudil hydrochloride - Google Patents
Method for detecting and analyzing fasudil nitrogen oxide impurity in fasudil hydrochloride Download PDFInfo
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- CN112611809A CN112611809A CN201910947088.0A CN201910947088A CN112611809A CN 112611809 A CN112611809 A CN 112611809A CN 201910947088 A CN201910947088 A CN 201910947088A CN 112611809 A CN112611809 A CN 112611809A
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Abstract
The invention discloses a method for detecting and analyzing an impurity fasudil nitrogen oxide in fasudil hydrochloride, which comprises the steps of adopting a high performance liquid chromatography, dissolving and diluting fasudil hydrochloride by using a solvent into a solution containing 1-100 mg of fasudil hydrochloride in each 1ml of fasudil hydrochloride solution to serve as a test solution, injecting the solution into a high performance liquid chromatograph, wherein the sample injection volume is 5-100 mu l, using an ultraviolet detector to detect the wavelength of 210-350 nm, using a methanol-water solution as a mobile phase, and using a stationary phase alkyl bonded silica gel chromatographic column to quantitatively determine the impurity fasudil nitrogen oxide in fasudil hydrochloride, wherein the flow rate of the mobile phase is 0.3-2.0 ml/min. The method for measuring the content of the sodium chloride has the advantages of simplicity, high precision, good stability and good reproducibility.
Description
Technical Field
The invention belongs to the field of new pharmaceutical technologies, and relates to a detection and analysis method for an impurity fasudil nitrogen oxide in fasudil hydrochloride, in particular to a detection and analysis method for an impurity fasudil nitrogen oxide in fasudil hydrochloride, which is a drug for improving and preventing cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia symptoms caused by the cerebral vasospasm.
Background
The fasudil nitrogen oxide is used as an impurity for oxidizing and degrading fasudil hydrochloride, and has a genotoxicity warning structure in the structure, and the structural formula is shown as follows, so that the content of the fasudil nitrogen oxide is strictly controlled. The related substances disclosed in fasudil hydrochloride at present are determined by an HPLC method (see the second part of the Chinese pharmacopoeia 2015), and the method comprises the following specific steps:
dissolving the related substances in mobile phase, and diluting to obtain solution containing 0.3mg per 1ml as test solution; the lml was measured precisely, placed in a 100ml measuring flask, diluted to the mark with the mobile phase, shaken up, and used as a control solution. Precisely measuring 5ml of the control solution, placing the control solution in a 100ml measuring flask, diluting the control solution to a scale with the mobile phase, and shaking up to obtain the sensitivity solution. Octadecylsilane chemically bonded silica is used as a filler, and 1.0% (v/v) triethylamine aqueous solution (pH value is adjusted to 7.0 by phosphoric acid) and methanol (50:50) (v/v) are used as a mobile phase; the detection wavelength was 275 nm. The theoretical plate number is not less than 3000 calculated according to fasudil hydrochloride peak. The separation degree of the fasudil hydrochloride peak and the adjacent impurity peak is in accordance with the requirement. And (3) taking 20 mu l of the sensitive solution, and injecting the solution into a liquid chromatograph to ensure that the signal-to-noise ratio of the chromatographic peak of the main component is not less than 10. Precisely measuring 20 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component chromatographic peak is 5 times. If an impurity peak exists in the chromatogram of the test solution, the area of a single impurity peak is not more than 0.1 time (0.1%) of the area of a main peak of the control solution (w/w), and the sum of the areas of the impurity peaks is not more than 1.0% of the area of the main peak of the control solution (w/w). The chromatographic peak smaller than the main peak area of the sensitivity solution in the chromatogram of the test solution is ignored (0.05%) (w/w).
The research shows that the method has the following defects in the actual operation process: the fasudil nitric oxide is coincided with the fasudil main peak.
Fasudil nitroxide
Disclosure of Invention
The invention aims to provide a method for detecting an impurity fasudil nitric oxide in fasudil hydrochloride, which has the advantages of good stability, good reproducibility, simple operation and high precision. The method is used for measuring fasudil oxynitride impurity in the medicine fasudil hydrochloride for treating, improving and preventing cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemia symptoms caused by the cerebral vasospasm, and is convenient and feasible, high in accuracy and small in harm to human bodies and environment.
The technical scheme adopted by the invention for realizing the aim is as follows:
a method for detecting and analyzing an impurity fasudil nitrogen oxide in fasudil hydrochloride comprises the steps of adopting a high performance liquid chromatography, dissolving and diluting fasudil hydrochloride by using a solvent into a solution containing 1-100 mg of fasudil hydrochloride in each 1ml of fasudil hydrochloride to serve as a test solution, injecting the solution into a high performance liquid chromatograph, wherein the sample injection volume is 5-100 mu l, an ultraviolet detector is used for detecting the wavelength of 210-350 nm, a methanol-water solution is used as a mobile phase, the flow rate of the mobile phase is 0.3-2.0 ml/min, and a stationary phase alkyl bonded silica gel chromatographic column is adopted for quantitatively determining the impurity fasudil nitrogen oxide in fasudil hydrochloride.
In one embodiment, fasudil hydrochloride is dissolved and diluted by a solvent to be a solution containing 1mg to 100mg of fasudil hydrochloride in each 1ml of fasudil hydrochloride as a test solution, wherein the solvent is a mobile phase or water, and is preferably a mobile phase; the concentration of the test solution is preferably 1-10 mg/ml.
In one embodiment, the flow rate of the mobile phase is 0.3-2.0 ml/min, preferably 1 ml/min.
In one embodiment, the mobile phase contains methanol in a volume proportion ranging from 5% to 80%, preferably 60%; the volume proportion range of the aqueous solution is 20-95%, and the optimal volume proportion range is 40%.
In one embodiment, the method for detecting and analyzing the fasudil nitric oxide as the impurity in the fasudil hydrochloride is characterized in that a high performance liquid chromatography is adopted, and the mass concentration range of the aqueous solution is 0.1-2%, and is preferably 1%.
In one embodiment, the aqueous solution is one or a combination of phosphoric acid solution, triethylamine solution and trifluoroacetic acid solution, and most preferably is triethylamine solution; the pH value of the water solution is 3-7.
In one embodiment, the injection volume is 5-100 μ l, preferably 10-100 μ l, and more preferably 20 μ l.
In one embodiment, the stationary phase is an alkyl-bonded silica gel column, preferably the stationary phase is an octadecyl-bonded silica gel column.
In one embodiment, the detection wavelength is 210nm to 350nm, preferably 220nm to 260nm, and more preferably 257 nm.
The invention has the beneficial effects that: the method utilizes convenient and rapid high performance liquid chromatography, adopts an ultraviolet detector, selects a proper mobile phase and a chromatographic column, and carries out quantitative analysis and detection on the fasudil nitric oxide serving as an impurity in the fasudil hydrochloride, fills the blank that the fasudil nitric oxide remains in the fasudil hydrochloride after salification and cannot be detected, and improves the detection means for controlling the quality of the fasudil hydrochloride product.
Drawings
FIG. 1 is a chromatogram of fasudil nitrogen oxide;
FIG. 2 is a chromatogram of a mixed sample of fasudil oxynitride and fasudil hydrochloride.
Detailed Description
The following examples illustrate the invention but do not limit it in any way.
The instrument comprises the following steps: the high performance liquid chromatograph comprises a liquid phase pump, an ultraviolet detector and a sample injector;
reagent: triethylamine (analytically pure), methanol (chromatographically pure);
a chromatographic column: octadecyl bonded silica gel chromatographic column.
Example 1:
measured according to high performance liquid chromatography (China pharmacopoeia 2015 edition four parts general rules 0512).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 1.0% triethylamine in water (pH adjusted to 7.0 with phosphoric acid) -methanol (20: 80) as mobile phase; the detection wavelength was 254 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: taking about 50mg of the product, precisely weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking uniformly to obtain a test solution; taking about 5mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 10ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring 20 mu l of each of the test solution and the reference solution, respectively injecting into a liquid chromatograph, recording a chromatogram with the flow rate of a mobile phase of 1ml/min, wherein FIG. 1 is a chromatogram of fasudil nitrogen oxide, and FIG. 2 is a chromatogram of a mixed sample of fasudil nitrogen oxide and fasudil hydrochloride. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Example 2:
the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 1.0% triethylamine in water (pH adjusted to 5.0 with phosphoric acid) -methanol (60: 40) as mobile phase; the detection wavelength was 257 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: weighing 100mg of the product, accurately weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking to obtain test solution; taking about 10mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 10ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring 10 μ l of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph at a mobile phase flow rate of 1ml/min, and recording chromatogram. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Example 3:
the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 1.0% triethylamine in water (pH 3.0 with phosphoric acid) -methanol (50:50) as mobile phase; the detection wavelength was 260 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: taking about 10mg of the product, precisely weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking uniformly to obtain a test solution; taking about 5mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 50ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring 100 μ l of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph at a mobile phase flow rate of 1ml/min, and recording chromatogram. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Example 4:
the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).
The chromatographic condition and system applicability test uses octyl silane bonded silica gel as filler; using 0.5% triethylamine water solution (pH adjusted to 7.0 with phosphoric acid) -methanol (20: 80) as mobile phase; the detection wavelength was 220 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: weighing 100mg of the product, accurately weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking to obtain test solution; taking about 10mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 10ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring the sample solution and the reference solution by 50 μ l each, injecting into a liquid chromatograph with mobile phase flow rate of 1ml/min, and recording chromatogram. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Example 5:
the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 1.0% triethylamine in water (pH 3.0 with phosphoric acid) -methanol (60: 40) as mobile phase; the detection wavelength was 257 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: taking about 20mg of the product, precisely weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking uniformly to obtain a test solution; taking about 5mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 25ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring 100 μ l of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph at a mobile phase flow rate of 1ml/min, and recording chromatogram. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Example 6:
the measurement is carried out according to high performance liquid chromatography (China pharmacopoeia 2015 edition of the general rules 0512 in four parts).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; 2.0% triethylamine in water (pH adjusted to 7.0 with phosphoric acid) -methanol (90: 10) was used as the mobile phase; the detection wavelength was 257 nm. The theoretical plate number is not less than 3000 calculated according to the nitrogen oxide peak of fasudil.
The determination method comprises the following steps: taking about 50mg of the product, precisely weighing, placing in a 10ml measuring flask, adding mobile phase for dissolving, diluting to scale, and shaking uniformly to obtain a test solution; taking about 5mg of fasudil nitrogen oxide reference substance, precisely weighing, placing in a 100ml measuring flask, adding mobile phase for dissolving, diluting to scale, shaking up, and taking as reference substance stock solution; precisely measuring 1ml of the reference stock solution, placing in a 50ml measuring flask, diluting with mobile phase to scale, shaking, precisely measuring 1ml, placing in a 10ml measuring flask, diluting with mobile phase to scale, and shaking to obtain reference solution. Precisely measuring 20 μ l of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph at a mobile phase flow rate of 1ml/min, and recording chromatogram. If a chromatographic peak consistent with the retention time of a fasudil nitric oxide peak exists in a chromatogram of a test solution, calculating the peak area according to an external standard method to obtain the product containing the fasudil nitric oxide, wherein the fasudil nitric oxide content is not more than 0.00167%.
Claims (10)
1. The method for detecting and analyzing the impurity fasudil nitrogen oxide in the fasudil hydrochloride is characterized in that the method comprises the steps of adopting a high performance liquid chromatography, dissolving and diluting the fasudil hydrochloride by using a solvent to obtain a solution containing 1-100 mg of fasudil hydrochloride in each 1ml of solution as a sample solution, injecting the solution into a high performance liquid chromatograph, wherein the sample injection volume is 5-100 mu l, using an ultraviolet detector, detecting the wavelength of 210-350 nm, using a methanol-water solution as a mobile phase, and the flow rate of the mobile phase is 0.3-2.0 ml/min, and adopting a stationary phase alkyl bonded silica gel chromatographic column to quantitatively determine the impurity fasudil nitrogen oxide in the fasudil hydrochloride.
2. The method of claim 1, wherein the aqueous solution is one or a combination of phosphoric acid solution, triethylamine solution and trifluoroacetic acid solution, preferably triethylamine solution; the pH value of the water solution is 3-7.
3. The method according to claim 1, wherein the solvent is a mobile phase or water, preferably a mobile phase.
4. The method of claim 1, wherein the concentration of the sample solution is 1-10 mg/ml.
5. The method of claim 1, wherein the mobile phase flow rate is 1 ml/min.
6. The process according to claim 1, characterized in that the mobile phase contains methanol in a proportion by volume ranging from 5% to 80%, preferably 60%; the volume proportion range of the aqueous solution is 20-95%, and preferably 40%.
7. The method of claim 1, wherein the aqueous solution has a mass concentration in the range of 0.1% to 2%, preferably 1%.
8. The method according to claim 1, wherein the injection volume is 10 to 100. mu.l, preferably 20. mu.l.
9. The method of claim 1, wherein the stationary phase is an octadecyl bonded silica chromatography column.
10. The method of claim 1, wherein the detection wavelength is 220 to 260nm, preferably 257 nm.
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