CN117451899A - Method for detecting impurities in crude drug of amino acid protein kinase inhibitor - Google Patents

Method for detecting impurities in crude drug of amino acid protein kinase inhibitor Download PDF

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CN117451899A
CN117451899A CN202311568387.6A CN202311568387A CN117451899A CN 117451899 A CN117451899 A CN 117451899A CN 202311568387 A CN202311568387 A CN 202311568387A CN 117451899 A CN117451899 A CN 117451899A
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solution
protein kinase
methanol
kinase inhibitor
amino acid
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徐东
王雪
张文玲
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Zibo High And New Technology Industry Development Districk Biomedicine Research Institute
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Zibo High And New Technology Industry Development Districk Biomedicine Research Institute
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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
    • 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
    • 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
    • G01N30/50—Conditioning of the sorbent material or stationary liquid
    • G01N30/52—Physical parameters
    • G01N30/54—Temperature
    • 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
    • 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
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • 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
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities

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  • Health & Medical Sciences (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)
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Abstract

The invention relates to the technical field of analysis and detection, in particular to a method for detecting impurities in a bulk drug of a protein kinase inhibitor. The analysis method comprises the steps of determining the content of 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in a raw material drug of a protein kinase inhibitor by using a liquid chromatograph, performing isocratic elution by using acetonitrile as a solvent and using a mixed solution of purified water and methanol-acetonitrile as a mobile phase, and analyzing the content of the impurities by using a standard curve method. The analysis method takes the mixed solution of purified water and methanol-acetonitrile as a mobile phase, directly samples, has short analysis time, overcomes the problem that the impurity is hydrolyzed in a short time when contacting water, and is difficult to determine, and has high efficiency and accuracy.

Description

Method for detecting impurities in crude drug of amino acid protein kinase inhibitor
Technical Field
The invention relates to the technical field of analysis and detection, in particular to a method for detecting impurities in a bulk drug of a protein kinase inhibitor.
Background
The amino acid protein kinase inhibitor can be used as a competitive inhibitor for combining ATP and tyrosine protein kinase, can also be used as an analogue of tyrosine to block peptide sites of an epidermal growth factor receptor and the coding of the tyrosine protein kinase, inhibit cell proliferation, and is expected to be developed into an antitumor drug, but does not show selectivity on intact cells. Methods for synthesizing protein kinase inhibitors or intermediates thereof are disclosed in patent CN114213430A, CN103373971A, CN106065016 a. During the synthesis of an amino acid protein kinase inhibitor, certain impurities are generated, for example, the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is an impurity which may exist in the bulk drug of the amino acid protein kinase inhibitor.
The impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol has unstable property, and is hydrolyzed in a short time when meeting water in the detection process, thus bringing difficulty to the detection. Therefore, it is necessary to design a simple and rapid analysis and detection method, and detect under the condition of ensuring the stability of the property, so as to improve the accuracy of the detection result.
Disclosure of Invention
The invention aims to solve the technical problems that: the method for detecting the impurities in the bulk drug of the inhibitor of the amino acid protein kinase solves the problems that the impurities 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol are hydrolyzed in a short time when meeting water and are difficult to detect, and realizes the effective separation of the impurities and a test sample, and the detection method is efficient and accurate.
According to the method for detecting the impurities in the crude drug of the amino acid protein kinase inhibitor, the content of the impurities 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in the crude drug of the amino acid protein kinase inhibitor is determined by using a high performance liquid chromatograph, acetonitrile is used as a solvent, a mixed solution of purified water and methanol-acetonitrile is used as a mobile phase, isocratic elution is carried out, and the content of the impurities is analyzed by using a standard curve method.
Specifically, the method for detecting impurities in the crude drug of the amino acid protein kinase inhibitor comprises the following steps:
(1) Setting parameter conditions of a high performance liquid chromatograph;
(2) Directly injecting the prepared reference substance solution and the prepared sample solution, collecting data, and then performing analysis and test;
(3) After the analysis is finished, the concentration of the impurity in the solution is calculated by using a standard curve according to the peak area of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol measured in the solution of the to-be-measured sample, and quantitative analysis is carried out.
The parameter conditions of the high performance liquid chromatography are as follows:
the sample injection mode is direct sample injection;
the sample injection amount is 5 μl;
the chromatographic column filler is octadecyl bonded silica gel with the specification of 4.6mm×250mm×5μm;
mobile phase a: purifying water; mobile phase B: methanol-acetonitrile mixed solution with the volume ratio of 50:50;
isocratic elution with mobile phase proportion of 50% mobile phase B;
the flow rate is 0.8ml/min;
the column temperature is 35 ℃;
the ultraviolet wavelength was 226nm.
The standard curve is a regression standard curve of the concentration of each linear solution to the peak area by preparing the linear standard solution and sequentially injecting the linear standard solution into a high performance liquid chromatograph.
As a preferred embodiment, the standard curve can be prepared by the following method:
(1) Preparing a 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution with the concentration of 3750ng/ml by taking acetonitrile as a solvent;
(2) Stock solutions of 3750ng/ml were precisely measured and diluted with acetonitrile to give linear solutions of 75ng/ml, 187.5ng/ml, 375.0ng/ml, 562.5ng/ml, and 750ng/ml, respectively.
Setting parameter conditions of gas chromatography and mass spectrum, then analyzing the linear solutions in turn, and making a regression standard curve according to the concentration of each linear solution to the peak area.
The regression standard curve equation for the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is as follows:
Y =36.1654X +727.258。
the preparation method of the sample solution comprises the following steps: the test sample is precisely weighed, and acetonitrile is added to prepare a test sample solution with the concentration of 1 mg/ml.
And (3) adopting direct sample injection, collecting data, calculating the concentration of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in the solution according to the measured peak area of the impurity, and analyzing the content of the impurity to be measured by a standard curve method.
Compared with the prior art, the invention has the following advantages:
(1) The detection and analysis method of the invention uses acetonitrile as a solvent, uses the mixed solution of purified water and methanol-acetonitrile as a mobile phase, has short detection time and simple operation, solves the problem that 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is hydrolyzed in a short time when meeting water, is difficult to detect, and has accurate quantification;
(2) The detection and analysis method has high sensitivity and strong specificity, and realizes the effective separation of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol and the test sample.
Drawings
FIG. 1 is a standard graph of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol;
FIG. 2 is a liquid chromatogram of the labeling solution-1 under the precision item.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications could be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.
The instrumentation used in the examples is as follows:
high performance liquid chromatograph: 2030 C PLUS.
The reagents, solutions used in the examples were as follows:
3750ng/ml of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution prepared by taking acetonitrile as a solvent.
The analytical conditions parameters in the examples are as follows:
the parameters of the liquid chromatograph were: the sample injection mode is direct sample injection; the sample injection amount is 5 μl; the chromatographic column filler is octadecyl bonded silica gel with the specification of 4.6mm×250mm×5μm; mobile phase a: purified water, mobile phase B: methanol-acetonitrile mixed solution with the volume ratio of 50:50; isocratic elution with mobile phase proportion of 50% mobile phase B; the flow rate is 0.8ml/min; the column temperature is 35 ℃; the ultraviolet wavelength was 226nm.
Examples
Linear and linear range analysis:
the method comprises the following steps:
accurately measuring a proper amount of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution respectively, and diluting with acetonitrile to prepare linear solutions with the concentrations of 75ng/ml, 187.5ng/ml, 375.0ng/ml, 562.5ng/ml and 750ng/ml respectively; and (3) sample injection detection, then sequentially analyzing the linear solutions, and respectively making regression curves according to the concentration of each linear solution and the peak area.
Discussion of results:
impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol standard curve is shown in fig. 1, y=36.1654x+727.258, r=0.9999; the linear relationship is good at the concentration of 75-750 ng/ml (namely 20% -200%).
Examples
Precision analysis:
the method comprises the following steps:
taking a proper amount of a test sample, precisely weighing, adding a proper amount of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution, dissolving with acetonitrile, preparing the test sample into a standard solution with the concentration of 2mg/ml, and adding the standard solution with the standard concentration of 375ng/ml, and preparing 6 parts by the same method.
Discussion of results:
the results of the precision investigation of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol are shown in Table 1.
Table 1 results of precision investigation
Examples
Accuracy analysis:
the method comprises the following steps:
test solution: taking a proper amount of test sample, precisely weighing, and adding a proper amount of acetonitrile to prepare a 1mg/ml test sample solution. 3 parts were prepared.
20% of labeled test sample solution: taking a proper amount of a test sample, precisely weighing, adding a proper amount of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution, dissolving with acetonitrile, preparing the test sample into a solution with the concentration of 1mg/ml, and adding a solution with the standard concentration of 75 ng/ml. 3 parts were prepared.
100% of test sample adding standard solution: taking a proper amount of a test sample, precisely weighing, adding a proper amount of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution, dissolving with acetonitrile, preparing the test sample into a solution with the concentration of 1mg/ml, and adding a solution with the standard concentration of 375 ng/ml. 3 parts of the mixture are prepared by the same method.
150% of test sample adding standard solution: taking a proper amount of a test sample, precisely weighing, adding a proper amount of impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution, dissolving with acetonitrile, preparing the test sample into a solution with the concentration of 1mg/ml, and adding a solution with the standard concentration of 562.5 ng/ml. 3 parts of the mixture are prepared by the same method.
Discussion of results:
the results of the accuracy analysis of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol are shown in Table 2.
TABLE 2 accuracy analysis results
Examples
And (3) detection limit analysis:
the method comprises the following steps:
100 μl of 375ng/ml stock solution was precisely measured, placed in a 10ml measuring flask, diluted to scale with acetonitrile, and shaken well. 3 needles were collected continuously.
Discussion of results:
the limit of detection analysis of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is shown in Table 3.
TABLE 3 detection limit analysis results
Examples
Analysis of test article:
the method comprises the following steps:
taking a proper amount of test sample, precisely weighing, and adding a proper amount of acetonitrile to prepare a 1mg/ml test sample solution; directly injecting sample into a high performance liquid chromatograph, collecting data, calculating the concentration of each impurity in the solution according to the peak area of the measured impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol, and analyzing the content of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol by a standard curve method.
The calculation formula is as follows: impurity content (ng/mg or ppm) =c×v/m;
wherein:
c: standard curve calculation to obtain concentration (ng/ml);
v: dissolving the volume (ml) of the solvent used for the test sample;
m: weighing the mass (mg) of the test sample.
Discussion of results:
the results of analysis of the content of 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in the test samples of the different batches are shown in Table 4.
TABLE 4 analysis results of impurity contents in test samples
The embodiment shows that the analysis method is suitable for detecting the content of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol, overcomes the problems that the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is unstable in property, is hydrolyzed in a short time when meeting water and is difficult to detect, and has the advantages of simple pretreatment, good precision, high accuracy, low detection limit, detection time conservation, high efficiency and accuracy.

Claims (8)

1. A method for detecting impurities in a bulk drug of a protein kinase inhibitor is characterized by comprising the following steps of: the content of 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in the crude drug of the inhibitor of the amino acid protein kinase is measured by using a high performance liquid chromatograph, acetonitrile is used as a solvent, a mixed solution of purified water and methanol-acetonitrile is used as a mobile phase, isocratic elution is carried out, and the content of the impurity is analyzed by a standard curve method.
2. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 1, wherein the method comprises the steps of: the method for detecting impurities in the crude drug of the amino acid protein kinase inhibitor comprises the following steps:
(1) Setting parameter conditions of a high performance liquid chromatograph;
(2) Directly injecting the prepared reference substance solution and the prepared sample solution, collecting data, and then performing analysis and test;
(3) After the analysis is finished, the concentration of the impurity in the solution is calculated by using a standard curve according to the peak area of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol measured in the solution of the to-be-measured sample, and quantitative analysis is carried out.
3. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 1 or 2, which is characterized in that: the parameter conditions of the high performance liquid chromatography are as follows:
the sample injection mode is direct sample injection;
the sample injection amount is 5 μl;
the chromatographic column filler is octadecyl bonded silica gel with the specification of 4.6mm×250mm×5μm;
mobile phase a: purifying water; mobile phase B: methanol-acetonitrile mixed solution with the volume ratio of 50:50;
isocratic elution with mobile phase proportion of 50% mobile phase B;
the flow rate is 0.8ml/min;
the column temperature is 35 ℃;
the ultraviolet wavelength was 226nm.
4. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 2, wherein the method comprises the steps of: the standard curve is a regression standard curve of the concentration of each linear solution to the peak area by preparing the linear standard solution and sequentially injecting the linear standard solution into a high performance liquid chromatograph.
5. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 2 or 4, which is characterized in that: the standard curve is prepared by the following method:
(1) Preparing a 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol stock solution with the concentration of 3750ng/ml by taking acetonitrile as a solvent;
(2) Precisely weighing 3750ng/ml stock solution, and diluting with acetonitrile to obtain linear solutions with concentrations of 75ng/ml, 187.5ng/ml, 375.0ng/ml, 562.5ng/ml and 750 ng/ml;
setting parameter conditions of gas chromatography and mass spectrum, then analyzing the linear solutions in turn, and making a regression standard curve according to the concentration of each linear solution to the peak area.
6. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 5, wherein the method comprises the steps of: the regression standard curve equation for the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol is as follows:
Y =36.1654X +727.258。
7. the method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 2, wherein the method comprises the steps of: the preparation method of the sample solution comprises the following steps: the test sample is precisely weighed, and acetonitrile is added to prepare a test sample solution with the concentration of 1 mg/ml.
8. The method for detecting impurities in a crude drug of an amino acid protein kinase inhibitor according to claim 2, wherein the method comprises the steps of: and (3) adopting direct sample injection, collecting data, calculating the concentration of the impurity 4- (1H-pyrazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-methanol in the solution according to the measured peak area of the impurity, and analyzing the content of the impurity to be measured by a standard curve method.
CN202311568387.6A 2023-11-23 2023-11-23 Method for detecting impurities in crude drug of amino acid protein kinase inhibitor Pending CN117451899A (en)

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