CN114428134A - Method for detecting brivaracetam intermediate isomer - Google Patents
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Abstract
The invention belongs to the technical field of drug analysis and detection, and particularly relates to a method for detecting a brivaracetam intermediate isomer. The method reduces the overall temperature rise program and the temperature of each stage, and can obtain better separation degree; meanwhile, the concentration of a sample to be detected is adjusted, so that the response value of the brivaracetam intermediate isomer (S) - (-) epichlorohydrin can be improved, and a stable detection result can be obtained; even if a chromatographic column with lower column efficiency is adopted, the separation degree, peak shape, repeatability and accuracy of the brivaracetam intermediate isomer (S) - (-) epoxy chloropropane in the sample can meet the requirements, the practicability is stronger, the service life of the chromatographic column is obviously prolonged, and the cost is effectively saved.
Description
Technical Field
The invention belongs to the technical field of drug analysis and detection. More particularly, relates to a method for detecting a brivaracetam intermediate isomer.
Background
Brivaracetam has high affinity, can selectively bind synaptovesicular protein 2A (SV2A) involved in regulating neurotransmitter release and vesicle circulation, reduces excitatory neurotransmitter release, and achieves the effect of controlling epileptic seizure by regulating the balance of excitatory and inhibitory neurotransmitters in the brain. Has been approved by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of partial seizures in patients aged 16 years and older. Compared with the Levetiracetam (Levetiracetam) of the previous generation, the affinity of the brivaracetam is 15-30 times that of the Levetiracetam, and the dosage is reduced by about 10 times.
In the preparation process of brivaracetam, (R) - (-) epichlorohydrin or levorotatory epichlorohydrin (BVC02, CAS: 51594-55-9) is an important intermediate, has an obvious chiral structure, and needs to strictly control the isomer (S) - (-) epichlorohydrin or dextrorotatory epichlorohydrin (BVC02-EN, CAS: 67843-74-7).
At present, a detection method aiming at BVC02-EN is less, and only a simple detection method (ARD01/STP/19147/01) provided by a raw material manufacturer is used, but the damage of sample injection to a chromatographic column is large, the column efficiency is reduced quickly after sample injection, a main peak and an isomer peak in a system applicability solution are adjacent, once the column efficiency is reduced, the tailing of the two peaks cannot be completely separated seriously, so that the system applicability is unqualified, and the tailing of the isomer peak is coincident with a base line when the isomer peak is serious, so that the isomer cannot be detected; in addition, the method uses a special chiral column, and if the column efficiency is reduced too fast, the chromatographic column cannot be used for conventional gas phase detection, so that the cost is too high.
Therefore, the method for detecting the brivaracetam intermediate isomer has the advantages of better separation degree, peak shape, repeatability and accuracy, stronger practicability, applicability even if the column efficiency is slightly reduced, prolonged service life of the chromatographic column and effective cost saving.
Disclosure of Invention
The invention aims to solve the technical problems of large damage of a chromatographic column, quick column efficiency reduction, incomplete separation of a target peak, unqualified system applicability and overhigh cost in the conventional detection method, and provides the method for detecting the intermediate isomer of brivaracetam, which has the advantages of high separation degree, peak shape, repeatability, accuracy and practicability, can be applied to the chromatographic column even if the column efficiency is slightly reduced, prolongs the service life of the chromatographic column and effectively saves the cost.
The above purpose of the invention is realized by the following technical scheme:
a method for detecting a brivaracetam intermediate isomer (S) - (-) epichlorohydrin is used for detecting the brivaracetam intermediate isomer, and specifically comprises the following steps:
preparing a sample solution to be detected and a reference solution, and carrying out sample injection detection under the following chromatographic conditions:
a chromatographic column: a cyclodextrin modified chiral column;
furnace temperature: the initial temperature is 100-110 ℃, the temperature is kept for 0min, the temperature is increased to 120 ℃ at the speed of 1 ℃/min, the temperature is kept for 0min, the temperature is increased to 140-160 ℃ at the speed of 5 ℃/min, and the temperature is kept for 10 min;
sample inlet temperature: 200-220 ℃; the mode is shunting, and the shunting ratio is (60-120): 1; the carrier gas is nitrogen;
linear velocity: (25-35) cm/s; flow rate mode: constant current;
detector temperature: 220-250 ℃, hydrogen: air: tail blowing 30:300: 30.
According to the method for detecting the brivaracetam intermediate isomer, the integral heating program and the temperature of each stage are reduced, and a better separation degree can be obtained; meanwhile, the concentration of a sample to be detected is adjusted, so that the response value of the brivaracetam intermediate isomer (S) - (-) epichlorohydrin can be improved, and a stable detection result can be obtained. In addition, in practical application, the column effect of the chromatographic column can be kept stable under the condition of the method, even if the chromatographic column with lower column effect cannot be detected in the original method by adopting the British intermediate isomer (S) - (-) epoxy chloropropane, under the condition of the method, the separation degree, the peak shape, the repeatability and the accuracy of the British intermediate isomer (S) - (-) epoxy chloropropane in a test sample can meet the requirements, the practicability is stronger, the service life of the chromatographic column can be obviously prolonged, and the cost is effectively saved.
Preferably, the column is a Lipodex E column, with a specification of 25m × 0.25mm, 0.25 μm.
Preferably, the temperature of the sample inlet is 210-220 ℃.
Furthermore, the sample injection amount is 0.8-1.2 mu L.
Further, the number of chromatographic plates of a chromatographic peak of the brivaracetam intermediate isomer (S) - (-) epichlorohydrin is not less than 25000.
Further, the resolution of the brivaracetam intermediate isomer chromatographic peak and other chromatographic peaks in the sample to be detected is not less than 1.5.
Furthermore, the method for preparing the sample solution to be detected and the reference substance solution comprises the steps of dissolving the sample to be detected or the reference substance in an organic solvent, fixing the volume, and uniformly mixing.
Preferably, the organic solvent is selected from one or two of methanol and ethanol.
Preferably, the concentration of the sample to be detected is (2-10) mg/mL.
Further, the detection limit of the detection method is 1000 ppm.
The invention has the following beneficial effects:
according to the method for detecting the brivaracetam intermediate isomer, the integral heating program and the temperature of each stage are reduced, and a better separation degree can be obtained; meanwhile, the concentration of a sample to be detected is adjusted, so that the response value of the brivaracetam intermediate isomer (S) - (-) epichlorohydrin can be improved, and a stable detection result can be obtained; even if a chromatographic column with lower column efficiency is adopted, the separation degree, the peak shape, the repeatability and the accuracy of the brivaracetam intermediate isomer (S) - (-) epoxy chloropropane in a test sample can also meet the requirements, the practicability is stronger, the service life of the chromatographic column is obviously prolonged, and the cost is effectively saved.
Drawings
FIG. 1 is a gas chromatogram of a solution suitable for use in the system of example 1 of the present invention.
FIG. 2 is a gas chromatogram of the test solution in example 1 of the present invention.
FIG. 3 is a gas chromatogram of the test sample-adding solution in example 2 of the present invention.
FIG. 4 is a gas chromatogram of a system suitability solution for the process provided by the feed manufacturer in comparative example 1 of the present invention.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 detection method of brivaracetam intermediate isomer (S) - (-) epichlorohydrin BVC02-EN
1. The chromatographic conditions are shown in table 1.
TABLE 1 chromatographic conditions
Diluent/blank solution: methanol;
system applicability solution: taking a BVC02 standard substance 50.0mg to 10mL measuring flask, precisely weighing, adding 0.5mL system applicability stock solution, diluting to constant volume to scale with diluent, and shaking up to obtain the product;
③ test solution: weighing a sample BVC0250.0 mg to 10mL, precisely weighing, dissolving with 3mL of diluent, diluting with the diluent to a constant volume to a scale, shaking up, and paralleling two parts to obtain the final product.
Referring to the chromatographic conditions in Table 1, 1-2 needles of blank solution, 1 needle of system applicability solution and 1 needle of each of 2 parts of sample solution are sequentially injected, and corresponding chromatograms are recorded.
2. The obtained maps of the experiments are shown in figures 1-2, and the results are shown in table 2.
As can be seen, the system applicability solution of the chromatographic condition method of the invention has no other interference peaks, the base line is smooth, and BVC02 and BVC02-EN can be completely separated; the test solution has 1 hetero peak, but the peak-forming time is earlier, and the peak-forming time does not influence the peak-forming of BVC02 and BVC 02-EN.
Results of detection of BVC02-EN in Table 2 BVC02
As can be seen from Table 2, the degree of separation between BVC02 and BVC02-EN in the solution with system applicability is more than 1.5, and the number of plates of BVC02 and BVC02-EN is more than 25000, which meets the requirement of system applicability, but the peak area of BVC02-EN in the tested sample BVC02-20210327-2 is much larger than the peak area of BVC02-EN in the solution with system applicability, and the content of BVC02-EN in the tested sample BVC02-20210327-2 does not meet the standard.
Example 2 examination of the detection methodology
1. System applicability
Diluent/blank solution: methanol;
system applicability solution: taking 50.0mg to 10mL of BVC02 standard substance, precisely weighing, adding 0.5mL of systematic applicability stock solution, diluting to constant volume with diluent, and shaking up to obtain the final product.
Referring to the chromatographic conditions in table 1 of example 1, after the system is balanced, 2 needles of blank solution and 6 needles of system applicability solution are sequentially injected, a chromatogram is recorded, and the results are calculated according to peak areas and are shown in table 3.
TABLE 3 results of the System suitability determination
As can be seen from the table, in the method of the invention, under the chromatographic conditions of Table 1, the RSD of the peak area of BVC02-EN is only 2.12%, the separation degrees of both the peak areas of BVC02 and BVC02-EN are more than 1.5, and the numbers of the plate numbers of both the peak areas of BVC02 and BVC02-EN are more than 25000, which completely meets the requirements.
2. Specificity
Diluent/blank solution: methanol;
second, system applicability stock solution: taking a BVC02-EN standard substance 5.0mg to 5mL measuring flask, precisely weighing, ultrasonically dissolving by using 2mL diluent, cooling, fixing the volume to scale by using the diluent, and shaking up to obtain the product;
third, system applicability solution: taking a 50.0mg to 10mL measuring flask of a BVC02 standard substance, precisely weighing, adding 0.5mL of systematic applicability stock solution, diluting to a constant volume with a diluent, and shaking uniformly to obtain the BVC02 standard substance;
fourthly, the test solution: weighing a sample BVC0250.0 mg to 10mL, precisely weighing, dissolving with 3mL of diluent, diluting with the diluent to a constant volume to a scale, shaking up, and parallel weighing to obtain two parts;
adding a standard solution into the sample: weighing a sample BVC0250.0 mg to be tested into a 10mL volumetric flask, precisely weighing, dissolving with 3mL of diluent, transferring 0.5mL of system applicability stock solution into the same volumetric flask, diluting with the diluent, fixing the volume to the scale, and shaking up to obtain the product.
Referring to the chromatographic conditions in table 1 of example 1, after the system is balanced, sequentially injecting a blank solution 2 needle, a system applicability solution 1 needle, a sample solution 1 needle and a sample labeling solution 1 needle, and recording a chromatogram, wherein the sample labeling solution chromatogram is shown in fig. 3, and the results are shown in table 4.
TABLE 4 results of specificity measurement
As can be seen from Table 4, the blank solution was found to be non-interfering in the vicinity of the peak of BVC02 and BVC02-EN, and the peak positions of BVC02 and BVC02-EN in the test solution were identical to those of the solution suitable for the system, and were completely in compliance with the regulations.
3. Repeatability of
Diluent/blank solution: methanol;
second, system applicability stock solution: taking a BVC02-EN standard substance 5.0mg to 5mL measuring flask, precisely weighing, ultrasonically dissolving by using 2mL diluent, cooling, fixing the volume to scale by using the diluent, and shaking up to obtain the product;
third, system applicability solution: taking a BVC02 standard substance 50.0mg to 10mL measuring flask, precisely weighing, adding 0.5mL system applicability stock solution, diluting to constant volume to scale with diluent, and shaking up to obtain the product;
fourthly, the test solution: weighing a sample BVC0250.0 mg to 10mL, precisely weighing, dissolving with 3mL of diluent, diluting with the diluent to a constant volume to a scale, shaking up, and parallel weighing to obtain two parts;
adding a standard solution into the sample: weighing a sample BVC0250.0 mg to be tested into a 10mL volumetric flask, precisely weighing, dissolving with 3mL of diluent, transferring 0.5mL of system applicability stock solution into the same volumetric flask, diluting with the diluent, fixing the volume to the scale, and shaking up to obtain the product.
Referring to the chromatographic conditions in table 1 of example 1, after the system is balanced, 2 needles of blank solution, 6 needles of system applicability solution, 1 needle of each of 3 parts of sample solution, and 1 needle of each of 3 parts of sample standard solution are sequentially injected, a chromatogram is recorded, and RSD and standard recovery rate are calculated, and the results are shown in table 5.
TABLE 5 results of repeated measurements
As can be seen from the table, the RSD of the BVC02-EN peak area in the 6-needle system applicability solution (solution c) continuously fed by the method is far less than 10.0 percent, the RSD of the BVC02-EN peak area in the test sample solution (solution c) and the test sample standard adding solution (solution fifth) continuously fed by the method is far less than 10.0 percent, and the standard adding recovery mean value is 103.03 percent, which completely meets the specified requirements.
Comparative example 1 detection method of brivaracetam intermediate isomer (S) - (-) epichlorohydrin BVC02-EN
The detection was carried out by the method described in Standard Test Procedure for (R) -4-propylanhydrofur an-2(3H) -one, which was supplied from the manufacturer of raw materials, under item 7.4.
1. Chromatographic conditions
TABLE 6 chromatographic conditions
Solution preparation:
diluent/blank solution: methanol;
system applicability solution: taking a BVC02 standard substance 50.0mg to 10mL measuring flask, precisely weighing, adding 0.5mL system applicability stock solution, diluting to constant volume to scale with diluent, and shaking up to obtain the product;
③ test solution: weighing the sample BVC0250.0 mg to 10mL, precisely weighing, dissolving with 3mL of diluent, metering to a certain volume with the diluent, shaking up, and paralleling for two parts to obtain the final product.
Referring to chromatographic conditions in Table 6, 1-2 needles of blank solution, 1 needle of system applicability solution and 1 needle of each of 2 parts of test solution are sequentially injected, and corresponding chromatograms are recorded.
2. Results of the experiment
The result is shown in FIG. 4, which shows that the system applicability solution has more impurity peaks and the later base line is shifted upwards; moreover, BVC02 and BVC02 isomers are seriously tailing, so that BVC02 isomers cannot generate peaks, and the compounds cannot be used for detecting test articles.
Therefore, the method for detecting the brivaracetam intermediate isomer reduces the overall temperature rise program and the temperature of each stage, and can obtain better resolution; meanwhile, the concentration of a sample to be detected is adjusted, so that the response value of the brivaracetam intermediate isomer (S) - (-) epichlorohydrin can be improved, and a stable detection result can be obtained. In addition, in practical application, the column effect of the chromatographic column can be kept stable under the condition of the method, even if the chromatographic column with lower column effect cannot be detected in the original method by adopting the British intermediate isomer (S) - (-) epoxy chloropropane, under the condition of the method, the separation degree, the peak shape, the repeatability and the accuracy of the British intermediate isomer (S) - (-) epoxy chloropropane in a test sample can meet the requirements, the practicability is stronger, the service life of the chromatographic column can be obviously prolonged, and the cost is effectively saved.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A method for detecting a brivaracetam intermediate isomer is characterized in that gas chromatography is adopted to detect the brivaracetam intermediate isomer (S) - (-) epichlorohydrin, and the method specifically comprises the following steps:
preparing a sample solution to be detected and a reference solution, and carrying out sample injection detection under the following chromatographic conditions:
a chromatographic column: cyclodextrin modified chiral columns;
furnace temperature: the initial temperature is 100-110 ℃, the temperature is kept for 0min, the temperature is increased to 120 ℃ at the speed of 1 ℃/min, the temperature is kept for 0min, the temperature is increased to 140-160 ℃ at the speed of 5 ℃/min, and the temperature is kept for 10 min;
sample inlet temperature: 200-220 ℃; the mode is shunting, and the shunting ratio is (60-120): 1; the carrier gas is nitrogen;
linear velocity: (25-35) cm/s; flow rate mode: constant current;
detector temperature: 220-250 ℃, hydrogen: air: tail blowing 30:300: 30.
2. The detection method according to claim 1, wherein the chromatographic column is a Lipodex E chromatographic column with a specification of 25m x 0.25mm, 0.25 μm.
3. The detection method according to claim 1, wherein the sample inlet temperature is 210-220 ℃.
4. The detection method according to claim 1, wherein the sample introduction amount of the sample introduction is 0.8 to 1.2. mu.L.
5. The detection method according to claim 1, wherein the brivaracetam intermediate isomer (S) - (-) epichlorohydrin has a chromatographic peak plate number of not less than 25000.
6. The detection method according to claim 1, wherein the separation degree of the brivaracetam intermediate isomer chromatographic peak and other chromatographic peaks in the sample to be detected is not less than 1.5.
7. The detection method according to claim 1, wherein the method for preparing the sample solution to be detected and the reference solution comprises the steps of dissolving the sample to be detected or the reference in an organic solvent, fixing the volume, and uniformly mixing.
8. The detection method according to claim 7, wherein the organic solvent is one or two selected from methanol and ethanol.
9. The detection method according to claim 7, wherein the concentration of the sample to be detected is (2-10) mg/mL.
10. The detection method according to any one of claims 1 to 9, wherein the detection limit of the detection method is 1000 ppm.
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| CN116735761A (en) * | 2023-08-16 | 2023-09-12 | 四川省药品检验研究院(四川省医疗器械检测中心) | UPLC-MS/MS detection method of brivaracetam in human plasma |
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