A method for determining trace elements in oral medications using ICP-MS and its application

Abstract

The invention discloses a method for determining trace elements in oral medicines by ICP-MS, comprising the following steps: grinding, digestion, secondary digestion, sampling and constant volume, and sample introduction analysis. A combined digestion solution of hydrofluoric acid and nitric acid is used in the pre-treatment process of the present invention, so that digestion can be complete, the blank value of the reagent is reduced, and the influence of interfering impurities on the elements to be measured is reduced. Microwave digestion is adopted after adding nitric acid simultaneously, and a temperature program is performed to improve the digestion effect, reduce the influence of the digestion reaction on the determination of element content, and after adding hydrofluoric acid, graphite digestion instrument is used for digestion, and 120 DEG C of digestion is performed for 60min, shortening the digestion time, improving digestion efficiency, and simultaneously using ICP-MS determination, the content of multiple elements in oral medicine tablets can be determined simultaneously, with low detection limit and high sensitivity, and is particularly suitable for the analysis of trace elements.

Description

Technical Field

[0001] The present invention relates to a method for determining trace elements in oral medicines by using ICP-MS, in particular to a method for testing or analyzing materials by determining the chemical or physical properties of the materials. Background Art

[0002] During the production and preparation of oral medications, impurities may be introduced due to the selection, production, and storage of raw materials. The use of instruments and equipment can also introduce impurities. The presence of impurities in tablets can reduce the proportion of active ingredients. Excessive impurities can also have side effects on the human body. Therefore, quality control of the impurity content of drugs is crucial. This application improves the efficiency of drug impurity analysis and control, and enhances the safety of drug use, by simultaneously determining seven elements: cadmium, lead, arsenic, mercury, cobalt, vanadium, and nickel.

[0003] Chinese invention patent CN202010570776.2 discloses a method for detecting impurity elements in raw materials. It uses a combination of nitric acid and hydrogen peroxide as a digester to reduce element loss caused by digestion and ensure the accuracy of the results. However, some impurities may be incompletely digested, interfering with the detection of the target substance. Chinese invention patent CN201910981240.7 discloses an electrochemical detection method for multiple harmful elements in traditional Chinese medicine. It uses an electrochemical method to analyze and detect multiple elements, which improves the detection sensitivity and reduces the detection limit. However, multiple elements need to be analyzed and sampled separately, and cannot be detected simultaneously. The detection process is time-consuming and inefficient. Summary of the Invention

[0004] In order to improve detection efficiency and increase detection sensitivity, the first aspect of the present invention provides a method for determining trace elements in oral medications using ICP-MS, comprising the following steps:

[0005] (1) Take an oral tablet and grind it into a sample powder in a mortar;

[0006] (2) Take the sample powder, add it to the microwave digestion tank, add the element mother solution, then add the digestion solution 1, put it on the graphite digester, and start digestion;

[0007] (3) After digestion, cool the mixture, add digestion solution 2, place the mixture in a microwave digestion apparatus, program the temperature, and perform secondary digestion to obtain a digestion solution;

[0008] (4) Transfer the digestion solution into a plastic volumetric flask, rinse the microwave digestion tank, obtain a digestion wash solution, combine the digestion wash solution with the digestion solution, mix and dilute to obtain the assay solution;

[0009] (5) The test solution is injected into the ICP-MS for qualitative and quantitative detection.

[0010] As a preferred embodiment, the oral tablet is a coated tablet. Preferably, the coated tablet is selected from a sugar-coated tablet, a film-coated tablet, and an enteric-coated tablet.

[0011] As a preferred embodiment, the coated tablet is a film-coated tablet, and preferably, the film-coated tablet is a quetiapine fumarate sustained-release tablet.

[0012] As a preferred embodiment, the element mother liquor is selected from one or a combination of gold element mother liquor, palladium element mother liquor, silver element mother liquor, and copper element mother liquor.

[0013] As a preferred embodiment, the element mother liquor is a gold element mother liquor.

[0014] As a preferred embodiment, the digestion solution A is selected from one or a combination of aqua regia, nitric acid, perchloric acid, sulfuric acid, hydrofluoric acid, and hydrogen peroxide.

[0015] As a preferred embodiment, the digestion solution A is hydrofluoric acid.

[0016] As a preferred embodiment, the digestion solution B is nitric acid.

[0017] As a preferred embodiment, the volume ratio of the digestion solution A to the digestion solution B is 1:(2-8).

[0018] As a preferred embodiment, the volume ratio of the digestion solution A to the digestion solution B is 1:(4-6).

[0019] As a preferred embodiment, the volume ratio of the digestion solution A to the digestion solution B is 1:5.

[0020] Quetiapine fumarate sustained-release tablets are a psychotropic drug. During the production and preparation of the tablets, inorganic impurities are inevitably introduced due to issues with raw materials and equipment. Furthermore, many structural analogs of quetiapine fumarate sustained-release tablets are difficult to remove during the production and purification process. Therefore, accurate trace metal element detection is required for oral quetiapine fumarate sustained-release tablets to control production quality. The applicant discovered that using a combination of hydrofluoric acid and nitric acid as a digestion solution during the pre-treatment phase of the test allows for accurate determination of trace metal elements. The applicant speculates that this may be due to the fact that the sustained-release coating of quetiapine fumarate sustained-release tablets may contain titanium dioxide or silicon oxide. Using nitric acid alone for digestion results in incomplete digestion or excessively long digestion times. Using hydrofluoric acid to digest the sustained-release coating of quetiapine fumarate sustained-release tablets significantly improves the digestion effect and eliminates the effects of interfering elements. The applicant further discovered that adding too much hydrofluoric acid results in excessively high acidity in the digestion solution, which affects the atomization efficiency in subsequent ICP-MS testing, resulting in tailing and affecting detection accuracy. A volume ratio of hydrofluoric acid to nitric acid of 1:5 can completely digest quetiapine fumarate sustained-release tablets without affecting the ICP-MS detection.

[0021] As a preferred embodiment, the digestion temperature in step 1 is 115-130° C., and the digestion time is 50-70 min.

[0022] As a preferred embodiment, the digestion temperature in step 1 is 120° C. and the digestion time is 60 min.

[0023] As a preferred embodiment, the volume ratio of the digestion solution A to the digestion solution B is 1:(3-8).

[0024] As a preferred embodiment, the programmed temperature step is: the reaction temperature is raised from room temperature to 145-155°C over 6-8 minutes, from 145-155°C to 210-230°C over 7-9 minutes, and kept at 210-230°C for 15-30 minutes.

[0025] As a preferred embodiment, the programmed temperature step is: the reaction is heated from room temperature to 150°C over 7 minutes, from 150°C to 220°C over 8 minutes, and kept at 220°C for 20 minutes.

[0026] As a preferred embodiment, the amount of sample powder added is 90-110 mg, the amount of element mother solution added is 90-110 μL, and the fixed volume is 50 mL.

[0027] As a preferred embodiment, the amount of sample powder added is 100 mg, the amount of element mother solution added is 100 μL, and the fixed volume is 50 mL.

[0028] As a preferred embodiment, the ICP-MS adopts KED mode and peak jump scanning mode.

[0029] The second aspect of the present invention provides an application of a method for determining trace elements in oral medications using ICP-MS, which is applied to sustained-release tablets, preferably, to the detection of quetiapine fumarate sustained-release tablets.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The method for determining trace elements in oral medicines by ICP-MS of the present invention uses a combined digestion solution of hydrofluoric acid and nitric acid during the pretreatment process, which can achieve complete digestion, reduce the blank value of the reagent, and reduce the influence of interfering impurities on the elements to be measured.

[0032] (2) The method of the present invention for determining trace elements in oral medicines by ICP-MS employs microwave digestion after adding nitric acid and performing programmed temperature increase, thereby improving the digestion effect and reducing the influence of the digestion reaction on the determined element content.

[0033] (3) The method of the present invention for determining trace elements in oral medicines by ICP-MS is as follows: after adding hydrofluoric acid, digestion is performed using a graphite digester at 120° C. for 60 min, thereby shortening the digestion time and improving the digestion efficiency.

[0034] (4) The method of the present invention for determining trace elements in oral medications using ICP-MS can simultaneously determine the contents of multiple elements in oral medication tablets using ICP-MS, has a low detection limit and high sensitivity, and is particularly suitable for the analysis of trace elements.

[0035] (5) In the method of determining trace elements in oral medicines using ICP-MS described in the present invention, the digestion solution uses hydrofluoric acid and nitric acid in a volume ratio of 1:5, which can improve the digestion effect while preventing the acidity of the digestion solution from being too high, thereby affecting the atomization efficiency in the subsequent steps. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the standard curve of vanadium element; Figure 2 This is the standard curve of cobalt element; Figure 3 This is the standard curve of nickel element;

[0037] Figure 4 This is the standard curve of arsenic; Figure 5 This is the standard curve of cadmium element; Figure 6 This is the standard curve of mercury element;

[0038] Figure 7 This is the standard curve of lead element. DETAILED DESCRIPTION

[0039] The present invention is described in detail below by way of examples. It is necessary to point out that the following examples are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by professionals in this field based on the above-mentioned contents of the present invention still fall within the scope of protection of the present invention.

[0040] In addition, unless otherwise stated, all raw materials used were commercially available.

[0041] Example 1

[0042] A method for determining trace elements in oral medicines using ICP-MS comprises the following steps:

[0043] (1) Take an oral tablet and grind it into a sample powder in a mortar;

[0044] (2) Take the sample powder, add it to the microwave digestion tank, add the element mother solution, then add the digestion solution 1, put it on the graphite digester, and start digestion;

[0045] (3) After digestion, cool the mixture, add digestion solution 2, place the mixture in a microwave digestion apparatus, program the temperature, and perform secondary digestion to obtain a digestion solution;

[0046] (4) Transfer the digestion solution into a plastic volumetric flask, rinse the microwave digestion tank three times to obtain a digestion wash solution, combine the digestion wash solution with the digestion solution, mix and dilute to 50 mL, and obtain the assay solution;

[0047] (5) The test solution is injected into the ICP-MS for qualitative and quantitative detection.

[0048] The oral tablets are coated tablets, which are quetiapine fumarate sustained-release tablets, with an added amount of 100 mg, purchased from AstraZeneca Pharmaceuticals Co., Ltd.

[0049] The element mother solution is gold element mother solution, the addition amount is 100 μL, and it is purchased from Yunguan (Shanghai) Biotechnology Co., Ltd.

[0050] The digestion solution A is hydrofluoric acid, the digestion solution B is nitric acid, and the volume ratio of hydrofluoric acid to nitric acid is 1:5.

[0051] The digestion temperature in step 1 is 120° C., and the digestion time is 60 min.

[0052] The programmed temperature increase steps are as follows: the reaction is heated from room temperature to 150° C. over 7 minutes, then from 150° C. to 220° C. over 8 minutes, and then kept at 220° C. for 20 minutes.

[0053] The ICP-MS adopted KED mode, peak jump scanning mode, and the sample residence time was 50 ms.

[0054] Performance testing:

[0055] 1. Standard curve: Different standard curves were established for different elements using the internal standard method. Standard solutions of vanadium with concentrations of 5.00μg / L, 10.00μg / L, 20.00μg / L, 30.00μg / L, and 60.00μg / L were prepared; standard solutions of cobalt with concentrations of 2.50μg / L, 5.00μg / L, 10.00μg / L, 15.00μg / L, and 30.00μg / L were prepared; standard solutions of nickel with concentrations of 10.00μg / L, 20.00μg / L, 40.00μg / L, 60.00μg / L, and 120.00μg / L were prepared; standard solutions of vanadium with concentrations of 0.750μg / L, 1.50μg / L, and 2.50μg / L were prepared; Prepare standard solutions of arsenic with concentrations of 0.250μg / L, 0.500μg / L, 1.00μg / L, 1.50μg / L, and 3.00μg / L; prepare standard solutions of cadmium with concentrations of 1.50μg / L, 3.00μg / L, 6.00μg / L, 9.00μg / L, and 18.00μg / L; prepare standard solutions of lead with concentrations of 0.250μg / L, 0.500μg / L, 1.00μg / L, 1.50μg / L, and 3.00μg / L, inject the samples, test the peak signals, and draw the standard curve. The values ​​are shown in Table 1, and the standard curve is shown in Table 1. Figure 1-7 .

[0056] 2. Repeatability: Using the method of Example 1, 6 replicates of the same solution were prepared and tested using an ICP-MS instrument under the same conditions. The test results are shown in Table 2.

[0057] 3. Intermediate Precision: Five days later, another analyst prepared a test solution using the same method as in Example 1. Six parallel samples were prepared and tested using a different ICP-MS instrument under the same conditions. The test results are shown in Table 2.

[0058] Table 1

[0059]

[0060]

[0061] Table 2

[0062] Repeatability RSD / % Intermediate precision RSD / % V 2 4 Co 2 4 Ni 3 4 As 3 9 Cd 3 3 Hg 2 2 Pb 2 8

Claims

1. A method for determining trace elements in oral medications using ICP-MS, characterized in that: The following steps are involved: (1) Take the oral tablets and grind them into sample powder in a mortar; (2) Take the sample powder, add it to the microwave digestion tank, add the element mother solution, then add digestion solution A, put it on the graphite digester, and start digestion; (3) After digestion, cool the mixture and add digestion solution B. Place the mixture in a microwave digestion apparatus and program the temperature to perform a second digestion to obtain a digestion solution. (4) Transfer the digestion solution into a plastic volumetric flask, rinse the microwave digestion tank, and obtain the digestion wash solution. Combine the digestion wash solution with the digestion solution, mix and adjust the volume to obtain the assay solution. (5) Inject the test solution into the ICP-MS for qualitative and quantitative detection; The oral tablet is a coated tablet, which is a quetiapine fumarate sustained-release tablet, and the sustained-release coating of the quetiapine fumarate sustained-release tablet contains titanium dioxide or silicon oxide; The digestion solution A is hydrofluoric acid; the digestion solution B is nitric acid; The volume ratio of the digestion solution A to the digestion solution B is 1:5; The programmed temperature rising step is as follows: the reaction is heated from room temperature to 145-155° C. over 6-8 minutes, then from 145-155° C. to 210-230° C. over 7-9 minutes, and then kept at 210-230° C. for 15-30 minutes.

2. The method for determining trace elements in oral medications using ICP-MS according to claim 1, wherein: The coated tablet is selected from one of sugar-coated tablets, film-coated tablets, and enteric-coated tablets.

3. The method for determining trace elements in oral medicines by ICP-MS according to claim 1, wherein: The element mother liquor is selected from one or a combination of gold element mother liquor, palladium element mother liquor, silver element mother liquor and copper element mother liquor.

4. The method for determining trace elements in oral medicines by ICP-MS according to claim 1, wherein: The digestion temperature in step 2 is 115-130° C., and the digestion time is 50-70 min.

5. The method for determining trace elements in oral medicines by ICP-MS according to claim 1, wherein: The amount of sample powder added is 90-110 mg, the amount of element mother solution added is 90-110 μL, and the fixed volume is 50 mL.

6. The method for determining trace elements in oral medicines by ICP-MS according to claim 1, wherein: The ICP-MS adopts KED mode and peak jump scanning mode.

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