CN103969344A - Method for detecting related substances in chemical drug - Google Patents
Method for detecting related substances in chemical drug Download PDFInfo
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- CN103969344A CN103969344A CN201310030718.0A CN201310030718A CN103969344A CN 103969344 A CN103969344 A CN 103969344A CN 201310030718 A CN201310030718 A CN 201310030718A CN 103969344 A CN103969344 A CN 103969344A
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Abstract
The present invention relates to a detection method for related substances in a chemical drug oxiracetam. According to the present invention, a set of the reliable, stable and completely-new related substance detection method is provided for the bulk drug and the preparation thereof, such that the process control of the bulk drug and the preparation thereof is stringent and reasonable, the quality is stable, and the guarantee is provided for effectiveness and safety of medication on patients.
Description
Technical field
The present invention is a kind of method that detects related substance in chemicals Oxiracetam, belongs to the technical field of medicine.
Background technology
Oxiracetam is synthetic first in 1974 by Italian SmithKline Bi Qiemu company; this medicine is the novel medicine for central nervous system that a class can promote ability of learning and memory; can optionally act on cerebral cortex and hippocampus; activate, protect or promote the functional rehabilitation of neurocyte; and itself is without direct vasoactive; also without central excitation effect, be a kind of lasting facilitation to the improvement of ability of learning and memory.Oxiracetam only acts on central nervous system, can improve brain generation, strengthen and promote juvenile intelligence, improve the complete and memory disorder of old cerebral function, treatment neurosis and mental act disorder, especially senile dementia, be U.S. FDA approval be used for the treatment of one of medicine of senile dementia.Also can be used for the rehabilitation of the brain diseases such as brain trauma, encephalitis.
Oxiracetam formulation is more, as conventional parenteral solution is applicable to the treatment of the disease such as brain damage and the neurological deficit causing, memory and disturbance of intelligence, Patients With Hypertensive Cerebral Hemorrhage, Medium or severe type patients with sevious craniocerebral injury, light, moderate Alzheimer's disease, dementia, children cerebral palsy patient and Patients with Chronic Schizophrenia are all had to certain curative effect.The demonstration of control experiment result, Oxiracetam curative effect is better than similar nootropic Piracetam.And Oxiracetam toxicity is extremely low, there is fabulous tolerance and there is the effect of the unexistent Antithrombin III of Piracetam, there is extremely wide application prospect.
No matter be medicinal chemicals or pharmaceutical preparation, all must ensureing on the controlled basis of constant product quality constantly more new development.Chemicals is synthetic at initiation material, technique, all may bring or produce new organic impurities in preparation and the process deposited, therefore find that method is easy, specificity is strong, favorable reproducibility, the high method of inspection of accuracy, guarantee that the impurity that medicine produces under any approach can accurately be detected, the guarantee people's drug safety, concerning enterprise and inspection department, it is also ideal selection.Chemicals, its impurity mainly comprises initiation material, process contaminants, degradation impurity.In order to ensure product quality, the impurity that any approach be produced all detects one by one, needs objective effective detection method.The initiation material of Oxiracetam is 4-chloro-3-hydroxyl-ethyl butyrate, may bring in the middle of final product in the process of producing.
At present Oxiracetam related substances detection method, be mainly in the middle of Oxiracetam product detected come impurity carried out overall control, not to single impurity carry out qualitative, determine quantitative analysis.The invention provides a kind of detection method, carried out qualitative analysis for the initiation material 4-chloro-3-hydroxyl-ethyl butyrate that may be brought in Oxiracetam finished product, and carried out the methodology checking of system.
Summary of the invention
The object of the invention is to: the detection method that a kind of chemicals related substance is provided, this method provides the index of detection, means, the technical method etc. of detection for following product to relevant production, testing agency, to better control the quality of said preparation, ensure the security of medication, can better instruct production, make controlling of production process more strict rationally, make the consumer can full appreciation product quality, institute's pin be Oxiracetam raw material and preparation thereof to product.
The present invention forms like this: adopt high performance liquid chromatography to detect the related substance 4-chloro-3-hydroxyl-ethyl butyrate in chemicals Oxiracetam, with cyano group bonded silica gel be filling agent; Methanol-water solution is mobile phase; Major component Self-control method is carried out quantitatively.The detection wavelength adopting is 205nm-215nm, is preferably 210nm.Described mobile phase methanol-aqueous solution proportioning is 35-45: 55-65, is preferably 38-42: 58-62.Described flow rate of mobile phase is 0.4-0.8ml/min, is preferably 0.5-0.7ml/min.The chromatographic column column temperature adopting is 25-40 DEG C.
Furtherly, method of testing is as follows: according to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (35-45:55-65) is mobile phase; Detect wavelength 210 ± 5nm; Column temperature 25-40 DEG C; Flow 0.4-0.8ml/min; Precision takes the western smooth bulk drug of load difficult to understand or preparation appropriate (being equivalent to Oxiracetam 40mg), adds deionized water dissolving and is diluted to the solution of every 1ml containing Oxiracetam 4mg, as need testing solution.By 1000 times of need testing solution dilutions, solution in contrast.Precision measures test solution and the each 10-20 μ of contrast solution l again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method quantitatively to detect.
Concrete method of testing is as follows: according to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (35-45:55-65) is mobile phase; Detect wavelength 210 ± 5nm; Column temperature 25-40 DEG C; Flow 0.4-0.8ml/min; Precision takes Oxiracetam bulk drug or preparation appropriate (being equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method quantitatively to detect.
The applicant is through lot of experiments, and the method providing is applicable to the detection method of this product.Selection such as column temperature: adopt 20 DEG C of column temperatures to detect, chromatographic peak retention time is longer, the hangover of peak type; While adopting 50 DEG C of column temperatures to detect, chromatographic peak retention time is shorter, causes chromatographic peak degree of separation not reach requirement, and therefore, column temperature does not all reach testing requirement in the time of 20 DEG C and 50 DEG C.Such as the selection of mobile phase, adopt methanol-water (30:70) to detect, chromatographic peak retention time is longer, and peak type is asymmetric; Adopt methanol-water (50:50) to detect, it is very fast that chromatographic peak goes out peak, between peak and peak, do not reach completely and separate, and therefore mobile phase does not all reach testing requirement in the time of methanol-water (30:70) and methanol-water (50:50).
The method research of experimental example related substance inspection
This product is as bulk drug, and impurity mainly comprises initiation material, process contaminants and degradation impurity, and for the initiation material that may be brought in finished product, we have set up effective detection method, and carries out comprehensive methodology checking.
1, drafting of chromatographic condition
Detection wavelength is determined: adopt ultraviolet spectrophotometer between 190-400nm, to carry out uv scan to Oxiracetam and 4-chloro-3-hydroxyl-ethyl butyrate, result shows that absorption maximum is at 190nm to 200nm.Consider that end absorbs interference more, selected 210nm is as detecting wavelength.
The polarity of considering in addition 4-chloro-3-hydroxyl-ethyl butyrate is less, and this experimental selection methanol-water (40: 60) is mobile phase, 30 DEG C of column temperatures, and flow velocity is 0.6ml/min.With this understanding, 4-chloro-3-hydroxyl-ethyl butyrate and Oxiracetam main peak degree of separation are more excellent, separate more complete.
Testing conditions is carried out to methodology checking below.
2, methodology checking
The detection of 2.1 impurity 4-chloro-3-hydroxyl-ethyl butyrates
2.1.1 chromatographic condition
Mobile phase: methanol-water (40: 60)
Flow velocity: 0.6ml/min
Column temperature: 30 DEG C.
2.1.2 specificity is investigated
2.1.2.1 Oxiracetam and 4-chloro-3-hydroxyl-ethyl butyrate degree of separation
Get Oxiracetam, 4-chloro-3-hydroxyl-ethyl butyrate each appropriate, dissolves and dilute with methanol-water (40: 60) and make mixed solution, get 20 μ l, injection high performance liquid chromatograph, the each peak-to-peak degree of separation of result demonstration all meets the requirements.
2.1.3 lowest detectable limit and minimum quantitative limit
Measure with reference to the signal to noise ratio (S/N ratio) method under 2010 editions two annex XIX A detectabilities of Chinese Pharmacopoeia.Precision takes Oxiracetam standard items 8.7mg, 4-chloro-3-hydroxyl-ethyl butyrate 10.5mg, uses respectively methanol-water (4: 6) constant volume in 10ml volumetric flask, and sesquialter is diluted as solution to be measured.Measure reference substance solution 20 μ l, inject high performance liquid chromatograph, record peak height, getting signal to noise ratio (S/N ratio) and be 10 concentration is minimum quantitative limit, and the concentration that signal to noise ratio (S/N ratio) is 3 is minimum detectable level.Recording result is: Oxiracetam minimum detection is limited to 3ng, and minimum is quantitatively limited to 6ng; 4-chloro-3-hydroxyl-ethyl butyrate minimum detection is limited to 10.6ng, and minimum is quantitatively limited to 15.8ng.
2.1.4 tolerance experiment
Carry out tolerance experiment, investigate the tolerance of Oxiracetam related substance inspection method.
Sample preparation: concentration value of detecting of 4-chloro-3-hydroxyl-ethyl butyrate must not exceed 0.5% of test liquid, therefore, the concentration of preparation mixed solution is: Oxiracetam 3.94mg/ml, 4-chloro-3-hydroxyl-ethyl butyrate 0.02mg/ml (concentration of 4-chloro-3-hydroxyl-ethyl butyrate be about Oxiracetam 0.5%).
Flow velocity: with the mobile phase condition of drafting, with different flow velocity 0.5ml/min, 0.6ml/min, 0.7ml/min, sample introduction 20 μ l respectively, record chromatogram, from collection of illustrative plates, the degree of separation of Oxiracetam main peak and impurity is all more than 1.5, post is imitated without significant change, retention time shortens with the increase of flow velocity, and flow velocity increases post and presses also obviously increase, and considering selected flow velocity is 0.6ml/min.
Column temperature: with the mobile phase condition of drafting, 30 DEG C of different column temperatures, 35 DEG C, at 40 DEG C, sample introduction 20 μ l respectively, record chromatogram, from collection of illustrative plates, the degree of separation of Oxiracetam main peak impurity is all more than 1.5, and post is imitated without significant change, retention time is not obvious with the increase of column temperature, therefore finally select 30 DEG C of conventional column temperatures.
Mobile phase ratio: with flow velocity, the column temperature drafted, change mobile phase ratio 38: 62,40: 60,42: 58, sample introduction 20 μ l, record chromatogram, from collection of illustrative plates respectively, under three ratios, the degree of separation of Oxiracetam main peak and impurity is all more than 1.5, and considering final selective flow phase ratio is 40: 60.
Finally draft condition: IntersilCN-3 post (5 μ m, 4.6*250mm, GL Sciences Inc.) is fixing phase, and methanol-water (40: 60) is mobile phase, and flow velocity is 0.6ml/min, 30 DEG C of column temperatures.
Above serviceability test result shows that the durability of this method is better, and at present definite testing conditions is feasible.
2.1.5 related substance inspection
Precision takes four crowdes of about 40mg of Oxiracetam bulk drug respectively, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, as need testing solution.Precision measures 1ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.
Get contrast solution 20 μ l, inject high performance liquid chromatograph, regulate detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.
Result shows, does not all detect 4-chloro-3-hydroxyl-ethyl butyrate in four batch samples.See shown in accompanying drawing 1-8.
Brief description of the drawings
Below in conjunction with drawings and Examples, the present invention is further described.
Fig. 1 is that the 1st batch of related substance of Oxiracetam raw material checks 0.1% contrast liquid HPLC collection of illustrative plates (CN-3 post)
Fig. 2 is that the 1st batch of related substance of Oxiracetam raw material checks test solution HPLC collection of illustrative plates (CN-3 post)
Fig. 3 is that the 2nd batch of related substance of Oxiracetam raw material checks 0.1% contrast liquid HPLC collection of illustrative plates (CN-3 post)
Fig. 4 is that the 2nd batch of related substance of Oxiracetam raw material checks test solution HPLC collection of illustrative plates (CN-3 post)
Fig. 5 is that the 3rd batch of related substance of Oxiracetam raw material checks 0.1% contrast liquid HPLC collection of illustrative plates (CN-3 post)
Fig. 6 is that the 3rd batch of related substance of Oxiracetam raw material checks test solution HPLC collection of illustrative plates
Fig. 7 is that the 4th batch of related substance of Oxiracetam raw material checks 0.1% contrast liquid HPLC collection of illustrative plates (CN-3 post)
Fig. 8 is that the 4th batch of related substance of Oxiracetam raw material checks test solution HPLC collection of illustrative plates (CN-3 post)
Concrete embodiment
Embodiment 1: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision takes the about 40mg of Oxiracetam bulk drug, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 2: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (38:62) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.7ml/min; Precision takes the about 40mg of Oxiracetam bulk drug, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 3: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (42:58) is mobile phase; Detect wavelength 210nm; 35 DEG C of column temperatures; Flow 0.5ml/min; Precision takes Oxiracetam bulk drug, puts in volumetric flask, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 4: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (35:65) is mobile phase; Detect wavelength 210nm; 25 DEG C of column temperatures; Flow 0.8ml/min; Precision takes Oxiracetam bulk drug, puts in volumetric flask, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 5: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (45:55) is mobile phase; Detect wavelength 210nm; 40 DEG C of column temperatures; Flow 0.4ml/min; Precision takes the about 40mg of Oxiracetam bulk drug, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 6: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 215nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision takes the about 40mg of Oxiracetam bulk drug, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 7: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in Oxiracetam bulk drug
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 205nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision takes the about 40mg of Oxiracetam bulk drug, puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 8: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision measures oxiracetam injection appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 9: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (38:62) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.7ml/min; Precision measures oxiracetam injection appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 10: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (42:58) is mobile phase; Detect wavelength 210nm; 35 DEG C of column temperatures; Flow 0.5ml/min; It is appropriate that precision measures oxiracetam injection, puts in volumetric flask, adds deionized water dissolving and be diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 11: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (35:65) is mobile phase; Detect wavelength 210nm; 25 DEG C of column temperatures; Flow 0.8ml/min; It is appropriate that precision measures oxiracetam injection, puts in volumetric flask, adds deionized water dissolving and be diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 12: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (45:55) is mobile phase; Detect wavelength 210nm; 40 DEG C of column temperatures; Flow 0.4ml/min; Precision measures oxiracetam injection appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 13: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 215nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision measures oxiracetam injection appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 14: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in oxiracetam injection
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 205nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision measures oxiracetam injection appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 15: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision takes this product powder appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 16: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (38:62) is mobile phase; Detect wavelength 210nm; 30 DEG C of column temperatures; Flow 0.7ml/min; Precision takes this product powder appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 17: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (42:58) is mobile phase; Detect wavelength 210nm; 35 DEG C of column temperatures; Flow 0.5ml/min; Precision takes this product powder appropriate (being approximately equivalent to Oxiracetam 40mg), puts in volumetric flask, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 18: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (35:65) is mobile phase; Detect wavelength 210nm; 25 DEG C of column temperatures; Flow 0.8ml/min; It is appropriate that precision takes this product powder, puts in volumetric flask, adds deionized water dissolving and be diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 19: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (45:55) is mobile phase; Detect wavelength 210nm; 40 DEG C of column temperatures; Flow 0.4ml/min; Precision takes this product powder appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 20: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 215nm; 30 DEG C of column temperatures; Flow 0.6ml/min; It is appropriate that precision takes this product powder, puts in 10ml measuring bottle, adds deionized water dissolving and be diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Embodiment 21: the detection method of impurity 4-chloro-3-hydroxyl-ethyl butyrate in injection Oxiracetam
According to high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water (40:60) is mobile phase; Detect wavelength 205nm; 30 DEG C of column temperatures; Flow 0.6ml/min; Precision takes this product powder appropriate (being approximately equivalent to Oxiracetam 40mg), puts in 10ml measuring bottle, adds deionized water dissolving and is diluted to scale, shakes up, as need testing solution.Precision measures 1.0ml, puts in 100ml measuring bottle, adds deionized water and is diluted to scale, shakes up, and precision measures 1.0ml, puts in 10ml measuring bottle, adds deionized water and is diluted to scale, shakes up, in contrast solution.Get contrast solution 20 μ l, injection liquid chromatography, regulates detector sensitivity, making major component peak height is 10% of full scale, precision measures need testing solution and the each 20 μ l of contrast solution again, injects high performance liquid chromatograph, records chromatogram to the more than 3 times of major component peak retention time.Adopt major component Self-control method to carry out quantitatively, result shows that impurity 4-chloro-3-hydroxyl-ethyl butyrate does not detect.
Claims (8)
1. a method that detects related substance in chemicals Oxiracetam, is characterized in that: adopt high performance liquid chromatography, with cyano group bonded silica gel be filling agent; Methanol-water solution is mobile phase; Major component Self-control method is carried out quantitatively.
2. the detection method described in 1 as requested, is characterized in that: the detection wavelength of employing is 205nm-215nm.
3. the detection method described in 2 as requested, is characterized in that: the detection wavelength of employing is preferably 210nm.
4. the detection method described in 1 as requested, is characterized in that: described mobile phase methanol-aqueous solution proportioning is 35-45:55-65.
5. the detection method described in 4 as requested, is characterized in that: described mobile phase methanol-aqueous solution proportion optimization is 38-42:58-62.
6. the detection method described in 1 as requested, is characterized in that: described flow rate of mobile phase is 0.4-0.8ml/min.
7. the detection method described in 6 as requested, is characterized in that: described flow rate of mobile phase is preferably 0.5-0.7ml/min.
8. the detection method described in 1 as requested, is characterized in that: the chromatographic column column temperature of employing is 25-40 DEG C.
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