CN110441449A - In relation to the detection method of substance in Fasudic hydrochloride raw material or injection - Google Patents
In relation to the detection method of substance in Fasudic hydrochloride raw material or injection Download PDFInfo
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- CN110441449A CN110441449A CN201910749248.0A CN201910749248A CN110441449A CN 110441449 A CN110441449 A CN 110441449A CN 201910749248 A CN201910749248 A CN 201910749248A CN 110441449 A CN110441449 A CN 110441449A
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01N30/28—Control of physical parameters of the fluid carrier
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8624—Detection of slopes or peaks; baseline correction
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- G01N30/8634—Peak quality criteria
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Abstract
The present invention relates to the detection methods in relation to substance in Pharmaceutical Analysis technical field more particularly to Fasudic hydrochloride raw material or injection.The present invention provides effective component and the method for synthesising by-product in Fasudic hydrochloride bulk pharmaceutical chemicals or preparation is detected with HPLC standard measure, method accuracy provided by the invention is high, and high sensitivity is reproducible.Experiment shows, to in the detection of general impurity, it is no more than 5% using the RSD value of 5 needle peak area of method continuous sample introduction provided by the invention, to in the detection of genotoxicity impurity, the RSD value of 5 needle peak areas is no more than 10%, error is small between multiple sample test results, and detection data is consistent with desired value, and to Fasudic hydrochloride and its minimum detection limit in relation to substance is all lower than Quality Control requirement.
Description
Technical field
The present invention relates to substances related in Pharmaceutical Analysis technical field more particularly to Fasudic hydrochloride raw material or injection
Detection method.
Background technique
Fasudic hydrochloride is a kind of newtype drug with extensive pharmacological action, its molecular structure is 5- isoquinolin sulphur
Amide derivatives are RHO kinase inhibitor, by increasing the activity expansion blood vessel of Myosin light chain phosphatase, reduce endothelium
The tension of cell improves brain tissue microcirculation, does not generate and aggravates robber's blood of brain, at the same can antagonism inflammatory factor, protection is neural
Anti-apoptotic promotes nerve regneration.This mitigates clinical symptoms the result shows that recovery of the Fasudic hydrochloride to nervous function is promoted,
Reducing disability rate has certain curative effect.
In the process for synthesizing the compound, when the 5- isoquinoline sulfonyl chloride of homopiperazine and 2 molecules can produce by-product
Dimer, there is likely to be other in Fasudic hydrochloride in relation to substance,
Related substance that may be present in 1 Fasudic hydrochloride of table
Detection method of the existing Fasudic hydrochloride in relation to substance, some are excessively single, only detect a certain impurity
Composition, and some are then excessively extensive, only consider largest single impurity, total miscellaneous relationship with Fasudic hydrochloride principal component.It considers
Drug is a kind of specialty goods, and the content of each impurity and Toxicity Relationships are to the safety of people in drug, and it is therefore necessary to salt
Related substance in sour Fasudil raw material and its preparation establishes impurity analysis and the control of system.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing related in Fasudic hydrochloride raw material or injection
The detection method of substance.Detection method provided by the invention can be sufficiently separated the by-product in Fasudic hydrochloride and synthesis process
Object, accuracy is high, and reproducible, sensitivity is higher, can control for the quality of Fasudic hydrochloride and provide reliable foundation.
Fasudic hydrochloride provided by the invention and its detection method in relation to substance include: I) and/or II):
I), by Fasudic hydrochloride bulk pharmaceutical chemicals or formulation dissolution, using the aqueous solution containing triethylamine and acetonitrile as mobile phase A
Phase carries out Fasudic hydrochloride and related substance with HPLC method qualitative or quantitative using acetonitrile as Mobile phase B phase；
The elution program of the HPLC are as follows:
0min~10min mobile phase A phase volume fraction is 100%；
10min~20min mobile phase A phase volume fraction is by 100% to 75%；
20min~30min mobile phase A phase volume fraction is by 75% to 35%；
30.1min~10min mobile phase A phase volume fraction is 100%；
II), by Fasudic hydrochloride bulk pharmaceutical chemicals or formulation dissolution, using aqueous formic acid as mobile phase A phase, to contain formic acid
Acetonitrile be Mobile phase B phase, the genotoxicity impurity of Fasudic hydrochloride is carried out with HPLC-MS method qualitative or quantitative；
The elution program of the HPLC are as follows:
0.01min~0.1min mobile phase A phase volume fraction is 98%；
0.1min~1.3min mobile phase A phase volume fraction is by 98% to 2%；
1.3min~1.79min mobile phase A phase volume fraction is by 2%；
1.79min~1.8min mobile phase A phase volume fraction is by 2% to 98%；
1.8min~2.3min mobile phase A phase volume fraction is 98%；
The ion mode of the MS is ESI+.
Carrying out quantitative detection to substance using high performance liquid chromatography (HPLC) is currently used detection method, in face of needing
When carrying out quantitative analysis to effective component in Fasudic hydrochloride bulk pharmaceutical chemicals or preparation and the content of synthesising by-product, using height
Effect liquid phase chromatogram is a kind of quickly and effectively mode.But in the prior art, there is no any methods adequately to divide
From Fasudic hydrochloride and its by-product, therefore, needs when being detected using HPLC to Fasudic hydrochloride and its by-product
Various identifications such as repeatability, accuracy, sensitivity are carried out to this method, specifically:
I) blank solvent does not interfere at the retention time of Fasudic hydrochloride and all known impurities.If so, then peak
Area is not more than the 1% of contrast solution peak area.Separating degree in system suitability solution between impurity 8 and impurity 10 is not less than
1.0.The RSD of Fasudic hydrochloride peak area is not more than 5% in continuous 5 needle reference substance solution.
II) blank solvent does not interfere at the retention time of 5- isoquinolin sulfonic acid.The chromatogram of sensitivity solution
In, the signal-to-noise ratio of 5- isoquinolin sulfonic acid should be greater than 10.In reference substance solution chromatogram, 5- in continuous 5 needle reference substance solution
The RSD of isoquinolin sulfonic acid peak area is not more than 10%.
I in), the diluent of the dissolution is 1.5% triethylamine (pH5.4): acetonitrile=85:15；
II in), the diluent of the dissolution is 70% acetonitrile.
Liquid chromatogram be sample component between column packing and mobile phase mass exchange and achieve the purpose that separate, therefore want
It asks flowing relative sample that there is certain solvability and does not generate chemical reaction with sample, viscosity is small as far as possible, so as to
To good separating effect；And the physico-chemical property of mobile phase will be adapted with the detector used.UV detector is such as used, then is answered
It is prepared using to the lower solvent of UV absorption.Its boiling point can not ether it is low, be otherwise easy to produce bubble, cause experiment can not be into
Row.For Fasudic hydrochloride and its related substance, carrying out gradient elution with mobile phase provided by the invention can guarantee
Better detection effect, better than the testing result of other mobile phases.
I in):
The mobile phase A is mutually made of the aqueous solution and acetonitrile of 1.5wt% triethylamine,
The aqueous solution of the 1.5wt% triethylamine and the volume ratio of acetonitrile are 87:13.
II in):
In the mobile phase A phase, the volume fraction of formic acid is 0.1%；
In the Mobile phase B phase, the volume fraction of formic acid is 0.1%.
For method provided by the invention, according to Fasudic hydrochloride and its polarity in relation to substance selects chromatographic column.
The size of chromatographic column can have an impact separating resulting, and internal diameter can have an impact the flow velocity of mobile phase, the shorter color of length
It is short to compose column runing time, column pressure is lower；The longer chromatography column resolution original text of length, but runing time increases.
I in), the chromatographic column of HPLC detection is octadecylsilane chemically bonded silica column.
I in) size of chromatographic column be 4.6 × 250mm, 5 μm, specifically, the chromatographic column used is YMC-Pack Pro
C18。
II in), the chromatographic column of HPLC detection is C8 chromatographic column.
II the size of chromatographic column is 5 μm of 4.6*50mm in), specifically, the chromatographic column used is Diamonsil C8.
The flow velocity of mobile phase is excessively high to reduce the number of plates, and the reduction of the number of plates will lead to the reduction of sample separating degree.It is right
The selection of column temperature need to consider the characteristic of substance to be separated itself, and column temperature, which influences mobile phase, also will affect the solubility of test substance
Column pressure.Under normal circumstances, it improves column temperature to be conducive to improve separating degree, but the excessively high column that will lead to of temperature presses through low, is unfavorable for substance
Detection.The use UV detector of high performance liquid chromatography, Detection wavelength need to be arranged according to the ultraviolet absorpting spectrum of determinand.
I in), HPLC testing conditions include: 30 DEG C of column temperature, flow rate of mobile phase 1mL/min, Detection wavelength 275nm, sample introduction body
20 μ L of product；
II in), HPLC testing conditions include: 25 DEG C of column temperature, flow rate of mobile phase 0.9mL/min, 10 μ L of sampling volume.
II in), MS testing conditions include: that first mass spectrometric ion Q1 is 238.3, and first mass spectrometric ion Q3 is 210.2, remove cluster
Voltage DP is 80, and impact energy CE is 24eV.
I in),
The appearance time of Fasudic hydrochloride is 10.229min,
The appearance time of 5- isoquinoline sulfonyl chloride hydrochloride is 6.035min,
The appearance time of dimer is 28.626min,
The appearance time of 8 position isomer derivatives is 12.756min,
The appearance time of degradation impurity is 21.015min,
The appearance time of 5- isoquinoline sulfonate moiety is 6.035min,
The appearance time of the chloro- 5- isoquinoline sulfonyl chloride derivative of 1- is 20.748min.
II in),
The appearance time of 5- isoquinolin sulfonic acid is that first mass spectrometric ion Q1 is 238.3, and first mass spectrometric ion Q3 is
210.2。
I in) or II), the Fasudic hydrochloride bulk pharmaceutical chemicals or the content of preparation of being dissolved to are 0.5mg/mL.
In the present invention, external standard method is used to Fasudic hydrochloride and its quantitative of related substances.
The present invention provides detect effective component and synthesis in Fasudic hydrochloride bulk pharmaceutical chemicals or preparation with HPLC standard measure
The method of by-product, method accuracy provided by the invention is high, and high sensitivity is reproducible.Experiment shows to general impurity
In detection, it is no more than 5% using the RSD value of 5 needle peak area of method continuous sample introduction provided by the invention, to genotoxicity impurity
In detection, the RSD value of 5 needle peak areas is no more than 10%, and error is small between multiple sample test results, detection data and desired value phase
Symbol, to Fasudic hydrochloride and its minimum detection limit in relation to substance is all lower than Quality Control requirement.
Detailed description of the invention
The chromatogram of Tu1Shi first part；
Fig. 2 shows the chromatogram and mass spectrogram of second part.
Specific embodiment
The present invention provides the detection method in relation to substance in Fasudic hydrochloride raw material or injection, those skilled in the art
Member can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications
Apparent to those skilled in the art, they are considered as being included in the present invention.Method and application of the invention
Be described by preferred embodiment, related personnel obviously can not depart from the content of present invention, in spirit and scope it is right
Methods herein and application are modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
Instrument that the present invention uses, test material are all common commercially available product, can all be bought in market.
Below with reference to embodiment, the present invention is further explained:
Embodiment 1
First part is miscellaneous using 6 in high-efficient liquid phase chromatogram technique analysis and control Fasudic hydrochloride raw material and its preparation
The method of matter (impurity 1, impurity 3, impurity 5, impurity 8, impurity 9, impurity 10) limit.Include the following steps:
(1) it takes Fasudic hydrochloride raw material diluent to dissolve and is diluted to the molten of the hydrochloric Fasudil 0.5mg of every 1ml
Liquid, as test solution.
(2) each impurity (impurity 3, impurity 5, impurity 8, impurity 9 and impurity 10) is taken to be dissolved and diluted with diluent respectively
To the solution of the impure 5 μ g of every 1ml, as impurity stock solution.
(3) precision weighs Fasudic hydrochloride about 5mg, sets in 10ml measuring bottle, and precision pipettes impurity stock solution 1.0ml, uses
Diluent dissolves and is diluted to scale, shakes up, as system suitability solution.
(4) it takes Fasudic hydrochloride diluent to dissolve and is diluted to the molten of the hydrochloric Fasudil 0.005mg of every 1ml
Liquid, as reference substance solution.
(5) above-mentioned solution is taken, is injected in high performance liquid chromatograph, chromatogram is recorded.
(6) chromatographic condition:
2 chromatographic condition of table
(7) testing result:
Blank solvent does not interfere at the retention time of Fasudic hydrochloride and all known impurities.If so, then peak face
Product is not more than 1% (Fig. 1) of contrast solution peak area.
Separating degree in system suitability solution between impurity 8 and impurity 10 is not less than 1.0.
The separating degree that table 3 detects
| Title | Appearance time | Relative retention time | Separating degree |
| Impurity 9 | 6.035 | 0.59 | / |
| Fasudil | 10.229 | 1.00 | 17.9 |
| Unknown impuritie | 12.296 | 1.20 | 6.8 |
| Impurity 5 | 12.756 | 1.24 | 1.5 |
| Impurity 10 | 20.748 | 2.03 | 36.2 |
| Impurity 8 | 21.015 | 2.05 | 2.1 |
| Impurity 3 | 28.626 | 2.80 | 59.2 |
The RSD of Fasudic hydrochloride peak area is 0.2% in continuous 5 needle reference substance solution.
The average value and RSD for the peak area that table 4 detects
| Number | Peak area |
| STD-01 | 96225 |
| STD-02 | 96397 |
| STD-03 | 95978 |
| STD-04 | 96189 |
| STD-05 | 96197 |
| Average value | 96197 |
| RSD% | 0.2 |
Chromatographic peak in deduction system and blank solution is calculated by the principal component reference substance external standard method of the correction up factor, is supplied
If any impurity peaks in the chromatogram of test sample solution, single impurity must not cross 0.1%, and total impurities should must not cross 1.0%.
Each lowest detection in relation to substance is limited to 0.071 μ g/ml, and linearly interval is 0.24 μ of μ g/ml~1.42 g/ml.
Second part is using high performance liquid chromatography-mass spectrometry technology, to Fasudic hydrochloride genotoxicity impurity 5-
The limit method being analyzed and controlled of isoquinolin methylmesylate, 5- isoquinolin sulfonic acid.
(1) 5- isoquinolin methylmesylate, 5- isoquinolin sulfonic acid about 2mg are taken, it is accurately weighed, it sets in 200ml measuring bottle, uses
Diluent dissolves and is diluted to scale, shakes up；Precision pipettes 1.0ml, sets in 200ml measuring bottle, is diluted to scale with diluent, shakes
Even, precision pipettes 3.0ml, sets in 20ml measuring bottle, is diluted to scale with diluent, shakes up, as reference substance solution.
(2) it takes Fasudic hydrochloride raw material or preparation diluent to dissolve and is diluted to the hydrochloric Fasudil of every 1ml
The solution of 0.5mg, as test solution.
(3) precision pipettes 1.0ml reference substance stock solution, sets in 50ml measuring bottle, is diluted to scale with diluent, shakes up, and makees
For sensitivity solution.
(4) above-mentioned solution is taken, injection reaches the liquid chromatography mass system of system suitability requirement, records chromatogram.
(5) liquid chromatogram and Mass Spectrometry Conditions
5 liquid chromatogram of table and Mass Spectrometry Conditions
(6) blank solvent does not interfere with (Fig. 2) at the retention time of 5- isoquinolin sulfonic acid.
In the chromatogram of sensitivity solution, the detection limit concentration of 5- isoquinolin sulfonic acid is 0.154ng/ml, concentration water
It puts down as 0.3ppm, signal-to-noise ratio 6.7；Line of the 5- isoquinolin sulfonic acid in 1.03ng/ml~10.25ng/ml concentration range
Property equation be y=10660x-73400, correlation coefficient r 0.9950.
In reference substance solution chromatogram, the RSD of 5- isoquinolin sulfonic acid peak area is in continuous 5 needle reference substance solution
5.1%.
6 peak area of table and RSD
The content that 5- isoquinolin sulfonic acid in test solution is calculated by external standard method, should be less than 15ppm.
The above is only the preferred embodiment of the present invention, it is noted that those skilled in the art are come
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (10)
1. Fasudic hydrochloride and its detection method in relation to substance characterized by comprising I) and/or II):
I): by Fasudic hydrochloride bulk pharmaceutical chemicals or formulation dissolution, using the aqueous solution containing triethylamine and acetonitrile as mobile phase A phase,
Using acetonitrile as Mobile phase B phase, Fasudic hydrochloride and related substance are carried out with HPLC method qualitative or quantitative；
The elution program of the HPLC are as follows:
0min~10min mobile phase A phase volume fraction is 100%；
10min~20min mobile phase A phase volume fraction is by 100% to 75%；
20min~30min mobile phase A phase volume fraction is by 75% to 35%；
30.1min~10min mobile phase A phase volume fraction is 100%；
II): by Fasudic hydrochloride bulk pharmaceutical chemicals or formulation dissolution, using aqueous formic acid as mobile phase A phase, with the second containing formic acid
Nitrile is Mobile phase B phase, is carried out with genotoxicity impurity of the HPLC-MS method to Fasudic hydrochloride qualitative or quantitative；
The elution program of the HPLC are as follows:
0.01min~0.1min mobile phase A phase volume fraction is 98%；
0.1min~1.3min mobile phase A phase volume fraction is by 98% to 2%；
1.3min~1.79min mobile phase A phase volume fraction is by 2%；
1.79min~1.8min mobile phase A phase volume fraction is by 2% to 98%；
1.8min~2.3min mobile phase A phase volume fraction is 98%；
The ion mode of the MS is ESI+.
2. detection method according to claim 1, which is characterized in that
I in), the diluent of the dissolution is 1.5% triethylamine (pH5.4): acetonitrile=85:15；
II in), the diluent of the dissolution is 70% acetonitrile.
3. detection method according to claim 1, which is characterized in that I) in:
The mobile phase A is mutually made of the aqueous solution and acetonitrile of 1.5wt% triethylamine,
The aqueous solution of the 1.5wt% triethylamine and the volume ratio of acetonitrile are 87:13.
4. detection method according to claim 1, which is characterized in that II) in:
In the mobile phase A phase, the volume fraction of formic acid is 0.1%；
In the Mobile phase B phase, the volume fraction of formic acid is 0.1%.
5. detection method according to claim 1, which is characterized in that
I in), the chromatographic column of HPLC detection is octadecylsilane chemically bonded silica column；
II in), the chromatographic column of HPLC detection is C8 chromatographic column.
6. detection method according to claim 1, which is characterized in that
I in), HPLC testing conditions include: 30 DEG C of column temperature, flow rate of mobile phase 1mL/min, Detection wavelength 275nm, sampling volume 20
μL；
II in), HPLC testing conditions include: 25 DEG C of column temperature, flow rate of mobile phase 0.9mL/min, 10 μ L of sampling volume.
7. detection method according to claim 1, which is characterized in that II) in, MS testing conditions include: first mass spectrometric from
Sub- Q1 is 238.3, and first mass spectrometric ion Q3 is 210.2, and removing cluster voltage DP is 80, and impact energy CE is 24eV.
8. detection method according to claim 1, which is characterized in that I) in,
The appearance time of Fasudic hydrochloride is 10.229min,
The appearance time of 5- isoquinoline sulfonyl chloride hydrochloride is 6.035min,
The appearance time of dimer is 28.626min,
The appearance time of 8 position isomer derivatives is 12.756min,
The appearance time of degradation impurity is 21.015min,
The appearance time of 5- isoquinoline sulfonate moiety is 6.035min,
The appearance time of the chloro- 5- isoquinoline sulfonyl chloride derivative of 1- is 20.748min.
9. detection method according to claim 1, which is characterized in that II) in,
The appearance time of 5- isoquinolin sulfonic acid is that first mass spectrometric ion Q1 is 238.3, and first mass spectrometric ion Q3 is 210.2.
10. detection method according to claims 1 to 9, which is characterized in that I) or II) in, it is described be dissolved to hydrochloric acid method relax
The content of ground that bulk pharmaceutical chemicals or preparation is 0.5mg/mL.
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| CN111624276A (en) * | 2020-05-18 | 2020-09-04 | 北京阳光诺和药物研究股份有限公司 | Method for simultaneously detecting genotoxic impurities 5-isoquinoline methyl sulfonate and 5-isoquinoline ethyl sulfonate in fasudil hydrochloride |
| CN112684038A (en) * | 2020-12-11 | 2021-04-20 | 河南省科学院高新技术研究中心 | Method for detecting 5-isoquinoline ethyl sulfonate in fasudil hydrochloride |
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| CN113358759B (en) * | 2020-03-05 | 2022-11-18 | 昆药集团股份有限公司 | Method for detecting related substances in fasudil hydrochloride starting material |
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| CN111624276B (en) * | 2020-05-18 | 2021-04-09 | 北京阳光诺和药物研究股份有限公司 | Method for simultaneously detecting genotoxic impurities 5-isoquinoline methyl sulfonate and 5-isoquinoline ethyl sulfonate in fasudil hydrochloride |
| CN112684038A (en) * | 2020-12-11 | 2021-04-20 | 河南省科学院高新技术研究中心 | Method for detecting 5-isoquinoline ethyl sulfonate in fasudil hydrochloride |
| CN112684038B (en) * | 2020-12-11 | 2022-03-22 | 河南省科学院高新技术研究中心 | Method for detecting 5-isoquinoline ethyl sulfonate in fasudil hydrochloride |
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