CN115219633A - Gas chromatography detection method for residual solvent in metoprolol succinate bulk drug - Google Patents
Gas chromatography detection method for residual solvent in metoprolol succinate bulk drug Download PDFInfo
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- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 229960000939 metoprolol succinate Drugs 0.000 title claims abstract description 77
- 239000013557 residual solvent Substances 0.000 title claims abstract description 48
- 238000001514 detection method Methods 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 229940079593 drug Drugs 0.000 title claims abstract description 30
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 195
- 239000000243 solution Substances 0.000 claims abstract description 52
- 239000011550 stock solution Substances 0.000 claims abstract description 26
- 239000013558 reference substance Substances 0.000 claims abstract description 22
- 239000012085 test solution Substances 0.000 claims abstract description 18
- 239000003085 diluting agent Substances 0.000 claims abstract description 15
- 238000000926 separation method Methods 0.000 claims abstract description 14
- 239000006228 supernatant Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 238000005303 weighing Methods 0.000 claims description 24
- IFDLXKQSUOWIBO-UHFFFAOYSA-N 1,3-dichloropropan-1-ol Chemical compound OC(Cl)CCCl IFDLXKQSUOWIBO-UHFFFAOYSA-N 0.000 claims description 17
- YYTSGNJTASLUOY-UHFFFAOYSA-N 1-chloropropan-2-ol Chemical compound CC(O)CCl YYTSGNJTASLUOY-UHFFFAOYSA-N 0.000 claims description 17
- ZXCYIJGIGSDJQQ-UHFFFAOYSA-N 2,3-dichloropropan-1-ol Chemical compound OCC(Cl)CCl ZXCYIJGIGSDJQQ-UHFFFAOYSA-N 0.000 claims description 17
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 17
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000012088 reference solution Substances 0.000 claims description 8
- 238000007865 diluting Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims description 4
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- QUMITRDILMWWBC-UHFFFAOYSA-N nitroterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 QUMITRDILMWWBC-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000011259 mixed solution Substances 0.000 description 22
- 239000000523 sample Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 11
- 230000014759 maintenance of location Effects 0.000 description 8
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000012795 verification Methods 0.000 description 6
- 239000012496 blank sample Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 239000012467 final product Substances 0.000 description 3
- 229960002237 metoprolol Drugs 0.000 description 3
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 238000012418 validation experiment Methods 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
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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
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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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
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
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- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
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Abstract
The invention belongs to the technical field of detection of medical impurities, and particularly relates to a gas chromatography detection method for residual solvent in a metoprolol succinate bulk drug. Preparing a metoprolol succinate solution by gas chromatography of a residual solvent in the metoprolol succinate bulk drug, adding a reference substance stock solution, mixing, and taking supernatant as a reference substance solution; preparing a test solution: preparing metoprolol succinate solution, adding ethyl acetate, mixing, and taking supernatant as test solution; and (3) determination: respectively injecting the diluent ethyl acetate, the reference substance solution and the test solution into a gas chromatograph, and recording a chromatogram; under the same gas chromatographic condition, metoprolol succinate and residual solvent thereof in the sample are separated. The invention provides a gas chromatography detection method for residual solvent in metoprolol succinate bulk drug, which has strong specificity, high separation degree, good reproducibility and quick and accurate detection.
Description
Technical Field
The invention belongs to the technical field of detection of medical impurities, and particularly relates to a gas chromatography detection method for residual solvent in a metoprolol succinate bulk drug.
Background
Metoprolol is a selective beta receptor blocker, has high selectivity to heart, and does not affect the metabolism of sugar and lipid. Metoprolol is rapidly absorbed after administration and is widely absorbed throughout the gastrointestinal tract, including the colon. Metoprolol succinate is the succinate salt of metoprolol, and the action mechanism of the metoprolol succinate is that the metoprolol succinate inhibits beta adrenergic receptors, thereby exerting the excitability of sympathetic nerves, slowing down conduction, slowing down heart rate and inhibiting myocardial contractility, thereby having the effects of reducing blood pressure, reducing myocardial oxygen consumption and improving myocardial ischemia. In clinic, it is often used for treating hypertension, coronary heart disease, angina pectoris, chronic heart failure and arrhythmia. The metoprolol succinate belongs to a sustained release preparation, belongs to one of five main-line hypotensive drugs, can slow down the release speed of the drugs, enables the blood concentration in a body to be relatively stable, does not suddenly generate a peak of the blood concentration, can keep the state of illness stable, can continuously act for 24 hours, and effectively reduces the medicine taking times of a patient.
In 2021, the sale amount of metoprolol succinate sustained release tablets in domestic hospitals and physical drug stores is about 31 hundred million yuan, and the raw material drug has wide market prospect.
However, in the preparation process of the metoprolol succinate bulk drug, various residual solvents exist, and need to be strictly controlled, so that the quality safety of the metoprolol succinate bulk drug is ensured.
Disclosure of Invention
The invention aims to solve the technical problem of providing a gas chromatography detection method for residual solvent in metoprolol succinate bulk drug, which has strong specificity, high separation degree, good reproducibility and quick and accurate detection.
The gas chromatography detection method for the residual solvent in the metoprolol succinate bulk drug comprises the following steps:
(1) Preparation of a reference solution:
respectively taking residual solvents, precisely weighing, adding a diluent ethyl acetate for dissolving, and quantitatively diluting to obtain a solution with a certain concentration as a reference substance stock solution;
taking metoprolol succinate, precisely weighing, adding water to prepare metoprolol succinate solution with a certain concentration, respectively adding the reference substance stock solution, performing liquid separation extraction and water removal, and taking the upper layer solution as the reference substance solution;
(2) Preparing a test solution:
taking metoprolol succinate, accurately weighing, adding water to prepare metoprolol succinate solution with a certain concentration, adding ethyl acetate serving as a diluent, performing liquid-separation extraction, removing water, and taking upper-layer liquid as a test solution;
(3) And (3) determination: respectively injecting the diluent ethyl acetate, the reference solution and the test solution into a gas chromatograph, and recording the chromatogram; under the same gas chromatography condition, the metoprolol succinate and the residual solvent thereof in the sample are separated.
Taking the residual solvent comprises: epichlorohydrin, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol, 2, 3-dichloropropanol; the structural formula is shown in table 1.
TABLE 1 residual solvent
The concentration of the residual solvent in the step (1) is less than or equal to 0.000375wt%.
In the chromatogram of the test solution, if a chromatographic peak consistent with the retention time of the residual solvent exists in the obtained test solution, the peak area of the chromatographic peak is calculated according to a standard addition method, and the epichlorohydrin, the 1-chloro-2-propanol, the 3-chloropropanol, the 1, 3-dichloropropanol and the 2, 3-dichloropropanol are not more than 0.000375wt%.
Taking 2.5 +/-0.05 g of metoprolol succinate in the step (1), precisely weighing, adding 15ml of water, and ultrasonically dissolving to prepare the metoprolol succinate solution.
Taking 2.5 +/-0.05 g of metoprolol succinate in the step (2), precisely weighing, adding 15ml of water, and ultrasonically dissolving to prepare the metoprolol succinate solution.
And (3) liquid separation and extraction in the step (1) and the step (2) are performed by adopting diluent ethyl acetate, and anhydrous sodium sulfate is adopted for water removal.
The chromatographic conditions of the gas chromatograph in the step (3) are as follows:
a detector: a FID detector;
and (3) chromatographic column: a capillary column taking polyethylene glycol modified by nitroterephthalic acid as a stationary phase; the model of the chromatographic column is preferably DB-FFAP, the specification of the chromatographic column is 30m multiplied by 0.32mm, and the size of the chromatographic column is 0.25 mu m.
Temperature rising procedure: as shown in table 2.
TABLE 2 temperature program
| Temperature program | Rate of speed/min | Temperature (. Degree.C.) | Time (min) |
| First stage | - | 50±5 | 0-5 |
| |
10±2 | 220±5 | 25±5 |
The injection port temperature is 240-260 ℃, and preferably 250 ℃;
the temperature of the detector is 270-290 ℃, and the preferred temperature is 280 ℃;
the nitrogen flow rate is 0.8-1.2ml/min, preferably 1.0ml/min;
the flow ratio is 2;
sample injection volume: 1-6 mul, the sample injection volume is 3 mul;
diluent agent: and (3) ethyl acetate.
Specifically, the gas chromatography detection method for the residual solvent in the metoprolol succinate bulk drug comprises the following steps:
(1) Preparation of a reference solution:
respectively taking proper amounts of residual solvents of epichlorohydrin, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol and 2, 3-dichloropropanol, precisely weighing, adding ethyl acetate for dissolving, and quantitatively diluting to obtain a solution containing 3.75 μ g per 1ml as a reference stock solution; taking about 2.5g of metoprolol succinate, accurately weighing, placing in a dry container, adding 15ml of water, ultrasonically dissolving, accurately adding 1ml of each reference substance stock solution, shaking for 5 minutes, transferring to a separating funnel, standing for 5 minutes, layering a mixed solution, taking an ethyl acetate layer, placing the ethyl acetate layer in another dry container, accurately adding 5ml of ethyl acetate into the residual water layer, shaking for 5 minutes, transferring to the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, accurately adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution as a reference substance solution.
(2) Preparing a test solution:
taking about 2.5g of metoprolol succinate, accurately weighing, placing in a dry container, adding 15ml of water, ultrasonically dissolving, accurately adding 5ml of ethyl acetate, shaking for 5 minutes, transferring to a separating funnel, standing for 5 minutes, layering, taking an ethyl acetate layer, placing the ethyl acetate layer in another dry container, accurately adding 5ml of ethyl acetate into the residual water layer, shaking for 5 minutes, transferring to the separating funnel, standing for 5 minutes, layering, combining the ethyl acetate layers, accurately adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking the supernatant as a sample solution.
(3) And (3) determination: precisely measuring the diluent, the reference solution and the test solution respectively, injecting into a gas chromatograph, and recording the chromatogram; and separating the metoprolol succinate and the residual solvent thereof under the same gas chromatography condition.
The chromatographic conditions of the gas chromatograph are as follows: a detector: an FID detector; a chromatographic column: the model is preferably DB-FFAP, the specification of a chromatographic column is 30m multiplied by 0.32mm, and the specification of the chromatographic column is 0.25 mu m; temperature rising procedure: the first stage is as follows: heating to 50 + -5 deg.C for 0-5min; and a second stage: the heating rate is 10 plus or minus 2 ℃/min, the temperature is increased to 220 plus or minus 5 ℃, and the heating time is 25 plus or minus 5min; the temperature of a sample inlet is 240-260 ℃; the temperature of the detector is 270-290 ℃; the nitrogen flow rate is 0.8-1.2ml/min; the flow splitting ratio is 2; sample introduction volume: 1-6 mul; diluent agent: and (3) ethyl acetate.
In the chromatogram of the test solution, if a chromatographic peak consistent with the retention time of the residual solvent exists in the obtained test solution, the peak area of the chromatographic peak is calculated according to a standard addition method, and the epichlorohydrin, the 1-chloro-2-propanol, the 3-chloropropanol, the 1, 3-dichloropropanol and the 2, 3-dichloropropanol are not more than 0.000375wt%.
Compared with the prior art, the invention has the beneficial effects that: the gas chromatography detection method for the residual solvent in the metoprolol succinate bulk drug provided by the invention has the advantages of high sensitivity, good separation degree and strong specificity, and can accurately, qualitatively and quantitatively detect various residual solvents in the metoprolol succinate bulk drug, so that the quality of the metoprolol succinate bulk drug can be objectively, accurately and comprehensively evaluated, and the gas chromatography detection method has important practical significance for controlling the product quality.
Drawings
FIG. 1 is a gas chromatogram of a blank solvent of a specificity verification experiment of an example;
FIG. 2 is a gas chromatogram of a proprietary mixed solution of the proprietary validation experiment of the example;
FIG. 3 is a gas chromatogram of a control solution in a system precision validation experiment of an example;
FIG. 4 is a gas chromatogram of a sample solution in examples.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Examples
The gas chromatography detection method for the residual solvent in the metoprolol succinate bulk drug comprises the following steps:
(1) Preparation of a reference solution:
respectively taking proper amounts of residual solvents of epoxy chloropropane, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol and 2, 3-dichloropropanol, precisely weighing, adding ethyl acetate for dissolving, and quantitatively diluting to obtain a solution containing 3.75 microgram per 1ml as a reference stock solution; taking about 2.5g of metoprolol succinate, accurately weighing, placing in a dry container, adding 15ml of water, ultrasonically dissolving, accurately adding 1ml of each reference substance stock solution, shaking for 5 minutes, transferring to a separating funnel, standing for 5 minutes, layering a mixed solution, taking an ethyl acetate layer, placing the ethyl acetate layer in another dry container, accurately adding 5ml of ethyl acetate into the residual water layer, shaking for 5 minutes, transferring to the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, accurately adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution as a reference substance solution.
(2) Preparing a test solution:
taking about 2.5g of metoprolol succinate, precisely weighing, placing in a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of ethyl acetate, shaking for 5 minutes, transferring to a separating funnel, standing for 5 minutes, layering, taking an ethyl acetate layer, placing in another dry container, precisely adding 5ml of ethyl acetate into the residual water layer, shaking for 5 minutes, transferring to the separating funnel, standing for 5 minutes, layering, combining ethyl acetate layers, precisely adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, taking the supernatant as a sample solution, and obtaining a gas chromatogram as shown in figure 4.
(3) And (3) determination: precisely measuring the diluent, the reference solution and the test solution respectively, injecting into a gas chromatograph, and recording the chromatogram; and separating the metoprolol succinate and the residual solvent thereof under the same gas chromatography condition.
The chromatographic conditions of the gas chromatograph are as follows: a detector: a FID detector; a chromatographic column: the model is preferably DB-FFAP, the specification of a chromatographic column is 30m multiplied by 0.32mm, and the specification of the chromatographic column is 0.25 mu m; temperature rising procedure: the first stage is as follows: heating to 50 deg.C for 0min; and a second stage: the heating rate is 10 ℃/min, the temperature is increased to 220 ℃, and the heating time is 25min; the temperature of a sample inlet is 250 ℃; the temperature of the detector is 280 ℃; the nitrogen flow rate is 1.0ml/min; the flow splitting ratio is 5; sample introduction volume: 3 mu l of the solution; diluent (b): and (3) ethyl acetate.
a) And (3) specificity verification:
each residual solvent stock solution: respectively taking about 37.5mg of epoxy chloropropane, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol and 2, 3-dichloropropanol respectively, precisely weighing, respectively placing into a 100ml measuring flask, adding ethyl acetate to dilute to a scale, and shaking up to obtain the product.
Residual solvent mixed stock solution: precisely measuring 1ml of each residual solvent stock solution, placing into a 100ml measuring flask, adding ethyl acetate to dilute to scale, and shaking up to obtain the final product.
A special mixed solution: precisely weighing 2.5g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of the residual solvent mixed stock solution, shaking for 5 minutes, transferring the mixture into a separating funnel, standing for 5 minutes, layering the mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the mixture into the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, precisely adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution to obtain the metoprolol succinate.
Precisely measuring a blank solvent ethyl acetate and a special mixed solution, injecting samples according to the chromatographic conditions, and recording a chromatogram, wherein the result is shown in Table 3. The gas chromatogram of the blank solvent ethyl acetate is shown in FIG. 1, and the gas chromatogram of the specific mixed solution is shown in FIG. 2.
TABLE 3 results of the specific mixed solution test
| Name(s) | Retention time (min) | Degree of separation |
| Epichlorohydrin | 5.254 | / |
| 1-chloro-2-propanol | 6.442 | 29.037 |
| 3-chloropropanol | 9.131 | 64.510 |
| 1, 3-Dichloropropanol | 11.455 | 54.467 |
| 2, 3-Dichloropropanol | 12.253 | 17.606 |
And (4) conclusion: as can be seen from fig. 1 and 2 and table 3, the blank solvent does not interfere with the detection of the residual solvent, the separation degree between peaks is greater than 1.5, and the separation effect is good.
b) And (3) verifying system precision:
each residual solvent stock solution: respectively taking 37.5mg of epichlorohydrin, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol and 2, 3-dichloropropanol respectively, precisely weighing, respectively placing in a 100ml measuring flask, adding ethyl acetate to dilute to scale, and shaking up to obtain the final product.
Residual solvent mixed stock solution: precisely measuring 1ml of each residual solvent stock solution, placing into a 100ml measuring flask, adding ethyl acetate to dilute to scale, and shaking up to obtain the final product.
Control solution: precisely weighing 2.5g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of the residual solvent mixed stock solution, shaking for 5 minutes, transferring the mixture into a separating funnel, standing for 5 minutes, layering the mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the mixture into the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, precisely adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution to obtain the metoprolol succinate.
Precisely measuring the reference substance solution, introducing sample according to the chromatographic conditions, recording chromatogram, calculating Relative Standard Deviation (RSD) of peak area and retention time of each peak, and showing test results of system precision retention time and system precision peak area in Table 5, wherein the reference substance solution is continuously introduced for 6 times.
TABLE 4 precision test results (Retention time)
| Name (R) | Epoxy chloropropane | 1-chloro-2-propanol | 3-chloropropanol | 1, 3-Dichloropropanol | 2, 3-Dichloropropanol |
| Reference substance-1 | 5.264 | 6.453 | 9.142 | 11.467 | 12.264 |
| Reference substance-2 | 5.266 | 6.455 | 9.144 | 11.468 | 12.264 |
| Reference substance-3 | 5.263 | 6.452 | 9.143 | 11.467 | 12.264 |
| Reference substance-4 | 5.263 | 6.452 | 9.142 | 11.467 | 12.265 |
| Reference substance-5 | 5.266 | 6.455 | 9.144 | 11.469 | 12.266 |
| Reference substance-6 | 5.266 | 6.454 | 9.144 | 11.468 | 12.266 |
| Mean value of | 5.265 | 6.454 | 9.143 | 11.468 | 12.265 |
| RSD％ | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 |
TABLE 5 precision test results (peak area)
| Name (R) | Epoxy chloropropane | 1-chloro-2-propanol | 3-chloropropanol | 1, 3-Dichloropropanol | 2, 3-Dichloropropanol |
| Reference substance-1 | 58780 | 42179 | 45848 | 42970 | 52827 |
| Reference substance-2 | 58267 | 41905 | 45621 | 42981 | 53261 |
| Reference substance-3 | 57004 | 40328 | 44851 | 42549 | 52539 |
| Reference substance-4 | 58398 | 42477 | 46323 | 43669 | 53971 |
| Control-5 | 58724 | 41601 | 46103 | 43648 | 53346 |
| Reference substance-6 | 58536 | 42544 | 46099 | 43903 | 53667 |
| Average peak area | 58285 | 41839 | 45808 | 43287 | 53269 |
| RSD％ | 1.2 | 2.0 | 1.2 | 1.3 | 1.0 |
And (4) conclusion: the reference substance solution is continuously injected for 6 times, the RSD of the area is less than 10.0 percent, the RSD of the retention time is less than 1.0 percent, and the system precision is good.
c) Verification of detection/quantitation limits
And (3) taking ethyl acetate as a solvent as a blank, adjusting the sensitivity of the instrument, continuously injecting samples for 3 times, recording the noise level of the instrument in the peak time range of the measured object, and calculating the average noise.
Detection limit: accurately preparing reference substance solution of the object to be detected, gradually diluting to a certain concentration, injecting sample, and continuously measuring for 3 times. And calculating the ratio of the peak height to the noise (signal-to-noise ratio), wherein the sample concentration with the signal-to-noise ratio (S/N) of more than 3 is the detection limit concentration, and the ratio of the signal-to-noise ratio to the theoretical sample concentration is the detection limit.
And (4) quantitative limit: accurately preparing reference substance solution of the object to be detected, gradually diluting to a certain concentration, injecting sample, and continuously measuring for 6 times. And calculating the ratio of the peak height to the noise (signal-to-noise ratio), wherein the sample concentration with the signal-to-noise ratio (S/N) of more than 10 is the quantitative limit concentration, and the ratio of the signal-to-noise ratio to the theoretical sample concentration is the quantitative limit.
Blank solvent: and (3) ethyl acetate.
Blank sample solution: precisely weighing 2.5g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of ethyl acetate, shaking for 5 minutes, transferring the metoprolol succinate into a separating funnel, standing for 5 minutes, layering a mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the mixture into a separating funnel, standing for 5 minutes, layering the mixed solution, combining ethyl acetate layers, precisely adding 0.5g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking a supernatant as a blank sample solution. 3 parts are prepared in parallel.
Metoprolol succinate is weighed as 2.50056g, 2.50074g and 2.50062g, and anhydrous sodium sulfate is weighed as 0.50081g, 0.50048g and 0.50034g.
Quantitative limiting stock solution: precisely measuring 1ml of epichlorohydrin stock solution under the 'specificity' verification, placing the epichlorohydrin stock solution in a 200ml measuring flask, precisely adding 1ml of 1-chloro-2-propanol and 1, 3-dichloropropanol stock solution, 1ml of 3-chloropropanol and 0.9ml of 2, 3-dichloropropanol stock solution respectively, adding ethyl acetate to dilute to a scale, shaking up, precisely measuring 3ml, placing the solution in a 10ml measuring flask, adding ethyl acetate to dilute to a scale, and shaking up to obtain the epichlorohydrin-based epoxy propane measuring and storing liquid.
Preparation of a quantitative limiting solution: precisely weighing 2.50031g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of quantitative limit stock solution, shaking for 5 minutes, transferring the metoprolol succinate into a separating funnel, standing for 5 minutes, layering a mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the mixture into the separating funnel, standing for 5 minutes, layering the mixed solution, combining ethyl acetate layers, precisely adding 0.50055g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution as a quantitative limit solution.
Detection limit: precisely measuring 3ml of the limiting solution, placing the limiting solution into a 10ml measuring flask, adding ethyl acetate to dilute to the scale, and shaking up to obtain the product.
Precisely measuring blank solvent, continuously injecting sample for 3 times according to the above chromatographic conditions, continuously injecting sample for each blank sample solution for 3 times, continuously injecting detection limit solution for 3 times, and continuously injecting quantitative limit solution for 6 times, recording chromatogram, and calculating signal-to-noise ratio, wherein the results are shown in tables 6, 7, 8 and 9.
TABLE 6 Baseline noise measurements
| Name (R) | Peak height 1 | Peak height 2 | Peak height 3 | Average peak height |
| Epichlorohydrin | 409 | 475 | 462 | 449 |
| 1-chloro-2-propanol | 401 | 414 | 398 | 404 |
| 3-chloropropanol | 393 | 395 | 386 | 391 |
| 1, 3-Dichloropropanol | 401 | 417 | 393 | 404 |
| 2, 3-Dichloropropanol | 425 | 412 | 391 | 409 |
TABLE 7 peak height results for each solvent in blank sample
| Name(s) | Peak height 1 | Peak height 2 | Peak height 3 | Average |
| Epoxy chloropropane | Undetected | Not detected out | Undetected | Undetected |
| 1-chloro-2-propanol | Undetected | Undetected | Undetected | Undetected |
| 3-chloropropanol | Not detected out | Undetected | Not detected out | Not detected out |
| 1, 3-Dichloropropanol | Not detected out | Not detected out | Not detected out | Not detected out |
| 2, 3-Dichloropropanol | Not detected out | Not detected out | Not detected out | Not detected out |
TABLE 8 determination of quantitative Limit
| Name (R) | Concentration (μ g/ml) | Average peak height (μ V) | S/N | Corresponding to the test concentration (%) |
| Epoxy chloropropane | 0.594 | 18824 | 26.7 | 0.00024 |
| 1-chloro-2-propanol | 0.575 | 13144 | 17.8 | 0.00023 |
| 3-chloropropanol | 0.560 | 15284 | 20.8 | 0.00022 |
| 1, 3-Dichloropropanol | 0.582 | 16099 | 19.6 | 0.00023 |
| 2, 3-Dichloropropanol | 0.574 | 24208 | 21.7 | 0.00023 |
TABLE 9 measurement results of detection limits
| Name (R) | Concentration (μ g/ml) | Average peak height (μ V) | S/N | Corresponding to the test concentration (%) |
| Epoxy chloropropane | 0.178 | 3688 | 8.2 | 0.00007 |
| 1-chloro-2-propanol | 0.173 | 2191 | 5.4 | 0.00007 |
| 3-chloropropanol | 0.168 | 2588 | 6.6 | 0.00007 |
| 1, 3-Dichloropropanol | 0.175 | 2613 | 6.5 | 0.00007 |
| 2, 3-Dichloropropanol | 0.172 | 2854 | 7.0 | 0.00007 |
And (4) conclusion: in the method, the sensitivity of residual solvents of epichlorohydrin, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol and 2, 3-dichloropropanol in the metoprolol succinate bulk drug meets the requirement.
d) Durability verification
Control stock solutions: 3-chloropropanol, 1, 3-dichloropropanol, 2, 3-dichloropropanol, 1-chloro-2-propanol and epichlorohydrin are weighed accurately and respectively in proper amount, ethyl acetate is added for dissolving and diluting to prepare mixed solution containing 3.75 mu g of each of 3-chloropropanol, 1, 3-dichloropropanol, 2, 3-dichloropropanol, 1-chloro-2-propanol and epichlorohydrin in each 1 ml.
Control solution: precisely weighing 2.50081g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of a reference substance stock solution, shaking for 5 minutes, transferring the metoprolol succinate into a separating funnel, standing for 5 minutes, layering a mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the ethyl acetate layer into the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, precisely adding 0.50024g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution as a reference substance solution.
Test solution (solubilizer): precisely weighing 2.50091g of metoprolol succinate, placing the metoprolol succinate into a dry container, adding 15ml of water, ultrasonically dissolving, precisely adding 5ml of a reference substance stock solution, shaking for 5 minutes, transferring the metoprolol succinate into a separating funnel, standing for 5 minutes, layering a mixed solution, placing an ethyl acetate layer into another dry container, precisely adding 5ml of ethyl acetate into a residual water layer, shaking for 5 minutes, transferring the mixture into the separating funnel, standing for 5 minutes, layering the mixed solution, combining the ethyl acetate layers, precisely adding 0.50032g of anhydrous sodium sulfate, slowly shaking for 1 minute, standing for 5 minutes, and taking an upper layer solution as a test sample (adding a solvent).
The results of the reports of the separation degree of the retention time of each solvent from the adjacent solvent peaks and the content of each solvent in the sample solution chromatogram under the conditions of the change in the gas chromatography parameters are shown in tables 10 and 11.
TABLE 10 durability-control solution test results
TABLE 11 durability-test results for solutions of spiked test articles
And (4) conclusion: when the temperature of the injection port changes by +/-10 ℃, the temperature of the detector changes by +/-10 ℃, chromatographic columns of the same manufacturer, the same model and different batches are replaced, and gas chromatographs of different manufacturers are replaced, compared with normal conditions, the detection amount of each solvent in the reference solution and the solution of the added standard test sample has no obvious difference. The results show that the chromatographic conditions are durable even when the chromatographic conditions are slightly varied.
The verification proves that the gas chromatography detection method for the residual solvent in the metoprolol succinate bulk drug has the advantages of high sensitivity, good separation degree, strong specificity, good durability and accurate method, and has very important significance for quality control of the metoprolol succinate bulk drug.
Of course, the foregoing is only a preferred embodiment of the invention and should not be taken as limiting the scope of the embodiments of the invention. The present invention is not limited to the above examples, and equivalent changes and modifications made by those skilled in the art within the spirit of the present invention should be included in the scope of the present invention.
Claims (8)
1. A gas chromatography detection method for residual solvent in metoprolol succinate bulk drug is characterized in that: the method comprises the following steps:
(1) Preparation of a reference solution:
respectively taking residual solvents, precisely weighing, adding a diluent ethyl acetate for dissolving, and quantitatively diluting to obtain a solution with a certain concentration as a reference substance stock solution;
taking metoprolol succinate, precisely weighing, adding water to prepare metoprolol succinate solution with a certain concentration, then respectively adding the reference substance stock solution, performing liquid-separation extraction and water removal, and taking the supernatant as the reference substance solution;
(2) Preparing a test solution:
taking metoprolol succinate, precisely weighing, adding water to prepare metoprolol succinate solution with a certain concentration, adding a diluent ethyl acetate, performing liquid separation extraction, removing water, and taking supernatant as a test solution;
(3) And (3) determination: respectively injecting the diluent ethyl acetate, the reference substance solution and the test solution into a gas chromatograph, and recording a chromatogram; under the same gas chromatographic condition, metoprolol succinate and residual solvent thereof in the sample are separated.
2. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1, which is characterized in that: taking the residual solvent comprises: epichlorohydrin, 1-chloro-2-propanol, 3-chloropropanol, 1, 3-dichloropropanol, 2, 3-dichloropropanol.
3. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1, which is characterized in that: the concentration of the residual solvent in the step (1) is less than or equal to 0.000375wt%.
4. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1 is characterized in that: taking 2.5 +/-0.05 g of metoprolol succinate from the step (1), precisely weighing, adding 15ml of water, and ultrasonically dissolving to prepare the metoprolol succinate solution.
5. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1, which is characterized in that: taking 2.5 +/-0.05 g of metoprolol succinate in the step (2), precisely weighing, adding 15ml of water, and ultrasonically dissolving to prepare the metoprolol succinate solution.
6. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1, which is characterized in that: and (3) liquid separation and extraction in the step (1) and the step (2) are performed by adopting diluent ethyl acetate, and anhydrous sodium sulfate is adopted for water removal.
7. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 1 is characterized in that: the chromatographic conditions of the gas chromatograph in the step (3) are as follows:
a detector: a FID detector;
a chromatographic column: a capillary column taking nitroterephthalic acid modified polyethylene glycol as a stationary phase;
temperature rising procedure: the first stage is as follows: heating to 50 + -5 deg.C for 0-5min; and a second stage: the heating rate is 10 plus or minus 2 ℃/min, the temperature is increased to 220 plus or minus 5 ℃, and the heating time is 25 plus or minus 5min;
the temperature of a sample inlet is 240-260 ℃;
the temperature of the detector is 270-290 ℃;
the nitrogen flow rate is 0.8-1.2ml/min;
the flow splitting ratio is 2;
sample injection volume: 1-6 mul;
diluent (b): and (3) ethyl acetate.
8. The gas chromatography detection method of residual solvent in metoprolol succinate bulk drug according to claim 7, which is characterized in that: the type of the chromatographic column is DB-FFAP, the specification of the chromatographic column is 30m multiplied by 0.32mm, and the size of the chromatographic column is 0.25 mu m.
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