CN110873761A - Gas chromatography detection method for escitalopram oxalate intermediate related substances - Google Patents
Gas chromatography detection method for escitalopram oxalate intermediate related substances Download PDFInfo
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Abstract
The invention belongs to the field of analytical chemistry, and discloses a method for rapidly separating and detecting related substances N, N-dimethyl-3-chloropropylamine of an escitalopram oxalate intermediate by using a gas chromatography. The method has the advantages of strong specificity, high accuracy, good durability and simple and quick operation.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring N, N-dimethyl-3-chloropropylamine which is a related substance of an escitalopram oxalate intermediate by using a gas chromatography.
Background
The escitalopram oxalate has the functions of enhancing the 5-hydroxytryptamine (5-HT) of the central nervous system and inhibiting the reuptake of the 5-hydroxytryptamine, is mainly used for treating depression and anxiety in clinic, and has the characteristics of quick response of the anxiolytic and antidepressant effects, less adverse reactions and good compliance of patients in taking medicines. The chemical name of the intermediate of the oxalic acid esoximelant is (-) -4- [ 4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl]-3-hydroxymethylbenzonitrile D- (+) -di-p-toluoyltartrate (2:1), molecular formula C60H64F2N4O12. The chemical structural formula is as follows:
adverse reactions generated by the drugs in clinical use are related to the pharmacological activity of the drugs and sometimes have great relation with impurities in the drugs, and the registered and declared drugs require the research and effective control of the impurities introduced in the process of the drugs in order to ensure the quality and safety of the drugs. (-) -4- [ 4-dimethylamino-1- (4-fluorophenyl) -1-hydroxybutyl ] -3-hydroxymethylbenzonitrile D- (+) -di-p-toluoyltartrate (2:1) was used as an intermediate for escitalopram oxalate and its quality was studied and controlled to allow the quality of the final product escitalopram oxalate to be controlled. The organic impurity introduced in the process for synthesizing the escitalopram oxalate intermediate is N, N-dimethyl-3-chloropropylamine, and the structural formula is as follows:
because the ultraviolet absorption of the compound is very weak, the invention adopts the gas chromatography to realize the separation and the detection of the N, N-dimethyl-3-chloropropylamine. The method has important significance for finally improving the quality of escitalopram oxalate and ensuring the medication safety.
Disclosure of Invention
The invention aims to provide a method for separating and detecting related substances N, N-dimethyl-3-chloropropylamine in an escitalopram oxalate intermediate, so that the purity and quality of the escitalopram oxalate intermediate are effectively controlled, and the quality and medication safety of the escitalopram oxalate are ensured.
The method for separating and measuring the substances related to the escitalopram oxalate intermediate adopts a gas chromatography analysis technology, selects a proper solvent to dissolve a sample, and selects a polyethylene glycol chromatographic column and a hydrogen flame ionization detector according to the structure and physicochemical properties of impurities to be analyzed.
The solvent can be dimethyl sulfoxide or N, N-dimethylformamide.
The chromatographic column is selected from Agilent, Supelco, Phenomenex or Restek.
The chromatographic column is a strong-polarity or medium-grade polyethylene glycol capillary chromatographic column.
The separation and measurement method of the present invention can be realized by the following method:
1) taking a proper amount of escitalopram oxalate intermediate, adding 1ml of dimethyl sulfoxide for dissolving to prepare a solution containing 10-100 mg of escitalopram oxalate intermediate in every 1ml, and taking the solution as a test solution; and dissolving N, N-dimethyl-3-chloropropylamine hydrochloride in a proper amount of dimethyl sulfoxide to prepare a solution containing 0.5-10 mu g of N, N-dimethyl-3-chloropropylamine in each 1ml of the solution as a reference solution. Taking a proper amount of the escitalopram oxalate intermediate, precisely adding 1ml of a reference solution for dissolving to prepare a system applicability solution containing 10-100 mg of the escitalopram oxalate intermediate and 0.5-10 mu g of N, N-dimethyl-3-chloropropylamine per 1 ml;
2) setting the temperature of a sample inlet to be 200-250 ℃, the flow rate of a carrier gas to be 1.0-1.5 mL/min, and performing a temperature-raising method, wherein the temperature-raising program is an initial temperature of 40 ℃, the temperature-raising speed of 10-20 ℃ per minute is 200-250 ℃, the temperature is kept for 4min, the temperature of a detector is 250-300 ℃, and the flow-splitting ratio is 20: 1;
3) taking 1 μ L of each of the sample solution and the reference solution in the step 1), and injecting into a gas chromatograph according to the chromatographic conditions of the step 2), wherein:
the type of the gas chromatograph has no special requirements, and the gas chromatograph adopted by the invention is an Shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-WAX UI capillary chromatography column (30 m × 0.32mm, 0.5 μm);
sample inlet temperature: 200 ℃;
detector temperature: 250 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ L
Column oven temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 40 | / |
| 10 | 200 | 4 |
The method adopts a gas chromatography, selects a polyethylene glycol strong-polarity capillary chromatographic column (30 m multiplied by 0.32mm, 0.5 mu m), can quickly and effectively separate and measure the related substance N, N-dimethyl-3-chloropropylamine of the escitalopram oxalate intermediate, solves the separation and measurement problem of the organic impurity N, N-dimethyl-3-chloropropylamine introduced in the process of synthesizing the escitalopram oxalate intermediate, and thus achieves the effective control of the purity of the escitalopram oxalate intermediate.
Drawings
FIG. 1 is a gas chromatogram of a solvent (dimethyl sulfoxide) in example 1;
FIG. 2 is a gas chromatogram of escitalopram oxalate intermediate in example 1;
FIG. 3 is a gas chromatogram of N, N-dimethyl-3-chloropropylamine, from example 1;
FIG. 4 is a gas chromatogram of a system suitability solution in example 1;
FIG. 5 is a gas chromatogram of N, N-dimethyl-3-chloropropylamine, from example 2;
FIG. 6 is a gas chromatogram of N, N-dimethyl-3-chloropropylamine, taken in example 3.
The specific implementation mode is as follows:
the following examples are presented to further understand the present invention, but are not intended to limit the scope of the practice. The method for detecting N, N-dimethyl-3-chloropropylamine, which is a related substance of an escitalopram oxalate intermediate, is further described in detail by way of examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and all the technologies realized based on the above contents of the present invention are within the scope of the present invention.
Example 1
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-WAX UI capillary chromatography column (30 m × 0.32mm, 0.5 μm);
sample inlet temperature: 200 ℃;
detector temperature: 250 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 μ L
Column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 40 | / |
| 10 | 200 | 4 |
Experimental procedure
Taking a proper amount of the escitalopram oxalate intermediate, adding 1ml of dimethyl sulfoxide for dissolving to prepare a solution containing 100mg of the escitalopram oxalate intermediate in every 1ml, and taking the solution as a test solution; an appropriate amount of N, N-dimethyl-3-chloropropylamine was dissolved in dimethyl sulfoxide to prepare a solution containing 7.5. mu.g of N, N-dimethyl-3-chloropropylamine hydrochloride per 1ml, which was used as a control solution. Taking a proper amount of the escitalopram oxalate intermediate, precisely adding 1ml of a reference solution for dissolution, and preparing a system applicability solution containing 100mg of the escitalopram oxalate intermediate and 7.5 mu g of N, N-dimethyl-3-chloropropylamine per 1 ml.
Injecting 1 μ L of each of the test solution, the reference solution and the system applicability solution into a gas chromatograph under the above chromatographic conditions, wherein the results are shown in figures 1-4, and figure 1 is a blank solution chromatogram; FIG. 2 is a chromatogram of a sample solution. FIG. 3 is a chromatogram of a control solution showing a chromatographic peak of N, N-dimethyl-3-chloropropylamine with a retention time of 6.127 min. FIG. 4 is a gas chromatogram of a solution with system suitability, wherein the chromatographic peak with retention time of 6.102min is N, N-dimethyl-3-chloropropylamine. As shown in the figures 1-4, the method provided by the invention can be used for quickly and effectively separating and measuring the related substance N, N-dimethyl-3-chloropropylamine of the escitalopram oxalate intermediate, so that the purity and the quality of the escitalopram oxalate intermediate can be effectively controlled.
Example 2
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-WAX UI capillary chromatography column (30 m × 0.32mm, 0.5 μm);
sample inlet temperature: 195 ℃;
detector temperature: 250 ℃;
carrier gas (nitrogen) flow rate: 1.5 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 mu L of the solution;
column oven temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 40 | / |
| 10 | 200 | 4 |
Experimental procedure
Taking a proper amount of N, N-dimethyl-3-chloropropylamine, adding dimethyl sulfoxide to dissolve, and preparing a solution containing 7.5 mu g of N, N-dimethyl-3-chloropropylamine in 1ml of solution as a reference solution; dimethyl sulfoxide was also used as a blank solution. And analyzing according to the chromatographic conditions, and recording a chromatogram. FIG. 5 is a chromatogram of a control solution, showing the chromatographic peak for retention time 6.092min of N, N-dimethyl-3-chloropropylamine.
Example 3
Apparatus and conditions
Chromatograph: shimadzu 2010 plus gas chromatograph;
a detector: a hydrogen flame ionization detector;
a chromatographic column: DB-WAX UI capillary chromatography column (30 m × 0.32mm, 0.5 μm);
sample inlet temperature: 220 ℃;
detector temperature: 300 ℃;
carrier gas (nitrogen) flow rate: 1.4 mL/min;
the split ratio is as follows: 20: 1;
sample introduction volume: 1 mu L of the solution;
column box temperature program:
| rate of temperature rise (. degree. C./min) | Temperature (. degree.C.) | Retention time (min) |
| / | 40 | / |
| 10 | 200 | 4 |
Experimental procedure
Taking a proper amount of N, N-dimethyl-3-chloropropylamine, adding dimethyl sulfoxide to dissolve, and preparing a solution containing 7.5 mu g of N, N-dimethyl-3-chloropropylamine hydrochloride in 1ml of solution as a reference solution; dimethyl sulfoxide was also used as a blank solution. And analyzing according to the chromatographic conditions, and recording a chromatogram. FIG. 6 is a chromatogram of a control solution, showing a chromatographic peak for a retention time of 6.285min of N, N-dimethyl-3-chloropropylamine.
The invention verifies the following items of the method for analyzing the related substance N, N-dimethyl-3-chloropropylamine of the escitalopram oxalate intermediate:
specificity
Taking a proper amount of the escitalopram oxalate intermediate, adding 1ml of dimethyl sulfoxide for dissolving to prepare a solution containing 100mg of the escitalopram oxalate intermediate in every 1ml, and taking the solution as a test solution; dissolving N, N-dimethyl-3-chloropropylamine hydrochloride in dimethyl sulfoxide to obtain a solution containing N, N-dimethyl-3-chloropropylamine (7.5 μ g/1 ml) as a reference solution; taking a proper amount of the escitalopram oxalate intermediate, precisely adding 1ml of a reference solution for dissolving to prepare a system applicability solution containing 100mg of the escitalopram oxalate intermediate and 7.5 mu g of N, N-dimethyl-3-chloropropylamine per 1 ml; dimethyl sulfoxide was also used as a blank solution. And analyzing according to the chromatographic conditions, and recording a chromatogram. The result is shown in attached figures 1-4, under the chromatographic condition, the peak shape of the N, N-dimethyl-3-chloropropylamine is good, the detection is not interfered by other impurities in a solvent and a sample, the separation degree of the N, N-dimethyl-3-chloropropylamine and adjacent impurities meets the requirement, the theoretical plate number meets the detection requirement, and the method has good specificity.
Sample introduction precision test
Taking a proper amount of N, N-dimethyl-3-chloropropylamine hydrochloride, adding dimethyl sulfoxide to dissolve the N, N-dimethyl-3-chloropropylamine hydrochloride, and preparing a solution containing 7.5 mu g of N, N-dimethyl-3-chloropropylamine in each 1ml of the solution to be used as a sample solution. And analyzing according to the chromatographic conditions, repeatedly injecting the sample solution for 5 times, recording a chromatogram, and inspecting the injection precision of the method. The result can be added, and the method has good injection precision.
Quantitative limit and detection limit
Taking a proper amount of N, N-dimethyl-3-chloropropylamine hydrochloride, adding dimethyl sulfoxide to dissolve the N, N-dimethyl-3-chloropropylamine hydrochloride to prepare a solution containing 7.5 mu g of N, N-dimethyl-3-chloropropylamine in each 1ml of the solution as a sample solution; and precisely measuring a proper amount of sample solution, diluting step by step, and carrying out sample injection investigation according to the chromatographic conditions of the embodiment 1. By using the signal-to-noise ratio method, when the S/N is about 10, the corresponding sample concentration is the limit of quantification, and when the S/N is about 3, the corresponding sample concentration is the limit of detection. The quantitative limit and detection limit data of N, N-dimethyl-3-chloropropylamine are shown in the following table:
linearity
Taking a proper amount of N, N-dimethyl-3-chloropropylamine hydrochloride, precisely weighing, and respectively dissolving with dimethyl sulfoxide to prepare a N, N-dimethyl-3-chloropropylamine hydrochloride stock solution; precisely measuring N, N-dimethyl-3-chloropropylamine hydrochloride stock solution, diluting the stock solution into N, N-dimethyl-3-chloropropylamine hydrochloride test solution with quantitative limit concentration, 50% limit concentration, 100% limit concentration, 120% limit concentration and 150% limit concentration, and performing sample injection investigation on each solution according to the chromatographic conditions of example 1, wherein the results are shown in the following table:
regression equation and correlation coefficient: y =0.543c-0.027 r =0.999
Durability
By fine-tuning the chromatographic conditions such as injection port temperature, carrier gas flow rate, etc., we further examined the durability of the method. The result shows that the method has good durability under the conditions of the temperature change of an injection port of +/-5 ℃, the flow rate change of carrier gas of +/-0.1 mL/min and the like, the retention time of the N, N-dimethyl-3-chloropropylamine is not obviously changed, and the effective separation can be achieved.
Claims (7)
1. A method for separating and measuring related substances N, N-dimethyl-3-chloropropylamine of an escitalopram oxalate intermediate by utilizing gas chromatography is characterized by comprising the following steps: and (3) selecting a proper solvent to dissolve the sample, and adopting a gas chromatography, a polyethylene glycol capillary chromatographic column and a hydrogen flame ionization detector.
2. The separation assay method according to claim 1, wherein the solvent is selected from the group consisting of dimethyl sulfoxide and N, N-dimethylformamide.
3. The separation and measurement method according to claim 1, wherein the column is selected from the group consisting of Agilent, Supelco, Phenomenex and Restek.
4. The separation assay of claim 1, wherein the chromatographic column is a highly polar or medium-grade polyethylene glycol capillary chromatographic column.
5. The separation assay method of claim 1, comprising the steps of:
1) taking a proper amount of escitalopram oxalate intermediate, adding 1ml of dimethyl sulfoxide for dissolving to prepare a solution containing 10-100 mg of escitalopram oxalate intermediate in every 1ml, and taking the solution as a test solution; and dissolving N, N-dimethyl-3-chloropropylamine hydrochloride in a proper amount of dimethyl sulfoxide to prepare a solution containing 0.5-10 mu g of N, N-dimethyl-3-chloropropylamine in each 1ml of the solution as a reference solution.
2) Setting the temperature of a sample inlet to be 200-250 ℃, the flow rate of a carrier gas to be 1.0-1.5 mL/min, and performing a temperature-raising method, wherein the temperature-raising program is an initial temperature of 40 ℃, the temperature-raising speed of 10-20 ℃ per minute is 200-250 ℃, the temperature is kept for 4min, the temperature of a detector is 250-300 ℃, and the split ratio is 20: 1.
3) taking 1 μ L of each of the sample solution and the reference solution in 1) and injecting into a gas chromatograph under the chromatographic conditions of 2).
6. The separation analysis method according to claim 5, wherein said carrier gas of step 2) is nitrogen or helium.
7. The separation and analysis method according to claim 5, wherein the programmed temperature raising method in step 2) is preferably a temperature raising program comprising:
。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114814049A (en) * | 2022-03-11 | 2022-07-29 | 陕西渭河煤化工集团有限责任公司 | Method for analyzing dimethyl oxalate |
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Cited By (2)
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