CN111650289A - Method for determining related substances of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride - Google Patents
Method for determining related substances of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride Download PDFInfo
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- CN111650289A CN111650289A CN202010303084.1A CN202010303084A CN111650289A CN 111650289 A CN111650289 A CN 111650289A CN 202010303084 A CN202010303084 A CN 202010303084A CN 111650289 A CN111650289 A CN 111650289A
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- 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
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- G—PHYSICS
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- 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
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- G—PHYSICS
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- 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
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Abstract
The invention discloses a method for measuring related substances of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, which adopts gas chromatography, wherein the chromatographic conditions comprise that: the chromatographic column is a special column for analyzing the bonded cross-linked amines, and the temperature of a sample inlet is 200 ℃; the temperature of a detector (FID) is 250 ℃, nitrogen is used as carrier gas, split-flow sample injection is carried out, and temperature programming is adopted. The method can effectively separate the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride from the impurities, thereby accurately and efficiently determining the existence and/or the content of the impurities.
Description
Technical Field
The invention relates to the technical field of chemical drug analysis methods, in particular to a method for determining substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride
Background
3-chloro-1- (N, N-dimethyl) propylamine hydrochloride of the formula C5H13Cl2N, molecular weight 158.07, its structural formula is as follows:
the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride can be used for synthesizing medicaments, is an intermediate of amitriptyline, tylosin, chlorpromazine, imipramine, doxepin and the like, so that the content of related substances is measured, and the method plays an important role in ensuring the quality of products. The compound is a hydrochloride, so that the compound cannot be directly measured, and after dissociation, corresponding free alkali is extracted to measure impurities. Based on this, it is necessary to develop a suitable method for controlling the impurities present in 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride.
Disclosure of Invention
The invention provides a method for measuring related substances of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, which can accurately and efficiently measure the existence and/or content of the related substances of the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride.
The invention provides a method for carrying out sample pretreatment by a dissociation extraction method and measuring related substances by adopting a gas chromatography.
The dissociation solvent is sodium hydroxide solution, and the extraction solvent is dichloromethane.
In order to achieve the purpose, the invention provides the following technical scheme:
(1) sample preparation
Control solution: taking a proper amount of an impurity reference substance, precisely weighing, adding dichloromethane for dissolving, diluting to prepare an impurity solution containing about 30 mu g of the impurity reference substance, transferring 5ml of the impurity reference substance solution into a 20ml headspace bottle, adding 5ml of 0.14mol/L sodium hydroxide solution, shaking uniformly, standing, fully layering, taking a lower layer solution into the headspace bottle, adding a proper amount of anhydrous sodium sulfate for dewatering, filtering, and taking a filtrate as the reference substance solution.
Test solution: precisely weighing about 50mg of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, adding 5ml of 0.14mol/L sodium hydroxide solution, shaking up, adding 5ml of dichloromethane, shaking up, standing, fully layering, taking the lower layer solution into a headspace bottle, adding a proper amount of anhydrous sodium sulfate to remove water, filtering, and taking the filtrate as a test solution.
System applicability solution: precisely weighing 50mg of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, placing the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride into a headspace bottle, precisely adding 5ml of 0.14mol/l sodium hydroxide solution for dissolution, then adding 5ml of dichloromethane for dissolution, quantitatively diluting to prepare a solution containing about 30 mu g of impurities in each 1ml of reference substance, shaking uniformly, standing, fully layering, taking out the lower-layer solution by using an injector, placing the lower-layer solution into the headspace bottle, adding a proper amount of anhydrous sodium sulfate for dewatering, filtering, and taking the filtrate as a system applicability solution.
(2) Chromatographic conditions are as follows:
gas chromatography is used, wherein the chromatographic conditions comprise: the chromatographic column is a special column for analyzing the bonded cross-linked amines, and the temperature of a sample inlet is 200 ℃; the temperature of a detector (FID) is 250 ℃, nitrogen is used as carrier gas, split-flow sample injection is carried out, and temperature programming is adopted.
The temperature programming process comprises the following steps: the initial temperature was 95 ℃ for 5 minutes, and the temperature was raised to 240 ℃ at a rate of 20 ℃ per minute for 8 minutes.
(3) And (3) determination:
and (3) sampling a system applicability solution of the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride under the chromatographic condition in the step (2) to determine the position of an impurity peak and the separation condition of the impurity from a main peak.
Detecting the test solution and the control solution of the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride by using the chromatographic conditions in the step (2), and determining the existence and/or content of each impurity in the test solution according to the peak position.
According to the invention, the column has a length of 30m and an internal diameter of 0.32 mm.
According to the invention, the type of the column: InertCap for Amines.
According to the invention, the flow rate of the carrier gas is between 1ml/min and 2ml/min, preferably 2 ml/min.
According to the invention, the split ratio is 10: 1-30: 1, preferably 20: 1.
According to the invention, the initial column temperature is from 30 ℃ to 95 ℃, preferably the initial column temperature is 95 ℃.
According to the present invention, after attempting to adjust the temperature programming conditions, it is preferable that the temperature programming is as follows:
the initial temperature was 95 ℃ for 5 minutes, and the temperature was raised to 240 ℃ at a rate of 20 ℃ per minute for 8 minutes.
The invention provides a method for measuring substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, which can effectively separate the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride from impurities thereof, has accurate and reliable results, and provides scientific basis for establishing a stable, comprehensive and reliable quality control method for detecting the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride.
Drawings
FIG. 1 is a flow chart of the measuring method of the present invention
FIG. 2 is a blank solution of example 1
FIG. 3 is a system suitability solution chromatogram in example 1
FIG. 4 is a chromatogram of the sample solution in example 1
FIG. 5 is a chromatogram of a control solution in example 1
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
Example 1
Gas chromatography conditions:
the chromatographic column is a bonding cross-linked amine analytical special column InertCap for Amines (30m multiplied by 0.32mm), the injection port temperature is 200 ℃, the detector (FID) temperature is 250 ℃, nitrogen is used as carrier gas, the flow rate is 2ml/min, split injection is carried out, the split ratio is 20:1, and temperature programming is adopted.
The temperature programming process comprises the following steps: the initial temperature was 95 ℃ for 5 minutes, and the temperature was raised to 240 ℃ at a rate of 20 ℃ per minute for 8 minutes.
Sample preparation:
blank solution: taking 5ml of dichloromethane in a 20ml headspace bottle, adding 5ml of 0.14mol/L sodium hydroxide solution, shaking uniformly, standing, fully layering, taking the lower layer solution in the headspace bottle, adding a proper amount of anhydrous sodium sulfate to remove water, filtering, and taking the filtrate as a blank solution.
Control solution: taking a proper amount of an impurity reference substance, precisely weighing, adding dichloromethane for dissolving, diluting to prepare an impurity solution containing about 30 mu g of the impurity reference substance, transferring 5ml of the impurity reference substance solution into a 20ml headspace bottle, adding 5ml of 0.14mol/L sodium hydroxide solution, shaking uniformly, standing, fully layering, taking a lower layer solution into the headspace bottle, adding a proper amount of anhydrous sodium sulfate for dewatering, filtering, and taking a filtrate as the reference substance solution.
Test solution: precisely weighing about 50mg of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, adding 5ml of 0.14mol/L sodium hydroxide solution, shaking up, adding 5ml of dichloromethane, shaking up, standing, fully layering, taking the lower layer solution into a headspace bottle, adding a proper amount of anhydrous sodium sulfate to remove water, filtering, and taking the filtrate as a test solution.
System applicability solution: precisely weighing 50mg of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, placing the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride into a headspace bottle, precisely adding 5ml of 0.14mol/l sodium hydroxide solution for dissolution, then adding 5ml of dichloromethane for dissolution, quantitatively diluting to prepare a solution containing about 30 mu g of impurities in each 1ml of reference substance, shaking uniformly, standing, fully layering, taking out the lower-layer solution by using an injector, placing the lower-layer solution into the headspace bottle, adding a proper amount of anhydrous sodium sulfate for dewatering, filtering, and taking the filtrate as a system applicability solution.
And (3) determination: precisely measuring blank solution, system applicable solution, sample solution and reference solution, respectively, 1 μ l injecting into gas chromatograph, and recording chromatogram, as shown in fig. 2-5.
As a result: under the condition of the method, the blank solution has no interference at the positions of the main peak and the impurity peak, and the main peak and the impurity can be completely separated, which shows that the method has good specificity.
Example 2
Gas chromatography conditions: the same as in example 1.
Sample preparation:
control solution: the same as in example 1.
Test solution: the same as in example 1.
And (3) determination: placing the reference solution and the test solution at normal temperature without light, preparing for 0h, 2h, 4h, 6h and 8h respectively, precisely measuring 1 μ l, injecting into a gas chromatograph, recording chromatogram, and recording stability result for 8 hours, wherein the test results are shown in tables 1 and 2.
And (4) conclusion: the result shows that the comparison product solution and the test product solution are relatively stable within 8 hours.
TABLE 1 results of 8-hour stability test of control solutions
TABLE 2 test results of 8-hour stability of test solutions
Example 3
Gas chromatography conditions: the same as in example 1.
Sample preparation:
taking a proper amount of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride and an impurity reference substance respectively, precisely weighing, adding dichloromethane for dissolving and diluting to prepare mixed stock solution containing 300 mu g of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride and each impurity reference substance in each 1 ml. An appropriate amount of the mixed stock solution is measured, dissolved with dichloromethane and diluted to prepare solutions with a series of concentrations. Respectively transferring 5ml of each concentration solution, placing the solution into a headspace bottle, adding 5ml of 0.14mol/L sodium hydroxide aqueous solution, shaking uniformly, standing, fully layering, taking out the lower layer solution into the headspace bottle, adding a proper amount of anhydrous sodium sulfate to remove water, filtering, and taking the filtrate into a sample injection vial to serve as a linear test solution; each 1. mu.l of the sample was measured precisely under the chromatographic conditions of example 1, and the sample was injected into a gas chromatograph and a gas chromatogram. The linear regression equation of each component was calculated with the concentration (. mu.g/ml) as the X-axis and the peak area as the Y-axis, respectively, and the results are shown in Table 3.
And (4) conclusion: the results show that under the condition of the method, the linear relation between each impurity reference substance and the 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride is good.
TABLE 3 regression equation for each component
Example 4
Gas chromatography conditions: the same as in example 1.
Sample preparation:
control solution: the same as in example 1.
Test solution: respectively taking a proper amount of impurity reference substances, precisely weighing, adding dichloromethane to dissolve and dilute to prepare a reference substance storage solution containing about 300 mu g of impurities in each 1ml, respectively taking 2.5ml, 5ml and 7.5ml of the reference substance storage solution, respectively placing the reference substance storage solution into a 50ml measuring flask, dissolving by using dichloromethane, quantitatively diluting to a scale, and shaking up to obtain low-concentration, medium-concentration and high-concentration impurity solutions. Precisely weighing 50mg and 9 parts of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, respectively placing the hydrochloride into a headspace bottle, respectively and precisely adding 5ml of low-concentration, medium-concentration and high-concentration impurity solutions to dissolve the hydrochloride, respectively adding 5ml of 0.14mol/L sodium hydroxide solution, shaking uniformly, standing, fully layering, taking the lower layer solution out of the headspace bottle by using an injector, adding a proper amount of anhydrous sodium sulfate to remove water, filtering, taking filtrate, and preparing 3 parts of filtrate at each concentration to be used as a test solution.
And (3) determination: precisely measuring 1 μ l of each of the reference solution and the sample solution, injecting into a gas chromatograph, recording chromatogram, and calculating the recovery rate of each impurity, the results are shown in Table 4.
And (4) conclusion: the results show that under the condition of the method, the recovery rate of the impurity A, the impurity B, the impurity C and the impurity D is good.
TABLE 4 test results for recovery of each impurity
Example 5
Gas chromatography conditions: the same as in example 1.
Sample preparation:
control solution: the same as in example 1.
And (3) determination: adjusting initial column temperature, column flow rate, split ratio, and injection port temperature, measuring 1ul of reference solution, injecting into gas chromatograph, and recording chromatogram, the results are shown in Table 5.
And (4) conclusion: when the initial column temperature, the column flow speed, the flow splitting ratio and the injection port temperature are changed in a small range, the number and the response value of theoretical plates of all measured related substances are high, and all spectral peaks can be completely separated, so that the method has good durability.
TABLE 5 durability test results
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (6)
1. A method for measuring substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride is characterized in that:
(1) preparing a system applicability solution, a test solution and a reference solution of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride by adopting a dissociation and extraction method;
(2) determining related substances by adopting gas chromatography, wherein the chromatographic conditions comprise: the chromatographic column is a column special for bonded cross-linked amine analysis, the temperature of a sample inlet is 200 ℃, the temperature of a detector (FID) is 250 ℃, nitrogen is used as carrier gas, split-flow sample injection is carried out, and temperature programming is adopted, wherein the temperature programming is as follows: the initial temperature was 95 ℃ for 5 minutes, and the temperature was raised to 240 ℃ at a rate of 20 ℃ per minute for 8 minutes.
2. The dissociation and extraction method of claim 1, wherein 3-chloro-1- (N, N-dimethyl) propylamine is extracted from the dissociation solution of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride, and the 3-chloro-1- (N, N-dimethyl) propylamine extract is dried by anhydrous sodium sulfate and then analyzed and detected by gas chromatography;
optionally, the dissociation liquid is selected from a sodium hydroxide aqueous solution, a potassium carbonate aqueous solution, a sodium hydroxide and potassium carbonate mixed solution, and the dissociation liquid is preferably a sodium hydroxide aqueous solution; wherein the concentration of the sodium hydroxide aqueous solution is 0.07 mol/L-10 mol/L, preferably the concentration of the sodium hydroxide aqueous solution is 0.14 mol/L;
optionally, the extractant is selected from dichloromethane, n-hexane and toluene, and the extractant is preferably dichloromethane.
3. The method for determining substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride as claimed in claim 1, wherein: the impurities are selected from at least one of the following structures:
4. the method for determining substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride as claimed in claim 1, wherein: the column length is 30m and the internal diameter is 0.32 mm.
5. The method for determining substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride as claimed in claim 1, wherein: type of the chromatographic column: InertCap for Amines.
6. The method for determining substances related to 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride as claimed in claim 1, wherein: the carrier gas flow rate was 2 ml/min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113156003A (en) * | 2021-04-01 | 2021-07-23 | 河北利德检测技术有限公司 | Method for detecting tert-butylamine in arotinolol hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113156003A (en) * | 2021-04-01 | 2021-07-23 | 河北利德检测技术有限公司 | Method for detecting tert-butylamine in arotinolol hydrochloride |
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