CN109765316A - A method of detecting right etiracetam from drug - Google Patents
A method of detecting right etiracetam from drug Download PDFInfo
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- CN109765316A CN109765316A CN201910106141.4A CN201910106141A CN109765316A CN 109765316 A CN109765316 A CN 109765316A CN 201910106141 A CN201910106141 A CN 201910106141A CN 109765316 A CN109765316 A CN 109765316A
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Abstract
The invention discloses the methods that right etiracetam (R- isomers) is detected from levetiracetam injection, qualitative or/and quantitative detection is carried out to R- isomers using the method for high performance liquid chromatography, the testing conditions of liquid chromatogram include: chromatographic column: cellulose-three (3,5- dichlorophenyl carbamate) silicagel column；Mobile phase: n-hexane, dehydrated alcohol；Wherein, n-hexane (vol.%): dehydrated alcohol (vol.%)=90~70: 10~30；Mobile phase uses isocratic elution.The right etiracetam in levetiracetam injection can be effectively detected using method of the invention, and there is specificity and stability to indicate ability.And detected after can directly diluting levetiracetam injection, it is convenient and efficient without carrying out pre-treatment to sample；The method of the present invention detection limit reaches 0.003%, and quantitative limit reaches 0.005%, accurate sensitive.
Description
Technical field
The present invention relates to checked for impurities fields in drug, more particularly to the method for detecting right etiracetam in drug.
Background technique
Levetiracetam (Levetiracetam), it is one that alias is happy all for La Xitan, Li Weixitan, left-handed etiracetam
The chemicals of kind white crystalline powder.Chemical name (S)-alpha-ethyl-2-oxo -1- pyrrolidine acetamide, molecular formula are
C8H14N2O2, molecular weight 170.20900.Levetiracetam is antiepileptic, is clinically mainly used for adult and 4 years old or more youngster
The add-on of virgin epileptic's partial seizures.
It is well known that the process impurity content in drug decides the quality of drug, and Levetiracetam is a chirality
Compound, has a chiral centre, and the anti-epileptic drug action of the right etiracetam of R- isomers is unobvious, it is seen then that right second
The content of La Xitan number can largely effect on the curative effect of medication of Levetiracetam related drugs, need the left second of stringent control to draw west
The content of right etiracetam in smooth drug.
In 40 material quality standard of USP, the R- isomers of Levetiracetam is controlled, limit 0.8%；
It is not controlled in injection quality standard；To R- isomery in levetiracetam injection import registered standard (JX20150256)
Body control limit is 0.80%；As it can be seen that the quality control standard limit of two kinds of standards is higher, drug matter cannot be controlled well
Amount.
Want to still need to most drug progress better quality control other than testing and analyzing its bulk pharmaceutical chemicals
Whole product carries out quality testing, and the quality that could be really got well to the drug to come into operation controls.
In 40 material quality standard of USP and levetiracetam injection import registered standard, the chromatographic column used is
Surface is coated with amylose three -3,5 dimethylphenylcarbamate porous spherical silicagel columns, such chromatographic column cannot contact
Water will lead to chromatographic column column effect rapid decrease if detecting for levetiracetam injection, can only be by levetiracetam injection
Sample carry out cumbersome pre-treatment, after removing the moisture in sample, then with detecting each substance in Levetiracetam bulk pharmaceutical chemicals
Method carries out quality testing, very troublesome.
Therefore, even if improved technology is reduced to Levetiracetam bulk pharmaceutical chemicals quality control standard limit, left second is improved
The Quality Control Technology of La Xitan bulk pharmaceutical chemicals also can not fundamentally solve how conveniently and accurately to inject Levetiracetam
The problem of quality control that liquid is got well.
Summary of the invention
The present invention provides a kind of methods for detecting right etiracetam, accurately convenient can delicately measure Levetiracetam
The content of right etiracetam in bulk pharmaceutical chemicals or injection, separating degree meet regulation.
Specifically, the present invention provides a kind of method for detecting right etiracetam, which is characterized in that use high performance liquid chromatography
Qualitative or/and quantitative detection is carried out, the testing conditions of liquid chromatogram include:
Chromatographic column: cellulose-three (3,5- dichlorophenyl carbamate) silicagel column；
Mobile phase: n-hexane, dehydrated alcohol；
Wherein, n-hexane (vol.%): dehydrated alcohol (vol.%)=82~78: 18~22；Mobile phase is washed using isocratic
It is de-.
The isocratic elution refers in liquid chromatogram operation, in the analytical cycle of sample component, the ratio of components of mobile phase
Example and the constant type of elution of constant flow rate.
In the specific embodiment of the present invention, n-hexane (vol.%) in the mobile phase: dehydrated alcohol
(vol.%)=80: 20.
In a specific embodiment of the invention, the liquid chromatographic detection condition further includes one in i~iv below
Item is multinomial:
I chromatographic column specification: 4.6 × 100~250mm, 5 μm；
Ii flow velocity: 0.5~1.5ml/min；
Iii column temperature: 25 DEG C~35 DEG C；
Iv Detection wavelength: 210~220nm.
Further, the liquid chromatographic detection condition further includes one or more in i~iv below:
I chromatographic column specification: 4.6 × 250mm, 5 μm；
Ii flow velocity: 1.0ml/min；
Iii column temperature: 30 DEG C；
Iv Detection wavelength: 215nm.
Chromatographic column used in the specific embodiment of the invention be CHIRALPAKIC, 250mm × 4.6mm, 5 μm, still,
In the equivalent chromatographic column of above-mentioned chromatographic column also detection method for use in the present invention.
Further, the detection method includes the following contents:
(1) test solution is prepared；
(2) reference substance solution is prepared；
(3) by reference substance solution sample detection；
(4) by test solution sample detection.
The analysis of the methods of area normalization method, Self-control method, internal standard method, external standard method, meter can be used in the detection method
Calculate testing result.
Further, the step of preparing test solution or/and contrast solution are as follows: dissolve sample with solvent, then with dilute
Dilution agent is released to prescribed concentration；Or directly sample is dissolved with diluent and is diluted to prescribed concentration.
Further, the solvent is selected from one of water, dehydrated alcohol, sodium chloride solution, Acetic acid-sodium acetate buffer
Or several mixed solvent；The diluent is selected from dehydrated alcohol.
Further, the test solution solution concentration is 5~15mg/ml, preferably 10mg/ml.
Further, the reference substance solution solution concentration is 10~50 μ g/ml, preferably 20 μ g/ml.
Further, sample volume is 10~50 μ l, preferably 20 μ l.
The method of the present invention individually can carry out quality control to levetiracetam injection, simultaneously because chromatographic column can be used directly
Detected in aqueous test sample, therefore share chromatographic column with bulk pharmaceutical chemicals quality testing in drug quality control, it is quick and convenient into
The control of the quality of row bulk pharmaceutical chemicals and injection.
The present invention also provides a kind of levetiracetam injection, including Levetiracetam and impurity, the impurity includes a left side
The R- enantiomter of etiracetam, wherein the content of the R- enantiomter is no more than 0.2%.
The beneficial effects of the present invention are:
(1) the present invention provides one kind can directly detect levetiracetam injection R- enantiomter impurity method,
Blank supplemented with levetiracetam injection method of quality control provides Levetiracetam drug quality and further controls
Method processed is conducive to improve drug quality.
(2) the R- isomers in Levetiracetam related drugs can effectively be detected using detection method of the invention, had
There are specificity and stability instruction ability, can effectively be separated with Levetiracetam main peak, this method durability is good, can expire well
Foot is to the impurity monitoring in technical process and the Control of Impurities requirement in Levetiracetam correlation finished product.
(3) levetiracetam injection can directly be diluted and be detected by the present invention, without carrying out to the water wherein contained
Pretreatment, obtained detection spectrogram peak shape is good, without hangover, it is convenient and efficient compared with the prior art very much, be first to draw west for left second
The method of the quality control of smooth injection.
(4) sensitivity of analytical method of the present invention is high, can the R- isomers to Levetiracetam carry out strict control, the present invention
Method detection limit reaches 0.003%, and quantitative limit reaches 0.005%, accurate sensitive, and isomers limit handling can must not be
0.2%, it can preferably control drug quality.
Detailed description of the invention
Fig. 1 is blank solvent under chromatographic condition of the present invention, system suitability, test sample overlapped spectra；
Fig. 2 is the detection spectrogram of blank solvent under chromatographic condition of the present invention；
Fig. 3 is the detection spectrogram of blank auxiliary under chromatographic condition of the present invention；
Fig. 4 is the detection spectrogram of Levetiracetam raceme under chromatographic condition of the present invention；
Fig. 5 is the detection spectrogram of Levetiracetam reference substance under chromatographic condition of the present invention；
Fig. 6 is the detection spectrogram under chromatographic condition of the present invention under chromatographic condition of the present invention；
Fig. 7 is the Levetiracetam raceme chromatogram using AD-H chromatographic column
Fig. 8 is the sample chromatogram figure (measuring injection for the first time) using AD-H chromatographic column.
Fig. 9 is raceme, reference substance, the test sample Overlay chromatograms (measuring injection again) using AD-H chromatographic column.
Specific embodiment embodiment 1
Blank solution: dehydrated alcohol.
Blank auxiliary stock solution: the blank solution for being free of Levetiracetam bulk pharmaceutical chemicals is prepared according to recipe quantity；Weigh chlorination
Sodium about 4.5g, it sodium acetate about 0.82g, measures in the water for injection of 5% acetic acid about 0.6ml to 500ml.
Blank auxiliary solution: precision measures blank auxiliary stock solution 1.0ml into 10ml measuring bottle, is diluted to dehydrated alcohol
Scale to get.
System suitability solution: Levetiracetam raceme reference substance 11.60mg is weighed, is set in 100ml measuring bottle, use is anhydrous
Ethyl alcohol dissolves and is diluted to scale, be made the solution in every 1ml containing about 0.1mg to get.
Levetiracetam reference substance solution: precision weighs Levetiracetam reference substance 11.03mg, sets in 200ml measuring bottle, uses
Dehydrated alcohol dissolves and is diluted to scale, be made the solution in every 1ml containing about 50 μ g/ml to get.
Test solution: taking levetiracetam injection 1.0ml, sets in 10ml measuring bottle, is settled to dehydrated alcohol dilution
Scale, be made the solution in every 1ml containing about 10mg/ml to get.
Compare the detection method in USP 40 and import registered standard to R- isomers.Because of 40 injection quality standard of USP
In do not control isomers, therefore compare its material quality standard (being shown in Table 1).
The comparison of 1 isomers quality standard of table
The chromatographic column of USP 40 and import registered standard, which represents model, CHIRALPAK AD-H (250mm × 4.6mm, 5 μ
M), such chromatographic column cannot contact water, if this method is detected for levetiracetam injection, too to sample pretreatment process
It is cumbersome, therefore chromatographic column is screened.
It because chromatographic column CHIRALPAK IC (250mm × 4.6mm, 5 μm) can be not only used for positive, and can be used for reverse phase, just select
It is tested with the chromatographic column with identical chromatographic condition.The results showed that as shown in figure 3, R- isomers goes out peak position exists
After main peak, separating degree meets the requirements.Determine detection method of the condition as levetiracetam injection.
The verifying of 2 analysis method of embodiment
The present invention tentatively establishes the chromatographic condition of R- isomers analysis method, and testing result shows that the above method can be with
R- isomers is efficiently separated with main ingredient.
Specific verification result such as table 4:
The verifying of 4 levetiracetam injection R- isomers analysis method of table is summarized
The result shows that the system suitability and specificity of detection method, detection limit and quantitative limit, linear and model
It encloses, precision, the durability of accuracy and method meet the requirements, it was demonstrated that the detection method draws west suitable for left second
The detection of smooth R- isomers.
Carry out further comparative illustration technical effect of the invention below by check experiment:
Comparative example 1
Using the chromatographic condition of USP40, chromatographic column uses CHIRALPAK AD-H (250mm × 4.6mm, 5 μm), to left second
La Xitan injection is detected, and for test sample preparation method with embodiment 1, testing result is as shown in Figure 7,8, Levetiracetam
Appearance time is later than the appearance time of its right etiracetam of R- isomers, and peak shape is preferable when measuring injection for the first time, and left second draws west
It is smooth to be efficiently separated with its right etiracetam of R- isomers.But prevent because the chromatographic column is from contacting water, it is subsequent to use the chromatography again
Column detects levetiracetam injection, and testing result is as shown in Figure 9, the results showed that, when aqueous in sample to be tested, color
The column for composing column imitates rapid decrease, and each peak hangover is serious, and peak type is poor, is unable to judge accurately R- content of isomer, and the chromatographic column
Expensive, accelerating loss will increase experimentation cost.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalent structure or equivalent flow shift made by bright specification and accompanying drawing content is applied directly or indirectly in other relevant skills
Art field, is included within the scope of the present invention.
Claims (10)
1. the detection method of R- enantiomter in levetiracetam injection, which is characterized in that using high performance liquid chromatography into
The qualitative or/and quantitative detection of row, the testing conditions of liquid chromatogram include:
Chromatographic column: cellulose-three (3,5- dichlorophenyl carbamate) silicagel column；Mobile phase: n-hexane, dehydrated alcohol；
Wherein, n-hexane (vol.%): dehydrated alcohol (vol.%)=90~70: 10~30；Mobile phase uses isocratic elution.
2. detection method according to claim 1, which is characterized in that n-hexane (vol.%) in the mobile phase: anhydrous
Ethyl alcohol (vol.%)=80: 20.
3. detection method according to claim 1, which is characterized in that the liquid chromatographic detection condition further includes below
It is one or more in i~iv:
I chromatographic column specification: 4.6 × 100~250mm, 5 μm；
Ii flow velocity: 0.5~1.5ml/min；
Iii column temperature: 25 DEG C~35 DEG C；
Iv Detection wavelength: 210~220nm.
4. detection method according to claim 3, which is characterized in that the liquid chromatographic detection condition further includes below
It is one or more in i~iv:
I chromatographic column specification: 4.6 × 250mm, 5 μm；
Ii flow velocity: 1.0ml/min；
Iii column temperature: 30 DEG C；
Iv Detection wavelength: 215nm.
5. detection method according to claim 1, which is characterized in that the detection method includes the following contents:
(1) test solution is prepared；
(2) reference substance solution is prepared；
(3) by reference substance solution sample detection；
(4) by test solution sample detection.
6. detection method according to claim 5, which is characterized in that prepare the step of test solution or/and contrast solution
Suddenly are as follows: sample is dissolved with solvent, then is diluted to prescribed concentration with diluent；Or directly sample is dissolved and diluted with diluent
To prescribed concentration.
7. detection method according to claim 6, which is characterized in that it is molten that the solvent is selected from water, dehydrated alcohol, sodium chloride
One or more of liquid, Acetic acid-sodium acetate buffer；The diluent is selected from dehydrated alcohol.
8. detection method according to claim 5, which is characterized in that the test solution solution concentration is 5~15mg/
Ml, preferably 10mg/ml；The reference substance solution solution concentration is 10~50 μ g/ml, preferably 20 μ g/ml.
9. detection method according to claim 1, which is characterized in that sample volume is the μ l of 1O~50, preferably 20 μ l.
10. a kind of levetiracetam injection, which is characterized in that including Levetiracetam and impurity, the impurity includes left second
The R- enantiomter of La Xitan, wherein the content of the R- enantiomter is no more than 0.2%.
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Cited By (2)
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| CN113125626A (en) * | 2021-04-09 | 2021-07-16 | 健民药业集团股份有限公司 | HPLC method for detecting dextroisomer from levetiracetam oral liquid |
| CN118518805A (en) * | 2024-07-25 | 2024-08-20 | 成都诺和晟泰生物科技有限公司 | Left-hand ethylene-propylene type drawing device oral solution of cetirizine method for detecting medium-right ethylracetam |
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| CN113125626A (en) * | 2021-04-09 | 2021-07-16 | 健民药业集团股份有限公司 | HPLC method for detecting dextroisomer from levetiracetam oral liquid |
| CN118518805A (en) * | 2024-07-25 | 2024-08-20 | 成都诺和晟泰生物科技有限公司 | Left-hand ethylene-propylene type drawing device oral solution of cetirizine method for detecting medium-right ethylracetam |
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