CN112964794B - Method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof - Google Patents
Method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof Download PDFInfo
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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
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The invention discloses a method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof by high performance liquid chromatography. The method comprises the following steps: 1) Preparing a sample solution: dissolving 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride samples by using a mobile phase to prepare 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample solutions; 2) Injecting the sample solution into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and detection of the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample; wherein, in the high performance liquid chromatography, the mobile phase is an organic phase with a volume ratio of 25-5; the organic phase is methanol or acetonitrile. The method can effectively separate 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof, thereby realizing the quality control of the platelet coagulation inhibitor drug raw material medicine and the preparation.
Description
Technical Field
The invention relates to the technical field of compound detection, in particular to a method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof by using a high performance liquid chromatography.
Background
4,5,6,7-tetrahydrothieno [3,2-c ] pyridine hydrochloride is a pharmaceutical intermediate, and is mainly used for synthesizing platelet coagulation inhibitors such as ticlopidine, clopidogrel, prasugrel, etc. In order to improve the quality of drug production, according to drug production specifications and product standards, such as the specifications of the United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP), the quality of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride, which is a key intermediate, needs to be effectively analyzed and controlled, the preparation and degradation process of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride is analyzed, and several possible impurity components exist:
at present, relatively mature relevant reports on the analysis and detection of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride are not seen for a while. The prior art is as follows: "research on synthesis of 4,5,6,7-tetrahydrothieno [3,2-c ] pyridine" on volume 13 of science, technology and engineering "discloses gradient elution for HPLC method, but the gradient elution procedure is not specified in the literature, and 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride cannot be completely separated from its related substances by using the method of the literature.
Therefore, the need in the art is to provide a method for analyzing the purity of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and effectively separating 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances, thereby realizing the quality control of the platelet coagulation inhibitor drug raw material and preparation.
Disclosure of Invention
In view of this, the present invention provides a method for detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances by high performance liquid chromatography, which is used to analyze 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride for purity, and effectively separate 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances, thereby achieving quality control of platelet coagulation inhibitor drug substances and preparations.
In order to achieve the purpose, the invention provides a method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof by high performance liquid chromatography, which takes an organic phase with a volume ratio of 25 to 75-5; the organic phase is methanol or acetonitrile.
Specifically, the method comprises the following steps:
1) Preparing a sample solution: dissolving 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride samples by using a mobile phase to prepare 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample solution;
2) Injecting the sample solution into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and detection of the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample; wherein, the mobile phase is an organic phase with a volume ratio of 25 to 75-5 and is 25mmol/L potassium dihydrogen phosphate buffer solution.
In one embodiment of the invention, the mobile phase of the high performance liquid chromatograph is a mixture of 25:75-5:95 (preferably 1:9) in 25mmol/L potassium dihydrogen phosphate buffer solution.
In one embodiment of the invention, the organic phase is methanol or acetonitrile.
In a preferred embodiment of the invention, the organic phase is acetonitrile.
The mobile phase can well elute impurities, so that impurity peaks in a main peak are effectively separated, and each spectrum peak has good separation degree.
In one embodiment of the invention, the pH of the potassium dihydrogen phosphate buffer solution is 2 to 4, preferably 2.2. Under the pH value, the main peak and the impurity peak have good symmetry, and the chromatographic peaks have good separation degree.
The potassium dihydrogen phosphate buffer solution may be commercially available or may be prepared by conventional techniques in the art. In one embodiment of the present invention, the potassium dihydrogen phosphate buffer solution is prepared by the following method: precisely weighing 3.4g of monopotassium phosphate, adding 1000ml of water, adding 1ml of triethylamine, and adjusting the pH value to obtain the monopotassium phosphate buffer solution. In one embodiment of the present invention, the pH of the potassium dihydrogen phosphate buffer solution may be adjusted by using phosphoric acid.
In one embodiment of the invention, the flow rate of the mobile phase is from 0.2 to 1.0ml/min. Preferably 0.5ml/min. At the flow rate, the time of chromatographic peak emergence is proper, if the flow rate is less than 0.2ml/min, the analysis time is too long, the analysis efficiency is influenced, and if the flow rate is more than 1.0ml/min, the time of emergence is too fast, and partial impurities can not be detected.
In one embodiment of the invention, the high performance liquid chromatograph column is Welch
XB-C18(250mm×4.6mm，5μm)。
In one embodiment of the present invention, the column temperature of the HPLC chromatograph is 20-40 deg.C, preferably 30 deg.C. At the column temperature, the method is favorable for peak shape, and the separation degree is not influenced by too early peak emergence time. If the temperature is less than 20 c, the peak shape is too broad to facilitate separation, and if the temperature is more than 40 c, the time to peak is too early.
In one embodiment of the invention, the chromatogram is a chromatogram recorded at a detection wavelength of 210-240nm, preferably 234nm. At this detection wavelength, each spectral peak has excellent ultraviolet absorption.
In one embodiment of the invention, the concentration of the sample solution is 0.2. + -. 0.1mg/ml of the concentration of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride.
In one embodiment of the present invention, the sample solution is introduced into the sample solution in the step 2) in an amount of 10. Mu.l.
In one embodiment of the present invention, the related substances include the following:
under the chromatographic conditions, the method can accurately detect the sample in a relatively short time, and has the advantages of high sensitivity, strong response, good stability and high efficiency.
The chromatogram obtained by the method has good peak appearance of each impurity peak, and the condition of each impurity can be clearly distinguished.
In a preferred embodiment of the invention, the method for detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances by high performance liquid chromatography separation comprises the following steps:
1) Preparing a sample solution: dissolving 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride samples by using a mobile phase to prepare 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample solutions with the concentration of 0.2 +/-0.1 mg/ml;
2) Injecting 10 mu l of the sample solution into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and detection of the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample;
wherein, the chromatographic conditions of the high performance liquid chromatograph are as follows: the chromatographic column is Welch
XB-C18 (250 mm. Times.4.6 mm,5 μm); the mobile phase is acetonitrile with a volume ratio of 25-5; the column temperature of the high performance liquid chromatograph is 20-40 ℃; the flow rate of the mobile phase is 0.2-1.0ml/min; the detection wavelength is 210-240nm.
In a further preferred embodiment of the present invention, the method for detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances by high performance liquid chromatography separation comprises the following steps:
1) Preparing a sample solution: dissolving 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride samples by using a mobile phase to prepare 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample solution with the concentration of 0.2 mg/ml;
2) Injecting 10 mu l of the sample solution into a high performance liquid chromatograph, recording a chromatogram, and completing the separation and detection of the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample;
wherein the chromatographic conditions of the high performance liquid chromatograph are as follows: the chromatographic column is Welch
XB-C18 (250 mm. Times.4.6 mm,5 μm); the mobile phase is acetonitrile and 25mmol/L potassium dihydrogen phosphate buffer solution with the volume ratio of 9, wherein the pH value of the potassium dihydrogen phosphate buffer solution is 2.2; the column temperature of the high performance liquid chromatograph is 30 ℃; the flow rate of the mobile phase is 0.5ml/min; the detection wavelength was 234nm.
The method of the invention has the following advantages:
1. the peak shape of each substance in the chromatogram obtained by the method is good, and the condition of each impurity can be clearly distinguished;
2. by the method, the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride can be well separated from the raw material and impurity peaks.
3. The method can stably and effectively analyze and detect 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and impurities thereof.
4. By the method, the spectral peaks have excellent ultraviolet absorption, high sensitivity and strong response.
5. By the method, the peak emergence time of a chromatographic peak is appropriate, and 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and impurities thereof can be efficiently detected, so that the efficiency is high.
Drawings
FIG. 1 is a high performance liquid chromatogram of the sample solution of example 1.
FIG. 2 is a high performance liquid chromatogram of the sample solution in example 2.
FIG. 3 is a high performance liquid chromatogram of the sample solution in example 3.
FIG. 4 is a high performance liquid chromatogram of the sample solution of example 4.
FIG. 5 is a high performance liquid chromatogram of the sample solution in comparative example 1.
FIG. 6 is a high performance liquid chromatogram of the sample solution in comparative example 1.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the present invention, the ratio of each substance in the mobile phase is volume ratio, unless otherwise specified.
Example 1:4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and its related substance separation and detection
The embodiment provides a method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances by high performance liquid chromatography, which comprises the following steps:
1) Weighing 20mg of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride sample, placing the sample in a 100ml volumetric flask, adding a mobile phase for dissolving, diluting to a scale, and shaking up to obtain a sample solution;
2) Carrying out high performance liquid chromatography analysis on the sample solution according to the following chromatographic conditions, and recording a chromatogram;
chromatographic conditions are as follows:
high performance liquid chromatograph: d, safety: ultiMate3000;
a chromatographic column: welch
XB-C18(250mm×4.6mm，5μm)；
Mobile phase: acetonitrile: 25mmol/L potassium dihydrogen phosphate buffer solution (precisely weigh 3.4g of potassium dihydrogen phosphate, add 1000ml of water, add 1ml of triethylamine, adjust pH to 2.2 with phosphoric acid) = 90;
flow rate: 0.5ml/min;
detection wavelength: 234nm;
column temperature: 30 ℃;
sample introduction volume: 10 μ L.
FIG. 1 is an HPLC chart of the most preferred conditions, in FIG. 1, the peak 1 is impurity A, the peak 2 is 4,5,6,7-tetrahydrothiophene [3,2-C ] pyridine hydrochloride, the peak 3 is 2-thienylethylamine, the peak 4 is impurity C, the peak 5 is impurity B, and the peak 6 is impurity D. Under the condition, the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride can be well separated from raw materials and impurities, and the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride is about 10 min.
Example 2
This example was conducted in the same manner as in example 1 except that the column temperature in this example was 35 ℃ to separate and detect 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and its related substances.
FIG. 2 is an HPLC chart at 35 ℃ showing that the peak 1 in FIG. 2 is impurity A, the peak 2 is 4,5,6,7-tetrahydrothiophene [3,2-C ] pyridine hydrochloride, the peak 3 is 2-thienylethylamine, the peak 4 is impurity C, the peak 5 is impurity B, and the peak 6 is impurity D. Under the condition, the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride can be well separated from raw materials and impurities, and the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride is about 9.7 min.
Example 3
This example was conducted in the same manner as in example 1 to separate and detect 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances, except that the mobile phase flow rate in this example was: 1.0ml/min.
FIG. 3 is an HPLC chart at a flow rate of 1.0ml/min for the mobile phase, in FIG. 3, the impurity A is shown as the peak 1, the impurity C is shown as the peak 2, the impurity C is shown as the peak 4,5,6,7-tetrahydrothiophene [3,2-C ] pyridine hydrochloride, the impurity C is shown as the peak 3, the impurity B is shown as the peak 4, and the impurity D is shown as the peak 5. It can be seen that the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride main peak can not achieve good separation from raw materials and impurities under the condition, and the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride main peak is about 5.7 min.
Example 4
This example was conducted in the same manner as in example 1 to separate and detect 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances, except that the mobile phase in this example was: acetonitrile 25mmol/L potassium dihydrogen phosphate buffer = 20.
FIG. 4 is an HPLC chart at 20 to 80 acetonitrile/buffer ratio, in FIG. 4, the peak 1 is impurity A, the peak 2 is 4,5,6,7-tetrahydrothiophene [3,2-C ] pyridine hydrochloride + 2-thienylethylamine, the peak 3 is impurity C, the peak 4 is impurity B, and the peak 5 is impurity D. It can be seen that the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride main peak can not achieve good separation from raw materials and impurities under the condition, and the 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride main peak is about 6.7 min.
Comparative example 1
This example was conducted in the same manner as in example 1 to separate and detect 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances, except that the potassium dihydrogen phosphate buffer solution of this example had a pH of 7.0; the flow rate of the mobile phase was 1.0ml/min.
FIG. 5 is an HPLC chart showing the case where the pH of the buffer solution is 7.0 and the flow rate of the mobile phase is 1.0ml/min, and in FIG. 5, the peak 1 is 2-thiethylamine, the peak 2 is 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride, the peak 3 is impurity A, and the peak 4 is impurity B. Under the condition, the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride can be well separated from raw materials and impurities, and the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride is about 12.7 min. However, the tail of each chromatographic peak is serious, and the baseline is not stable, so that the integration of the chromatographic peak is not facilitated.
Comparative example 1
The comparative example provides a method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof by using a high performance liquid chromatography, and the method comprises the following steps:
1) Weighing 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride 20mg, placing in a 100ml volumetric flask, adding mobile phase for dissolving and diluting to a scale, and shaking uniformly to obtain a sample solution;
2) Taking a sample solution, carrying out high performance liquid chromatography analysis according to the following chromatographic conditions, and recording a chromatogram:
chromatographic conditions are as follows:
high performance liquid chromatograph: d, safety: ultiMate3000;
a chromatographic column: welch
XB-C18(250mm×4.6mm，5μm)；
Mobile phase: mobile phase a sodium dihydrogen phosphate buffer solution (precisely weighing 6.0g of sodium dihydrogen phosphate, adding 1000ml of water, adding 1ml of triethylamine, and adjusting PH to 7.0 with phosphoric acid);
mobile phase B: methanol
Elution procedure:
TABLE 1
| Time (min) | A％ | B％ |
| 0-20 | 90 | 10 |
| 20-40 | 90→32 | 10→68 |
| 40-55 | 32 | 68 |
| 55-56 | 32→90 | 68→10 |
| 56-65 | 90 | 10 |
Flow rate: 1.0ml/min;
detection wavelength: 234nm;
column temperature: 30 ℃;
sample introduction volume: 10 μ L.
FIG. 6 shows a HPLC chart of gradient elution at pH 7.0 of the buffer solution, methanol in the organic phase and 1.0ml/min in the mobile phase, in FIG. 6, peak 1 is 2-thienylethylamine, peak 2 is 4,5,6,7-tetrahydrothiophene [3,2-C ] pyridine hydrochloride, peak 3 is impurity A, peak 4 is impurity B, peak 5 is impurity C, and peak 6 is impurity D. Under the condition, the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride can be well separated from raw materials and impurities, and the main peak of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride is about 21.5 min. However, the tail of each chromatographic peak is serious, and the baseline is not stable, so that the integration of the chromatographic peak is not facilitated.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (3)
1. A method for separating and detecting 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride and related substances thereof by high performance liquid chromatography is characterized in that:
mobile phase: acetonitrile: 25mmol/L potassium dihydrogen phosphate buffer =10, and the preparation method of the 25mmol/L potassium dihydrogen phosphate buffer solution is as follows: weighing 3.4g of monopotassium phosphate, adding 1000ml of water, adding 1ml of triethylamine, and adjusting the pH value to 2.2 by using phosphoric acid;
the flow rate of the mobile phase is 0.5ml/min;
the chromatographic column is Welch
XB-C18 with the specification of 250mm multiplied by 4.6mm and 5 μm;
the detection wavelength is 210-240nm;
the related substances comprise 2-thiophene ethylamine, an impurity B, an impurity A, an impurity C and an impurity D, and the structural formula of the related substances is as follows:
2. the method of claim 1, wherein: the temperature of the chromatographic column is 20-40 ℃.
3. The method of claim 1, wherein: the concentration of 4,5,6,7-tetrahydrothiophene [3,2-c ] pyridine hydrochloride in the sample solution was 0.2. + -. 0.1mg/ml.
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