Analysis method for measuring content of cesium element in crizotinib starting material

Abstract

The invention discloses an analysis and detection method for determining the content of a cesium element in a crizotinib starting material based on graphite furnace atomic absorption spectrometry without adding a matrix modifier. 2% nitric acid aqueous solution is used as a solvent, is economical, practical and environment-friendly, shortens experimental time and improves efficiency; a sample is dissolved, substrate interference is reduced, and the service life of an atomic absorption instrument is prolonged; the use of high-precision instruments is more efficient and environment-friendly; in the subsequent method development, the method can be used for reference for detection items with low limit and high concentration of a test solution.

Description

Technical Field

[0001] The invention belongs to the field of analytical chemistry, and in particular relates to an analytical detection method for determining the cesium content in medicines based on graphite furnace atomic absorption spectrometry. Background Art

[0002] Crizotinib (English trade name Xalkori) is an ATP-competitive multi-target protein kinase inhibitor developed by Pfizer that inhibits Met / ALK / ROS. Its chemical name is (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-alkyl-1 hydrogen-pyrazole-4-alkyl)-pyrimidin-2-indane, and it has a structure shown in the following formula (I):

[0003] It can be used to treat patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are positive for anaplastic lymphoma kinase (ALK) as determined by a CFDA-approved test method.

[0004] The synthetic route for preparing the important intermediates of crizotinib is as follows:

[0005]

[0006] The method described uses cesium carbonate as an acid-binding agent for the nucleophilic substitution reaction. The use of excessive cesium carbonate will cause the residue of cesium in the intermediate product IV, and ultimately affect the quality of the crizotinib raw material. In order to better control the quality of crizotinib and improve the safety of the drug, the cesium element used in the crizotinib synthesis process needs to be strictly monitored. Summary of the invention

[0007] At present, there is no relevant report on the analytical detection method for the cesium content in the crizotinib starting material. In order to solve the deficiencies of the prior art, the present invention provides an analytical detection method for determining the cesium content in the crizotinib starting material based on graphite furnace atomic absorption spectrometry without adding a matrix modifier. The present invention provides the following technical solutions:

[0008] An analytical method for determining the cesium content in crizotinib starting materials using graphite furnace atomic absorption spectrometry, the method comprising:

[0009] (1) Dissolving the crizotinib starting material with a solvent to dilute it into a solution containing 0.1 mg to 0.3 mg of the crizotinib starting material per 1 ml as a test solution, wherein the solvent is a mixed solution of nitric acid and water; injecting the test solution into an atomic absorption spectrometer, the parameters of the atomic absorption spectrometer are as follows: cesium hollow cathode lamp and graphite furnace atomizer, element Cs, wavelength 852.12 nm, slit width 0.7 nm, lamp current: 70 mA;

[0010] (2) Heating program: The heating program includes drying temperature, ashing temperature, atomization temperature, and residue removal temperature;

[0011] The drying temperature includes the first drying temperature and the second drying temperature;

[0012] The first step drying temperature is 100°C to 120°C, and the ramp-up time is 1 second to 10 seconds;

[0013] The drying temperature of the second step is 100℃~200℃, and the ramp-up time is 15 seconds~40 seconds;

[0014] The combined effect of the temperature and ramp-up time of the two-step drying and the one-step drying of the present invention is to quickly raise the temperature to a temperature slightly below the boiling point, and then slowly raise the temperature to just above the boiling point and maintain it for a certain time to remove the solvent of the sample solution. The sample solution dripped into the graphite tube is heated to evaporate and remove the solvent, without allowing any loss of the elements to be analyzed.

[0015] The ash temperature is 150℃~800℃;

[0016] The purpose of the ashing process of the present invention is to remove all or most of the coexisting substances in the sample as much as possible and to ensure that no elements to be analyzed are lost.

[0017] Atomization temperature is 1000℃~2500℃;

[0018] The residual removal temperature is 2200℃~2700℃;

[0019] Quantitative determination of cesium in crizotinib starting materials.

[0020] Preferably, the first step drying temperature is 110°C.

[0021] The first step drying temperature ramp-up time is 3 to 7 seconds, preferably 5 seconds;

[0022] The drying temperature in the second step is 120°C to 180°C, more preferably 150°C.

[0023] The second drying temperature ramp-up time is 25 to 35 seconds, preferably 30 seconds;

[0024] The ashing temperature is 200°C to 300°C, preferably 250°C;

[0025] The atomization temperature is 1500-2000°C;

[0026] The residual removal temperature is 2300~2500℃;

[0027] Furthermore, the present invention provides the above-mentioned analytical method for determining the cesium content in the crizotinib starting material using graphite furnace atomic absorption spectrometry, wherein the method further comprises the step of testing the cesium standard stock solution and preparing a standard curve.

[0028] Use the same solvent as that for preparing the test solution to prepare the cesium standard curve solution, inject the test solution and the cesium standard curve solution into the atomic absorption spectrometer respectively, and calculate the cesium content by the external standard method.

[0029] Furthermore, in step (1), the maximum sensitivity value of the cesium element of the atomic absorption spectrometer is 20 μg / L. According to the sensitivity value of the atomic absorption spectrometer, the appropriate concentration of the test solution is screened, and then the concentration of the 100% standard curve solution is calculated. This concentration is less than the sensitivity value, and a linear correlation coefficient r value with good linearity can be obtained. This can effectively avoid blindly preparing a series of standard curve solutions and greatly reduce the workload.

[0030] Furthermore, the sample pretreatment method in step (1) is digestion or non-digestion, preferably a non-digestion system. Considering that in the non-digestion system, the sample solution preparation process is simple and the tedious work of microwave digestion is omitted, the best pretreatment method is the non-digestion system.

[0031] Furthermore, the present invention provides the above-mentioned analytical method for determining the cesium content in the crizotinib starting material by graphite furnace atomic absorption spectrometry, wherein the crizotinib starting material is dissolved and diluted with a solvent to form a solution containing 0.1 mg to 0.3 mg of crizotinib starting material per 1 ml as the test solution, preferably 0.2 mg / ml.

[0032] Furthermore, the present invention provides the above-mentioned analytical method for determining the cesium content in the crizotinib starting material by graphite furnace atomic absorption spectrometry, wherein the solvent is a mixed solution of nitric acid-water, and the mixing volume ratio is 1 to 5:100, preferably 2:100.

[0033] Furthermore, the injection volume in step (1) is 20 μl.

[0034] The beneficial effects of the present invention are:

[0035] The present invention uses a graphite furnace atomic absorption spectrometry method without adding a matrix modifier to screen suitable test sample concentration, dissolution method and solvent, and optimizes the two-step drying temperature, ramp-up time and ashing temperature in a heating program, so as to accurately detect the content of cesium in the crizotinib starting material, which is beneficial to effectively detect and control product quality.

[0036] The analytical method of the present invention can comprehensively control the content of cesium in the crizotinib starting material, improve the safety of the drug, and provide a basis for formulating the quality standard of the crizotinib raw material. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is the blank solvent chromatogram;

[0038] Figure 2 It is the chromatogram of the series standard curve solution;

[0039] Figure 3 Spectrum of the starting material of crizotinib DETAILED DESCRIPTION

[0040] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0041] In order to make the technical means, creative features, objectives and effects achieved by the present invention easy to understand, the present invention is further explained below in conjunction with specific implementation methods.

[0042] Instrument: Atomic absorption spectrometer, including cesium hollow cathode lamp, graphite furnace atomizer, monochromator, detector, graphite tube, graphite furnace autosampler

[0043] Reagents: Nitric acid (electronic grade), water (Milli-Q)

[0044] Test article: Crizotinib starting material.

[0045] The following examples illustrate the present invention but do not limit the present invention in any way.

[0046] Embodiment 1:

[0047] The graphite furnace was used as an atomizer and the determination was made at a wavelength of 852.12 nm according to the atomic absorption spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0406, Method 1). The concentration and the absorption value were linearly regressed to obtain a standard curve.

[0048] Instrument parameters

[0049]

[0050] Determination method

[0051] Solvent nitric acid-water (2:100, volume ratio)

[0052] Test solution Take 0.02 g of the product, weigh accurately, place in a 100 ml volumetric flask, add 2 ml of nitric acid to dissolve, dilute to the mark with water, shake well, and make a solution containing about 0.2 mg per 1 ml.

[0053] Cesium standard stock solution (200 μg / L): Take 1 ml of cesium standard solution (20 mg / L), place it in a 100 ml volumetric flask, dilute to the scale with 2% nitric acid solution, shake well, and the solution is ready.

[0054] Standard curve: Accurately measure 1ml, 2ml, 3.5ml, 5ml and 3.5ml of cesium standard stock solution and place them in 50ml, 50ml, 50ml, 50ml and 25ml volumetric flasks respectively. Dilute to the scale with 2% nitric acid solution and shake well to obtain a series of reference solutions of 4μg / L, 8μg / L, 14μg / L, 20μg / L and 28μg / L, which are equivalent to 20%, 57%, 100%, 143% and 200% of the limit concentration respectively.

[0055] Inject the test solution and cesium standard curve solution into the atomic absorption spectrometer respectively. The chromatograms of the series of standard curve solutions are as follows: Figure 2 As shown, the chromatogram of the test solution is Figure 3 As shown, the cesium content of the test sample is calculated by the external standard method and the cesium content does not exceed 70ppm.

[0056] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. An analytical method for determining the cesium content in crizotinib starting materials using graphite furnace atomic absorption spectrometry, It is characterized in that The method includes: (1) Dissolve the crizotinib starting material in a solvent to dilute it into a solution containing 0.1 mg to 0.3 mg of the crizotinib starting material per 1 ml as a test solution, wherein the solvent is a mixed solution of nitric acid and water; prepare a cesium standard curve solution with the same solution, and inject the test solution and the cesium standard curve solution into an atomic absorption spectrometer respectively. The parameters of the atomic absorption spectrometer are as follows: a cesium hollow cathode lamp and a graphite furnace atomizer, element Cs, wavelength 852.12 nm, slit width 0.7 nm, lamp current: 70 mA; (2) Heating program: The heating program includes drying temperature, ashing temperature, atomization temperature, and residue removal temperature; The drying temperature includes the first drying temperature and the second drying temperature; The first step drying temperature is 100°C to 120°C. The first step of drying temperature ramp-up time is 1 second to 10 seconds; The drying temperature of the second step is 100℃~200℃. The second step drying temperature ramp-up time is 15 to 40 seconds; The ash temperature is 150℃~800℃; Atomization temperature is 1000℃~2500℃; The residual removal temperature is 2200℃~2700℃; The cesium element in the crizotinib starting material was quantitatively determined and the cesium content was calculated by the external standard method.

2. The analysis method according to claim 1, It is characterized in that Step (1) The maximum sensitivity value of cesium element in the atomic absorption spectrometer is 20 μg / L. According to the sensitivity value of the atomic absorption spectrometer, a suitable concentration of the test solution is screened, and then the concentration of the 100% standard curve solution is calculated.

3. The analysis method according to claim 1, It is characterized in that The pretreatment method of the sample in step (1) is digestion or non-digestion, preferably a non-digestion system.

4. The analysis method according to claim 1, It is characterized in that The injection volume in step (1) is 20 μl.

5. The analysis method according to claim 1, It is characterized in that The mixing volume ratio of nitric acid to water in the solvent of step (1) is 1 to 5:

100. Preferably, the mixing volume ratio of nitric acid to water in the solvent of step (1) is 2:

100.

6. The analysis method according to claim 1, It is characterized in that In step (2), the first drying temperature is 110° C., and the first drying temperature ramp-up time is 3 to 7 seconds, preferably 5 seconds.

7. The analysis method according to claim 1, It is characterized in that Step (2) The drying temperature of the second step is 120°C to 180°C, preferably 150°C, and the ramp-up time of the drying temperature of the second step is 25 to 35 seconds, preferably 30 seconds.

8. The analysis method according to claim 1, It is characterized in that The ashing temperature in step (2) is 200°C to 300°C, preferably 250°C.

9. The analysis method according to claim 1, It is characterized in that The atomization temperature in step (2) is 1500-2000°C.

10. The analysis method according to claim 1, It is characterized in that The residue removal temperature in step (2) is 2300-2500°C.

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