CN107228906B - Method for determining residual quantity of N, N-diisopropylethylenediamine in acotiamide bulk drug by using gas chromatograph - Google Patents
Method for determining residual quantity of N, N-diisopropylethylenediamine in acotiamide bulk drug by using gas chromatograph Download PDFInfo
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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
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Abstract
The invention discloses a method for determining the residual quantity of N, N-diisopropylethylenediamine in acotiamide bulk drug by using a gas chromatograph, wherein the analysis conditions of the method are as follows: adopting a nonpolar capillary chromatographic column; the temperature control mode is temperature programming, the sample injection adopts a flow distribution mode, the carrier gas is nitrogen, and the sample injection is carried out through a headspace sample injector; the detector is a hydrogen flame ionization detector. The method has the advantages of high sensitivity, high accuracy, strong specificity, good reproducibility, simple operation and simple calculation, thereby realizing the quality control of the acotiamide bulk drug and ensuring the safety of clinical medication.
Description
Technical Field
The invention relates to the field of chemical analysis, in particular to a method for determining the residual quantity of N, N-diisopropylethylenediamine in acotiamide raw material medicine by using a gas chromatograph.
Background
Acotiamide Hydrochloride (Acotiamide Hydrochloride) is shown as a formula I, and has a chemical name of N- {2- [ bis (1-methylethyl) amino ] ethyl } -2- [ (2-hydroxy-4, 5-dimethoxybenzoyl) amino ] thiazole-4-formamide Hydrochloride trihydrate. Acotiamide hydrochloride is used for treating postprandial fullness, epigastric fullness and early fullness of Functional Dyspepsia (FD), and is the first medicament for treating Functional Dyspepsia (FD) in the world. Developed by Anstela pharmaceutical company, Japan, with Zelims New drug Co., Ltd, approved in 3 and 25 in 2013, and marketed in Japan in 6 and 6 days 2013. By 12 months in 2015, no acotiamide hydrochloride bulk drug and preparation is approved by CFDA for marketing in China.
Acotiamide hydrochloride is a novel selective acetylcholinesterase (AChE) inhibitor. The neurotransmitter acetylcholine ACh is an important regulator of gastrointestinal motility, and acetylcholinesterase (AChE) is an enzyme that degrades (through its hydrolytic activity) ACh into choline and acetate, acting to terminate synaptic transmission. Acotiamide inhibits the decomposition of acetylcholine ACh free at nerve terminal by inhibiting the activity of acetylcholinesterase AChE, so that the ACh in the vestibule and the corpus of the stomach is increased to cause contraction and movement.
In the second step of the synthesis of acotiamide hydrochloride, N-diisopropyl ethylenediamine serving as a raw material is used. Although the limits of N, N-diisopropylethylenediamine are not specified in the Chinese pharmacopoeia and ICH, the limit of triethylamine in EMEA is specified to be 320ppm, and N, N-diisopropylethylenediamine and triethylamine belong to the same type of solvent and should be strictly controlled at 320 ppm.
At present, the analysis method for detecting the N, N-diisopropyl ethylenediamine is mainly an acid-base titration method, the content of pure N, N-diisopropyl ethylenediamine can be determined by adopting the acid-base titration method, but if the residue of the N, N-diisopropyl ethylenediamine in other substances needs to be determined, the accuracy and the sensitivity of the method are poor. On the other hand, N-diisopropylethylenediamine has no ultraviolet absorption and is not suitable for detection in a liquid phase.
At present, the method for determining the residual quantity of N, N-diisopropylethylenediamine in the bulk drugs still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a method for measuring the residual quantity of N, N-diisopropylethylenediamine in acotiamide bulk drug by using a gas chromatograph, which has the advantages of high sensitivity, high accuracy, strong specificity and good reproducibility, directly dissolves a sample, detects the sample by using a headspace gas method, calculates by using an external standard method, is simple and convenient to operate and simple to calculate, realizes the quality control of acotiamide, and ensures the safety of clinical medication.
The invention provides a method for determining the residual quantity of N, N-diisopropylethylenediamine in acotiamide raw material medicines by using a gas chromatograph. According to an embodiment of the invention, the analysis conditions of the method are:
adopting a nonpolar capillary chromatographic column;
the temperature control mode is temperature programming, the sample injection adopts a flow distribution mode, the carrier gas is nitrogen, and the sample injection is carried out through a headspace sample injector;
the detector is a hydrogen flame ionization detector.
Therefore, according to the method for determining the residual quantity of the N, N-diisopropylethylenediamine in the acotiamide bulk drug by using the gas chromatograph, disclosed by the embodiment of the invention, the interference of a blank peak on a target peak can be effectively avoided by adopting a mode of direct sample injection by temperature programming, so that the detection accuracy is improved, meanwhile, the rapid and efficient separation and content determination of the residual quantity of the N, N-diisopropylethylenediamine in the acotiamide bulk drug can be realized by adopting the method, and the detection method is strong in specificity, high in precision, strong in accuracy and convenient to operate, so that the quality of a drug is effectively controlled.
The method for determining the residual amount of the N, N-diisopropylethylenediamine in the acotiamide bulk drug by using the gas chromatograph according to some embodiments of the invention can further have the following additional technical features:
in some embodiments of the present invention, the sample solution to be tested is prepared by mixing the raw material drug with a diluent.
In some embodiments of the invention, the control solution is prepared by mixing N, N-diisopropylethylenediamine with a diluent.
In some embodiments of the invention, the nonpolar capillary chromatography column is a DB-1 capillary chromatography column. The separation effect obtained thereby is optimal.
In some embodiments of the invention, the temperature programming is: the initial temperature is 30-50 deg.C, and maintained for about 3-7min, and then increased to 220 deg.C at a rate of 10-30 deg.C/min, and maintained for about 3-7 min.
In some embodiments of the invention, the temperature programming is: keeping at 40 deg.C for 5min, and heating to 220 deg.C at 20 deg.C/min for 5 min. This can further improve the accuracy of the measurement of the residual amount of N, N-diisopropylethylenediamine.
In some embodiments of the invention, the feed split ratio is: (5:1-15:1), preferably 10: 1. The separation effect obtained thereby is optimal.
According to some embodiments of the invention, the flow rate of the carrier gas is 1.8-2.2ml/min, preferably 2 ml/min.
In some embodiments of the invention, the headspace sampling conditions are: headspace equilibrium temperature: 100 ℃ and 120 ℃, quantitative ring equilibrium temperature: 110-: 120 ℃ 140 ℃, headspace equilibration time: 20-30min, GC cycle time: and (5) 25-30 min. This can further improve the degree of separation.
In some embodiments of the invention, the detector gas flow rate is: hydrogen 30ml/min, air 400ml/min, tail-blown nitrogen: 30 ml/min.
In some embodiments of the invention, the diluent is a mixture comprising DMSO and an aqueous potassium carbonate solution, wherein the initial concentration of the aqueous potassium carbonate solution is 8% by volume.
In some embodiments of the invention, the volume ratio of the DMSO and the aqueous potassium carbonate solution in the diluent is 3: 2.
in some embodiments of the invention, the concentration of the sample solution to be tested is 100 mg/ml.
In some embodiments of the invention, the control solution has a concentration of 0.032 mg/ml.
In some embodiments of the invention, the gas chromatograph has a sample inlet temperature of 220 ℃. Therefore, the N, N-diisopropyl ethylenediamine in the sample can be completely gasified, and the detection accuracy is improved.
In some embodiments of the invention, the temperature of the detector is 280 ℃. Therefore, the water vapor condensation and impurity attachment in the chromatographic system can be prevented from remaining in the detector to damage the detector, so that the detection accuracy is further improved.
In some embodiments of the invention, the gas chromatograph is an Agilent 7890A gas chromatograph.
In some embodiments of the invention, the headspace sampler is an Agilent 7697A headspace sampler.
According to a specific embodiment of the invention, the measurement is carried out using a DB-1 capillary chromatography column of 30 m.times.0.32 mm.times.1.0. mu.m, the temperature being controlled in such a way that:
| temperature rise Rate/. degree.C./min | Temperature/. degree.C | Retention time/min |
| / | 40 | 5 |
| 20 | 220 | 5 |
Wherein the injection port temperature of the gas chromatograph is 220 ℃, the temperature of the detector is 280 ℃, and the split ratio is 10: 1.
The invention aims to be realized by the following technical scheme: the method for measuring the residual N, N-diisopropyl ethylenediamine in acotiamide comprises the following steps:
a: preparing a sample solution to be tested: taking a proper amount of acotiamide sample, dissolving the acotiamide sample by using a dimethyl sulfoxide-8 volume percent potassium carbonate aqueous solution (3:2) (v/v) and diluting the acotiamide sample into a solution of 100mg/ml, wherein the solution is used as a sample solution to be detected;
b: preparation of a control stock solution: an appropriate amount of N, N-diisopropylethylenediamine control was dissolved in dimethyl sulfoxide and diluted to a solution of 1.6 mg/ml.
Control solution: precisely transferring 1ml of the above control stock solution, placing in a 50ml measuring flask, diluting with methyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) to scale, and shaking to obtain control solution (0.032 mg/ml).
C: detecting by adopting a headspace gas chromatography, and recording a chromatogram.
D: and (3) calculating: the content of N, N-diisopropylethylenediamine is calculated according to an external standard method.
In the formula：CControl: concentration of control solution; cSample to be tested: the concentration of the sample solution to be measured;
Acontrol: peak area of the control solution; a. theSample to be tested: peak area of the sample solution to be measured;
wherein the gas chromatography conditions are:
a chromatographic column: a capillary column (the column length is 30m, the inner diameter is 0.32mm, and the liquid film thickness is 1.0um) with 100 percent of dimethyl polysiloxane as a stationary liquid is a chromatographic column; temperature programming: initial temperature is 30-50 deg.C, maintaining for about 3-7min, then raising to 220 deg.C at a speed of 10-30 deg.C/min, and maintaining for about 3-7 min; the temperature of a sample inlet is 220 ℃, the detector is a hydrogen flame ionization detector, and the temperature of the detector is 250-; the carrier gas is nitrogen, and the flow rate of the carrier gas is 1.8-2.2ml per minute.
The invention has the following advantages: the method for determining the residual solvent N, N-diisopropyl ethylenediamine in acotiamide has the advantages of high accuracy, strong specificity, high detection sensitivity (detection limit: 1ppm), and simple and rapid determination, can qualitatively or quantitatively detect the residual N, N-diisopropyl ethylenediamine in acotiamide, ensures the quality of the acotiamide, and improves the safety of clinical medication.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a chromatogram for detection limit of N, N-diisopropylethylenediamine in example 1;
FIG. 2 is a quantitative limit chromatogram of N, N-diisopropylethylenediamine in example 1;
FIG. 3 is a chromatogram of the sample-application/collection solution in example 2;
FIG. 4 is a chromatogram of a control solution from example 3;
FIG. 5 is a chromatogram of acotiamide sample solution 1 from example 3;
FIG. 6 is a chromatogram of acotiamide sample solution 2 from example 4.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The acotiamide raw material medicine used in the embodiment of the invention is prepared by self.
N, N-diisopropylethylenediamine control: batch number: L5B0N20 manufacturer: j ﹠ K
Example 1 detection and quantitation limits
1. Chromatographic conditions are as follows: a chromatographic column: DB-1 capillary chromatographic column (30m x 0.32mm x 1.0um)
A detector: hydrogen flame ionization detector
Sample inlet temperature: 220 deg.C
Detector temperature: 280 deg.C
Column temperature: heating at 40 deg.C for 5min, heating to 220 deg.C at 20 deg.C/min, and maintaining for 5min
Flow rate of carrier gas: nitrogen (2ml/min)
Detector gas flow rate: hydrogen gas: 30ml/min air: blowing nitrogen gas at the tail of 400 ml/min: 30ml/min
The split ratio is as follows: 10:1
Operating time: 19min
And (3) headspace setting: headspace equilibrium temperature: 110 ℃; quantitative ring equilibrium temperature: 120 ℃; transfer line temperature: 130 ℃; headspace equilibrium time: 20min GC cycle time: 25min
2. The experimental method comprises the following steps:
reference stock solution: 81.58mg of N, N-diisopropylethylenediamine reference substance is weighed, precisely weighed, placed in a 50ml measuring flask and diluted to the scale with dimethyl sulfoxide.
Control solution: precisely transferring 1ml of the reference stock solution, placing into a 50ml measuring flask, and diluting with dimethyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) (v/v) to scale to obtain reference solution.
Quantitative limiting solution: precisely transferring 1ml of the control solution, placing in a 100ml measuring flask, diluting with dimethyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) (v/v) and fixing to the scale, precisely measuring 5ml, placing in a 20ml headspace flask, capping and sealing.
Detection limiting solution: precisely transferring 3ml of the limiting solution, placing the limiting solution in a 10ml measuring flask, diluting the limiting solution with dimethyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) (v/v) and fixing the volume to a scale, precisely measuring 5ml, placing the limiting solution in a 20ml headspace flask, and sealing by covering.
And (4) respectively taking the quantitative limiting solution and the detection limiting solution, injecting the quantitative limiting solution and the detection limiting solution into a gas chromatograph, and recording the chromatogram. The quantitative limit and detection limit maps are respectively shown in the figure 1 and the figure 2, and the analysis results are shown in the table 1:
TABLE 1 analytical results
| Parameter(s) | Concentration (μ g/ml) | Percent (ppm) | Peak area | Signal to noise ratio |
| Detection limiting solution | 0.0979 | 1 | 0.31 | 3.8 |
| Quantitative limiting solution | 0.3263 | 3 | 1.09 | 14.8 |
And (4) conclusion: the detection sensitivity of the N, N-diisopropylethylenediamine in acotiamide is high, the detection limit is 1ppm, and the quantification limit is 3 ppm.
Example 2 accuracy test
1. Chromatographic conditions are as follows: same as example 1
2. The experimental method comprises the following steps:
blank solution: dimethyl sulfoxide-8% by volume aqueous potassium carbonate solution (3:2) (v/v)
Preparing a sample solution to be detected: about 500mg of acotiamide sample is weighed, precisely weighed, placed in a 20ml headspace bottle, 5ml of dimethyl sulfoxide-8 volume percent potassium carbonate aqueous solution (3:2) (v/v) is removed for dissolution, covered and sealed, and 2 parts are prepared in parallel for each batch.
Preparing a reference substance solution: precisely transferring 2ml of the reference stock solution in example 1, placing the reference stock solution in a 100ml measuring flask, and diluting the reference stock solution to a scale by using a diluent to obtain a reference solution. The control solution was measured precisely 5ml, placed in a 20ml headspace bottle, and capped and sealed (6 aliquots removed in parallel).
Sample adding and solution recovering: weighing about 500mg of acotiamide, precisely weighing, weighing 6 parts in parallel, respectively placing into 20ml headspace bottles, respectively transferring 5ml of control solution to dissolve, and sealing with a cover. 6 parts are prepared in parallel.
And (3) injecting the blank solution, the sample solution to be detected and the sample adding and recovering solution into a gas chromatograph, and recording the chromatogram (figure 3). The recovery of N, N-diisopropylethylenediamine was calculated, and the analysis results are shown in Table 2.
TABLE 2 analytical results
And (4) conclusion: the recovery rate of the N, N-diisopropyl ethylenediamine in the acotiamide is 84.92%, the recovery rate is high, and the residual quantity of the N, N-diisopropyl ethylenediamine in the acotiamide can be accurately detected.
Example 3 detection of residual N, N-diisopropylethylenediamine in Acotiamide
A: preparing a sample solution to be tested: acotiamide sample 501.12mg was weighed precisely into a 20ml headspace bottle, dissolved with 5ml of dimethyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) (v/v), and sealed with a cap.
B: preparing a reference substance solution: the same as in example 1.
C: and (4) respectively injecting the reference substance solution and the sample solution to be detected into a gas chromatograph, and recording the chromatogram.
D: and (3) calculating: the amount of residual N, N-diisopropylethylenediamine was calculated by the external standard method.
Chromatographic conditions are as follows: same as example 1
The experimental results are as follows: the chromatogram of the N, N-diisopropylethylenediamine reference solution is shown in figure 4, the chromatogram of the sample solution to be tested is shown in figure 5, the N, N-diisopropylethylenediamine peak is not detected in the chromatogram, and the residual quantity of the N, N-diisopropylethylenediamine in acotiamide is 0% by calculation.
Example 4 detection of residual N, N-diisopropylethylenediamine in Acotiamide
A: preparing a sample solution to be tested: acotiamide sample 502.58mg was weighed precisely into a 20ml headspace bottle, dissolved with 5ml of dimethyl sulfoxide-8 vol% potassium carbonate aqueous solution (3:2) (v/v), and sealed with a cap.
B: preparing a reference substance solution: the same as in example 1.
C: and (4) respectively injecting the reference substance solution and the sample solution to be detected into a gas chromatograph, and recording the chromatogram.
D: and (3) calculating: the amount of residual N, N-diisopropylethylenediamine was calculated by the external standard method.
Chromatographic conditions are as follows: same as example 1
The experimental results are as follows: the chromatogram of the sample solution to be tested is shown in fig. 6, wherein no peak of N, N-diisopropylethylenediamine is detected, and the residual amount of N, N-diisopropylethylenediamine in acotiamide is 0% by calculation.
Claims (12)
1. A method for determining the residual quantity of N, N-diisopropylethylenediamine in acotiamide bulk drug by using a gas chromatograph is characterized in that the analysis conditions of the method are as follows:
adopting DB-1 capillary chromatographic column;
the temperature control mode is temperature programming, the sample injection adopts a flow distribution mode, the carrier gas is nitrogen, and the sample injection is carried out through a headspace sample injector;
the detector is a hydrogen flame ionization detector;
the headspace sampling conditions were:
headspace equilibrium temperature: 100-120 ℃;
quantitative ring equilibrium temperature: 110-130 ℃;
transfer line temperature: 120-140 ℃;
headspace equilibrium time: 20min-30 min;
GC cycle time: 25min-30 min;
the sample solution to be tested is prepared by mixing the raw material medicines and a diluent, wherein the diluent is a mixed solution containing DMSO and a potassium carbonate aqueous solution;
the temperature programming procedure is that the temperature is kept at 40 ℃ for 5min, then the temperature is increased to 220 ℃ at the speed of 20 ℃/min, and the temperature is kept for 5 min;
the temperature of a sample inlet of the gas chromatograph is 220 ℃, the temperature of the detector is 280 ℃, and the sample injection split ratio is 10: 1.
2. The method of claim 1, wherein the control solution is prepared by mixing N, N-diisopropylethylenediamine with a diluent.
3. The method of claim 1, wherein the carrier gas has a flow rate of 1.8-2.2 ml/min.
4. The method of claim 1, wherein the carrier gas has a flow rate of 2 ml/min.
5. The method of claim 1, wherein the gas flow rate of the detector is: hydrogen 30ml/min, air 400ml/min, tail-blown nitrogen: 30 ml/min.
6. The process of claim 2, wherein the initial concentration of the aqueous potassium carbonate solution is 8 vol%.
7. The method according to claim 1, wherein the volume ratio of the DMSO to the aqueous potassium carbonate solution in the diluent is 3: 2.
8. the method of claim 1, wherein the concentration of the sample solution to be tested is 100 mg/ml.
9. The method of claim 2, wherein the control solution has a concentration of 0.032 mg/ml.
10. The method of claim 1, wherein the dimensions of the DB-1 capillary chromatography column are 30m x 0.32mm x 1.0 μ ι η.
11. The method of claim 1, wherein the gas chromatograph is an Agilent 7890A gas chromatograph.
12. The method of claim 1, wherein the headspace sampler is an Agilent 7697A headspace sampler.
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