Method for producing sample for analysis and verification of X-ray fluorescence analyzer, and method for analysis and verification of X-ray fluorescence analyzer

Abstract

In the present invention, target elements including Cd, Pb, As, Hg, Co, V, and Ni are divided into a plurality of groups such that As and Pb are the same group and As, Pb, and Hg are different groups, and for each group, liquids (12, 121-128) containing the target elements belonging to the group are added to a powder (11) comprising a material that does not contain any of the target elements and mixed such that the target elements belonging to the group are each at a predetermined concentration.

Description

Technical Field

[0001] This invention relates to a method for preparing samples used in the analytical verification (validity confirmation test) of a fluorescence X-ray analysis device, and a method for the analytical verification of a fluorescence X-ray analysis device using the sample. Background Technology

[0002] If harmful metallic elements are mixed in as impurities in pharmaceuticals or food, they may pose health risks to those who ingest them. Therefore, standards have been established to regulate the concentration of specific metallic elements. Particularly in the pharmaceutical field, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has developed an international standard called "Guideline for Elemental Impurities Q3D" (hereinafter referred to as "ICH Q3D") (see Non-Patent Literature 1).

[0003] ICH Q3D specifies acceptable daily intakes (ADIs) for 24 metallic elements, and the permissible concentrations for each pharmaceutical preparation are determined based on these ADIs. These 24 metallic elements are divided into four categories (Category 1, Category 2A, Category 2B, and Category 3) based on their toxicity and likelihood of contamination in pharmaceuticals. Category 1 consists of four elements with particularly high toxicity: Cd (cadmium), Pb (lead), As (arsenic), and Hg (mercury). Category 2A consists of three elements derived from natural sources and with a high likelihood of contamination in pharmaceuticals: Co (cobalt), V (vanadium), and Ni (nickel). Category 2B consists of ten elements, including Pd (palladium), which, while less likely to be contaminated from natural sources, may be contaminated from substances used in the manufacturing process, such as catalysts. Category 3 consists of seven elements with lower toxicity than the aforementioned 17 elements, which do not require assessment in oral preparations but are subject to assessment in injectable or inhaled preparations.

[0004] When assessing the concentration of metal elements in pharmaceuticals according to ICH Q3D, the assessment object must include at least the seven elements belonging to categories 1 and 2A. Furthermore, among the ten elements belonging to category 2B, any elements that may have been introduced during the manufacture of the pharmaceutical product must also be included in the assessment object. For example, when assessing oral preparations manufactured using Pd, the eight elements (the seven mentioned above plus Pd) are considered as assessment objects. Pd is an element used as a catalyst in the manufacture of many pharmaceutical products. Additionally, in the case of injectable or inhaled preparations, some or all of the seven elements belonging to category 3 may be included in the assessment object as needed.

[0005] In Non-Patent Literature 1, inductively coupled plasma mass spectrometry (ICP-MS) was used as the concentration analysis method for the target element. However, ICP-MS suffers from time-consuming and laborious sample pretreatment. To address this, Non-Patent Literature 2 proposed using fluorescence X-ray analysis, which involves simpler sample pretreatment, for the concentration analysis of the target element. In fluorescence X-ray analysis, sample pretreatment only requires pulverizing the pharmaceutical product into a uniform powder.

[0006] In fluorescence X-ray analysis, to ensure the proper functioning of the apparatus and analytical conditions used to assess the concentration of the target element, periodic analytical validation is required. This involves performing fluorescence X-ray analysis on a validation sample containing a known concentration of the target element to confirm that the correct concentration has been obtained. Since the original analyte is measured in powder form, the validation sample is prepared by adding a predetermined amount of standard solution containing a predetermined concentration of the target element to the powder (e.g., cellulose powder used as a pharmaceutical additive) and mixing them.

[0007] Existing technical documents Patent documents Non-Patent Literature 1: Ichinose Takayuki et al., “Pharmaceutical Elemental Impurities Guidelines (ICH Q3D) and ICP-MS: The Status Quo as Seen from the Perspective of the Person in Charge of Analysis,” Kanto Chemical Co., Ltd., THE CHEMICAL TIMES, Vol. 255, pp. 7-13, January 2020. Non-Patent Document 2: "Regarding the Management of Elemental Impurities in Pharmaceuticals", [Online], Shimadzu Corporation, [Searched October 30, 2023], Internet <https: / / www.an.shimadzu.co.jp / products / elemental-analysis / edx-fs / pharmaceutical-elemental-impurities-analysis-system / index.html> Summary of the Invention The technical problem that the invention aims to solve If analytical verification samples are prepared element-by-element, the same number of analytical verification operations must be performed for the same number of elements being evaluated, which is very time-consuming. On the other hand, by adding predetermined amounts of standard solutions of multiple elements to the same powder, analytical verification samples containing all of those elements can be prepared, thus reducing the number of analytical verification operations compared to the number of elements. However, research has found that, for the same fluorescence X-ray analysis device, although the correct concentration can be obtained when using analytical verification samples prepared element-by-element, if analytical verification samples containing multiple elements are used, only values ​​lower than the actual concentrations can be obtained, and the concentration values ​​fluctuate between each prepared sample, making accurate analytical verification impossible.

[0008] The problem to be solved by the present invention is to provide a method for preparing analytical samples for a fluorescence X-ray analysis device that can accurately perform analysis and verification while suppressing labor, and a method for analyzing and verifying the fluorescence X-ray analysis device.

[0009] Solution to the above technical problems In the method for preparing analytical verification samples for a fluorescence X-ray analysis apparatus, which was completed to solve the above-mentioned problems, the target elements comprising Cd, Pb, As, Hg, Co, V and Ni are divided into multiple groups such that As and Pb are in the same group and As and Pb and Hg are in different groups. For each of the multiple groups, a liquid containing the target element of that group is added to a powder made of a material that does not contain any of the target elements and the mixture is stirred, such that the target elements of that group are at predetermined concentrations.

[0010] In the analytical verification method of the fluorescence X-ray analysis device of the present invention, multiple analytical verification samples prepared by the above-described manufacturing method are subjected to fluorescence X-ray analysis using a fluorescence X-ray analysis device as the analytical verification object, thereby determining the concentration of the object element and determining whether the difference between the obtained concentration and the predetermined concentration is within a predetermined range.

[0011] Invention Effects The analytical verification sample prepared by the method for preparing analytical verification samples using the fluorescence X-ray analysis apparatus of the present invention necessarily contains seven elements as the target elements: all elements belonging to category 1 (Cd, Pb, As, and Hg) and all elements belonging to category 2A (Co, V, and Ni). In addition to these seven elements, other elements such as Pd may also be included as target elements in the analytical verification sample of the present invention. Of course, it may also contain only the aforementioned seven elements (excluding the constituent elements of the powder).

[0012] The inventors prepared various samples with different combinations of target elements within the same group and used these samples to perform analytical verification operations on a pre-confirmed functioning fluorescence X-ray analysis device. The results showed that when As and / or Pb were included in the same group with Hg, the concentrations of one to three of these As, Pb, and Hg became lower than expected, and fluctuations occurred between each sample. The reason for this is unclear, but it is presumed that if a solution containing Hg is added to the powder along with a solution containing As and / or Pb, for some reason, some of these three elements will not be fixed to the powder. Therefore, in this invention, As, Pb, and Hg are separated into different groups, and analytical verification samples are prepared for each group. This prevents the concentrations of As, Pb, and Hg obtained during analytical verification from falling below the predetermined concentrations, thereby enabling accurate analytical verification.

[0013] On the other hand, multiple elements with similar characteristic X-ray wavelengths need to be included in the same group. This is because, when evaluating a sample containing such multiple elements, the concentration of each element is determined after data processing called overlap correction, where the profiles obtained from fluorescence X-ray analysis are overlapping. Therefore, analytical verification is also performed under overlapping profiles to have the same conditions as when analyzing the sample being evaluated. In the elements of this invention, the energy of As's Kα rays (10.532 keV) is close to that of Pb's Lα1 rays (10.552 keV). Therefore, in this invention, by including these As and Pb elements in the same group, an analytical verification sample capable of correct analytical verification can be obtained.

[0014] Furthermore, in the method for preparing analytical verification samples according to the present invention, since a sample containing multiple elements is prepared for at least one group containing As and Pb, the labor required for analytical verification can be reduced compared to the case where samples are prepared separately for each of the target elements. Attached Figure Description

[0015] [ Figure 1 [Illustration] is a schematic diagram illustrating one embodiment of the method for preparing a sample for analysis and verification of the fluorescence X-ray analysis apparatus according to the present invention. It shows the state (e) of the sample for analysis and verification of the fluorescence X-ray analysis apparatus after the following steps: preparing powder (a), preparing liquid containing each target element (b), adding liquid containing the target element to the powder (c), drying the powder to evaporate the liquid containing the target element (d), and stirring the powder.

[0016] [ Figure 2[ ] is a diagram illustrating the analytical verification operation of a fluorescence X-ray analysis apparatus performed using an analytical verification sample prepared by the preparation method of this embodiment. Detailed Implementation

[0017] Reference Figure 1 and Figure 2 This invention describes the method for preparing samples for analysis and verification of the fluorescence X-ray analysis apparatus and the implementation method of the analysis and verification method of the fluorescence X-ray analysis apparatus.

[0018] In this embodiment, the description will consider both cases where the target elements are the seven elements belonging to categories 1 and 2A, namely Cd, Pb, As, Hg, Co, V, and Ni, and cases where the target elements are the eight elements including Pd. Pd is an element belonging to category 2B that is used as a catalyst in the manufacturing process of many pharmaceutical products. In the following description, the case where Pd is included in the target elements will be used as an example. When only the above seven elements are used as target elements, the process for Pd can be performed simply by removing the process for Pd from the steps described below. In this embodiment, the eight (or seven) target elements are divided into a first group consisting of Cd, Pb, As, Co, and Ni, and a second group consisting of Hg, V, and Pd (Hg and V in the case of "seven"). A first analytical verification sample 101 containing the target elements of the first group and a second analytical verification sample 102 containing the target elements of the second group are prepared.

[0019] Furthermore, the grouping of object elements and the number of groups are not limited to this example. Additionally, as long as the above 7 elements are included, other elements belonging to category 2B or category 3 can also be included in the object element. However, As and Hg must be in different groups, while As and Pb must be included in the same group.

[0020] Figure 1 The steps of the method for preparing the analytical verification sample according to this embodiment are shown. First, a powder 11 composed of a material that does not contain any of the eight target elements described above is prepared. As the material of powder 11, materials such as cellulose or lactose hydrate, which are used as additives in pharmaceuticals made of tablets or powders, are preferably used. Alternatively, materials from the same production batch as tablets or powders of pharmaceuticals that have been confirmed not to contain the eight elements described above may be used (in the case of tablets, these materials are pulverized). Powder 11 is divided into two portions (first powder 111, second powder 112), and each portion is leveled to flatten its upper surface. Figure 1 (a)).

[0021] At the same time, prepare 8 kinds of liquids (the object element contains liquid) 12, each of the 8 liquids contains one of the above 8 elements ( Figure 1(b)). The object element containing liquid 12 is Cd containing liquid 121, Pb containing liquid 122, As containing liquid 123, Hg containing liquid 124, Co containing liquid 125, V containing liquid 126, Ni containing liquid 127, and Pd containing liquid 128.

[0022] Liquid 12 is a liquid that can be preferably used as a standard sample in atomic absorption spectrometry, inductively coupled plasma emission spectrometry, and inductively coupled plasma mass spectrometry.

[0023] Furthermore, since Hg, V, and Pd form stable complexes in hydrochloric acid, Hg-containing liquid 124, V-containing liquid 126, and Pd-containing liquid 128 can be prepared by separately adding Hg, V, and Pd salts to hydrochloric acid. Moreover, because Hg, V, and Pd share the common characteristic of forming stable complexes in hydrochloric acid, even mixing these Hg, V, and Pd elements in the same analytical validation sample will not lead to a decrease in the concentration of these elements obtained during analytical validation.

[0024] Next, predetermined amounts of Cd-containing liquid 121, Pb-containing liquid 122, As-containing liquid 123, Co-containing liquid 125, and Ni-containing liquid 127 are added to the upper surface of the first powder 111, and predetermined amounts of Hg-containing liquid 124, V-containing liquid 126, and Pd-containing liquid 128 are added to the upper surface of the second powder 112. Figure 1 (c) The amount of liquid 121 to 128 contained in each target element is set such that, in the case that all the target element remains in the first analytical verification sample 101 and the second analytical verification sample 102 obtained in the end, the target element reaches a predetermined concentration in the first analytical verification sample 101 and the second analytical verification sample 102. This predetermined concentration is set such that characteristic X-rays of sufficient intensity can be obtained by performing fluorescence X-ray analysis on the first analytical verification sample 101 and the second analytical verification sample 102.

[0025] When the target element containing liquid 12 is added to the first powder 111 or the second powder 112, if the target element containing liquids containing different target elements mix with each other (although the reason is not yet clear), the concentration of some of these target elements will be lower than the actual value and will be detected. Therefore, it is preferable to add each target element containing liquid 12 to different positions in the first powder 111 or the second powder 112 (refer to...). Figure 1 (c)).

[0026] After adding the target element-containing liquid 12 to the first powder 111 and the second powder 112 respectively, the powders 111 and 112 are dried without stirring, so that the solvent in the target element-containing liquid 12 evaporates. Figure 1 (d) At this time, the first powder 111 and / or the second powder 112 may be heated, but if the complex of the target element contained in the liquid 12 is volatile, the heating shall be lower than the temperature at which the complex volatilizes. The temperature is set, for example, in the range of 30 to 70°C, and the heating time is set, for example, in the range of 8 to 72 hours.

[0027] Next, the first powder 111 is stirred to distribute the target elements of the first group, namely Cd, Pb, As, Co, and Ni, which are added to the first powder 111, as uniformly as possible. The powder stirring can be performed using a mortar and pestle or a commercially available grinder. The second powder 112 is also stirred to distribute the target elements of the second group, namely Hg, V, and Pd, as uniformly as possible. Through the above operations, the analytical verification sample 10 of this embodiment, consisting of the first analytical verification sample 101 in which the target elements of the first group are added to the first powder 111, and the second analytical verification sample 102 in which the target elements of the second group are contained in the second powder 112, is obtained. Figure 1 (e)).

[0028] Next, the experimental results using the actual prepared analytical verification sample 10 will be explained. In this experiment, a fluorescence X-ray analysis device that had been previously verified by known methods to determine the content (concentration) of the above-mentioned eight target elements within a normal error range was used.

[0029] First, as Example 1, an analytical verification sample 10 was prepared, consisting of a first analytical verification sample 101 containing Cd, Pb, As, Co, and Ni, and a second analytical verification sample 102 containing Hg and V (excluding Pd). Furthermore, as Comparative Example 1, an analytical verification sample was prepared by adding all seven target element-containing liquids 12 (121-127), each containing one of the aforementioned seven target elements, to the same powder 11. The powder 11 was a pharmaceutical technical material composed of an organic compound, and was confirmed to be free of any of the seven target elements. In Example 1 and Comparative Example 1, the concentration and amount of each target element-containing liquid were adjusted to target values ​​for the target element concentrations in each sample as follows: Cd 3.0 ppm, Pb 3.0 ppm, As 9.0 ppm, Hg 20 ppm, Co 30 ppm, V 60 ppm, and Ni 100 ppm. Here, "ppm" stands for "μg / g", which means the mass of the object element contained in the liquid per unit mass (unit: g) of the object element (unit: μg).

[0030] For the first analytical verification sample 101 and the second analytical verification sample 102 of Example 1, and the analytical verification sample of Comparative Example 1, fluorescence X-ray determination was performed using a confirmed and functioning fluorescence X-ray analysis device to quantify the concentration of the target element in each sample. Each sample underwent fluorescence X-ray determination three times, and the concentration was taken as the average of the three determinations. The results are shown in Table 1. The "Recovery Rate" in Table 1 is the percentage obtained by dividing the quantified concentration value obtained from the fluorescence X-ray analysis by the target concentration value when the target element is present in liquid.

[0031] [Table 1]

[0032] In the analytical validation sample of Comparative Example 1, the recovery rate of As was 77.7%, which is relatively low. Furthermore, the recoveries of Hg (91.5%) and Pb (93.3%) were also slightly low. In contrast, in Example 1, the concentration quantifications and recoveries of these As, Hg, and Pb were all higher than in Comparative Example 1. This is believed to be because Comparative Example 1 contained As, Hg, and Pb in the same analytical validation sample, while in Example 1, "Hg (and V)" and "As and Pb" were contained in different analytical validation samples (the former was contained in the first analytical validation sample 101, and the latter in the second analytical validation sample 102).

[0033] Next, as Example 2 and Comparative Example 2, instead of the original drug powder, powder obtained by pulverizing pharmaceutical tablets was used as powder 11 to prepare analytical verification samples. In Example 2 and Comparative Example 2, the concentration and amount of liquid containing each target element were adjusted to achieve the target values ​​for the concentration of the target elements in each sample as follows: Cd 3.0 ppm, Pb 3.0 ppm, As 9.0 ppm, Hg 18 ppm, Co 30 ppm, V 60 ppm, and Ni 120 ppm. In Example 2, similar to Example 1, a first analytical verification sample 101 containing Cd, Pb, As, Co, and Ni, and a second analytical verification sample 102 containing Hg and V (excluding Pd) were prepared. In Comparative Example 2, similar to Comparative Example 1, analytical verification samples containing all seven target elements were prepared. Other experimental conditions were the same as in Example 1 and Comparative Example 1. The results are shown in Table 2.

[0034] [Table 2]

[0035] In the analytical validation sample of Comparative Example 2, the recoveries of Hg and Pb were 72.2% and 80.0%, respectively, which were relatively low. Furthermore, Ni, whose recovery rate was not significantly reduced (98.1%) in Comparative Example 1, also became a relatively low value of 80.5% in Comparative Example 2. In contrast, in Example 2, the concentration quantifications and recoveries of Hg, Pb, and Ni were all higher than in Comparative Example 2. This is believed to be because Comparative Example 2 contained both "As, Pb, and Ni" and "Hg and V" in the same analytical validation sample, while Example 2 contained them in different analytical validation samples (the former was included in the first analytical validation sample 101, and the latter was included in the second analytical validation sample 102).

[0036] This further clarifies that the concentration of Co can sometimes fluctuate when all seven elements are added together. In Comparative Example 3 below, the quantified concentration of Co decreased, and the recovery rate was significantly lower than 100% (95%). To address this, a first analytical validation sample 101 containing Cd, Pb, As, Co, and Ni, and a second analytical validation sample 102 containing only Hg and V were prepared, and their concentration quantifications and recoveries were determined. The results showed that the quantified concentration of Co also increased, and the recovery rate of Co almost reached 100%.

[0037] [Table 3]

[0038] Furthermore, regarding V, in Examples 1 and 2, even when included in the same second analytical validation sample 102 as Hg, a recovery rate close to 100% was obtained. Based on the inventors' experiments, since Hg and V can exist as stable complexes in the same solvent (hydrochloric acid), it is considered that adding them to the same sample would not easily lead to a decrease in concentration. Since the same tendency was observed between Hg and Pd, it is considered that when adding Pd to the target element, Hg and Pd can be added to the same sample.

[0039] As shown in Comparative Example 4 in Table 4, although the target elements were added to a powder composed of a material containing no target elements at the same concentration as in Comparative Example 3, the measured concentrations were sometimes lower than in Comparative Example 3. In the sample of Comparative Example 4, Hg showed a recovery rate of 69.5%, which was lower than that of Comparative Examples 1-3. In cases where the recovery rate (and concentration quantification) of Hg is particularly low, it is preferable to use a sample containing only Hg in one of the multiple analytical validation samples. In Example 4 shown in Table 4, a first analytical validation sample containing six target elements other than Hg and a second analytical validation sample containing only Hg were prepared. As a result, the recovery rate of Hg was increased to 100.0%. Furthermore, not only Hg, but the recoveries of the other six target elements were also higher than in Comparative Example 4, reaching values ​​of 100% or close to 100%. In Examples 1-3, Hg and V were included in the same analytical validation sample. However, the results of Example 4 show that by adding Hg separately to an analytical validation sample that is different from the other six target elements, not only can the recovery rate of Hg itself be improved, but the recovery rates of the other six target elements can also be improved. Furthermore, the target elements other than Hg can be in the same group (i.e., added to the same sample) as in Example 4, or they can be divided into several different groups. To reduce labor intensity by decreasing the number of analytical validation operations (measured using a fluorescence X-ray device), it is preferable that the target elements other than Hg are in the same group.

[0040] [Table 4]

[0041] Next, a method for performing analytical verification using a fluorescence X-ray analysis apparatus on an analytical sample prepared by the method of this embodiment will be described. In the analytical verification method of this embodiment, the method described in "General Test Method 2. Physical Test Method 2.6.6 Elemental Impurities" of the 18th revised edition of the Japanese Pharmacopoeia, "3. Validation Requirements for Analytical Methods 3.1 Limit Test Procedures," is adopted. Furthermore, in the method described in the 18th revised edition of the Japanese Pharmacopoeia, the apparatus used for analytical verification is not limited to a fluorescence X-ray analysis apparatus. In this embodiment, whether the three compliance standards (i) detection sensitivity, (ii) specificity, and (iii) precision are met is determined by the following methods.

[0042] In the analytical verification method of this embodiment, two types of analytical verification samples with different concentrations of target elements are prepared according to the preparation method of this embodiment. In one type of analytical verification sample (hereinafter referred to as "Sample A," note that Sample A itself consists of multiple samples corresponding to the aforementioned multiple groups), the concentration of each target element is adjusted to satisfy the following mathematical formula: the permissible daily exposure (PDE value) of each target element in the original analytical pharmaceutical product is divided by the maximum daily dose of the pharmaceutical product, and then multiplied by a coefficient of 0.3. In the other type of analytical verification sample (hereinafter referred to as "Sample B," which also consists of multiple samples corresponding to the aforementioned multiple groups), the concentration of each target element is adjusted to 0.8 times the concentration of each target element determined in Sample A.

[0043] [Number 1]

[0044] exist Figure 2 In the example shown, the first analytical verification sample 1011, belonging to sample A, contains Cd, Pb, As, Co, and Ni as target elements, with concentrations calculated using the above formulas. Similarly, the second analytical verification sample 1021, also belonging to sample A, contains Hg and V (which may also include Pd) as target elements, with concentrations calculated using the above formulas. On the other hand, the first analytical verification sample 1012, belonging to sample B, contains Cd, Pb, As, Co, and Ni as target elements, with concentrations calculated using the above formulas at 80% of their respective concentrations. Similarly, the second analytical verification sample 1022, also belonging to sample B, contains Hg and V (which may also include Pd) as target elements, with concentrations calculated using the above formulas at 80% of their respective concentrations.

[0045] For each sample belonging to group A and each sample belonging to group B, characteristic X-rays were measured three times using the fluorescence X-ray analyzer of the analytical verification object. The concentration of each target element was calculated using a known method based on the average of the three measurements. Then, for all target elements, if the calculated concentration was within ±15% of the original concentration of the samples belonging to group A and group B, and the calculated concentration of sample B was less than that of sample A, it was determined that the (i) detection sensitivity compliance standard was met (other than this, it was determined that it was not met).

[0046] Furthermore, based on the obtained fluorescence X-ray spectrum, if the peaks of each target element can be clearly distinguished (except for As and Pb, which are essential target elements and can be corrected for overlap), and the difference in peak intensity between the unadded sample and the sample with the added standard sample is significant, and the accuracy requirement (recovery rate in the range of 85-115%) is met, it is judged to meet the (ii) specificity compliance standard (other cases are judged to not meet the standard).

[0047] Furthermore, regarding sample A, if the relative standard deviation (RSD) of the quantitative concentration values ​​of each target element measured in each of the six measurements is less than 20%, it is determined to meet the precision standard of (iii) (other than this, it is determined not to meet the standard).

[0048] The above describes the method for preparing samples for analysis and verification of the fluorescence X-ray analysis device and the implementation method of the analysis and verification method of the fluorescence X-ray analysis device involved in this invention. However, this invention is not limited to the above implementation method and can be modified in various ways.

[0049] For example, in the above implementation, the seven elements Cd, Pb, As, Hg, Co, V and Ni, or the eight elements with Pd added, are used as object elements. However, as long as the object elements contain the above seven elements, one or more of the 24 elements specified in ICH Q3D (16 after removing the above eight) can also be included in the object elements.

[0050] Furthermore, in the above embodiment, the target elements were divided into two groups and samples were prepared separately, but it is also possible to divide them into three or more groups and prepare samples separately. However, if the number of samples increases, it will be more troublesome to perform analytical verification measurements. Therefore, from the viewpoint of reducing this labor, the number of groups is preferably set to two.

[0051] [plan] It will be apparent to those skilled in the art that the above exemplary embodiments are specific examples of the following schemes.

[0052] (Item 1) A method for preparing an analytical verification sample for a fluorescence X-ray analysis device according to one aspect of the present invention is as follows: the target elements comprising Cd, Pb, As, Hg, Co, V and Ni are divided into multiple groups such that As and Pb are in the same group and the As and Pb and Hg are in different groups; for each of the multiple groups, a liquid containing the target element of that group is added to a powder made of a material that does not contain any of the target elements and the mixture is stirred such that the target elements of that group are at predetermined concentrations.

[0053] The analytical verification sample prepared by the method described in paragraph 1 necessarily contains seven elements as the target elements, consisting of all elements belonging to category 1 (Cd, Pb, As, and Hg) and all elements belonging to category 2A (Co, V, and Ni). In addition to these seven elements, other elements such as Pd may also be included as the target elements in the analytical verification sample of the present invention. Of course, it may also contain only the aforementioned seven elements (excluding the constituent elements of the powder).

[0054] The inventors prepared various samples with different combinations of target elements contained in the same group and used these samples to perform analytical verification operations on a pre-confirmed functioning fluorescence X-ray analysis device. The results showed that when As and / or Pb were included in the same group with Hg, the concentration values ​​of one to three of these As, Pb, and Hg became lower than expected, and fluctuations occurred between each sample. The reason for this is unclear, but it is presumed that if a solution containing Hg is added to the powder along with a solution containing As and / or Pb, for some reason, some of these three elements will not be fixed to the powder. Therefore, in the preparation method described in the first claim, As, Pb, and Hg are separated into different groups, and analytical verification samples are prepared for each group. This prevents the concentrations of As, Pb, and Hg obtained during analytical verification from being lower than the predetermined concentrations, thereby enabling correct analytical verification.

[0055] On the other hand, among the elements requiring analytical verification, multiple elements with similar characteristic X-ray energies need to be included in the same group. This is because, when the sample being evaluated contains such multiple elements, the concentration of each element is determined after data processing called overlap correction, where the spectra obtained from fluorescence X-ray analysis overlap. Therefore, analytical verification is also performed under the same conditions as when analyzing the sample being evaluated. In the method described in the first paragraph, the energy of As's Kα rays (10.532 keV) is close to that of Pb's Lα1 rays (10.552 keV). In the preparation method described in the first paragraph, the energy of As's Kα rays (10.532 keV) is close to that of Pb's Lα1 rays (10.552 keV). Therefore, in the preparation method described in the first paragraph, by including As and Pb in the same group, an analytical verification sample capable of correct analytical verification can be obtained.

[0056] Furthermore, in the method for preparing analytical verification samples involved in the first item, since samples containing multiple elements are prepared for at least one group containing As and Pb, the labor required for analytical verification can be reduced compared to the case where samples are prepared separately for each of the target elements.

[0057] Furthermore, the number of groups must be at least 2 and at most one less than the number of target elements (because As and Pb belong to the same group). For example, if the target elements are only Cd, Pb, As, Hg, Co, V, and Ni (7 elements in total), then the maximum number of groups is 6. However, increasing the number of groups will be time-consuming due to the increased number of analytical samples required for validation. Therefore, setting the number of groups to 2 is sufficient if this is a priority.

[0058] (Item 2) The method for preparing the sample for the analytical verification of the fluorescence X-ray analysis device involved in Item 2 is that, in the preparation method involved in Item 1, Hg and Ni and / or Hg and Co belong to different groups.

[0059] According to the manufacturing method described in item 2, the concentration of Ni and / or Co can be prevented from becoming lower than the actual value, thereby enabling correct analytical verification.

[0060] (Item 3) The method for preparing the sample for the analytical verification of the fluorescence X-ray analysis device involved in Item 3 is that, in the preparation method involved in Item 1 or Item 2, Hg and V belong to the same group.

[0061] Since Hg and V can exist as stable complexes in the same solvent (hydrochloric acid), their concentrations are not easily reduced even when added to the same sample. Therefore, Hg and V can be grouped together as described in Section 3.

[0062] (Item 4) The method for preparing the sample for analysis and verification of the fluorescence X-ray analysis device involved in Item 4 is that, in any one of the preparation methods involved in Items 1 to 3, the object element further includes Pd.

[0063] Pd is an element belonging to category 2B that is used as a catalyst in the manufacturing processes of many pharmaceutical products. In the preparation method described in item 4, by including Pd in ​​the target element contained in the sample for analytical validation, a validation sample can be obtained that can be appropriately analyzed and validated using a fluorescence X-ray analysis apparatus used in evaluating pharmaceutical impurities for which Pd is being evaluated.

[0064] (Item 5) The method for preparing the sample for the analytical verification of the fluorescence X-ray analysis device involved in Item 5 is that, in the preparation method involved in Item 4, Hg and Pd belong to the same group.

[0065] Since Hg and Pd (as in the case of Hg and V) can exist as stable complexes in the same solvent (hydrochloric acid), Hg and Pd can be grouped together as described in Section 5. Furthermore, in addition to Hg and Pd, V can also be grouped together.

[0066] (Item 6) The method for preparing the sample for the analytical verification of the fluorescence X-ray analysis device involved in Item 6 is that, in any of the preparation methods involved in Items 1 to 3, the plurality of groups consists of the following two groups: a first group consisting of Cd, Pb, As, Co and Ni; and a second group consisting of Hg and V.

[0067] (Item 7) The method for preparing the sample for analysis and verification of the fluorescence X-ray analysis device involved in Item 7 is that, in the preparation method involved in Item 6, the object element further includes Pd, which belongs to the second group.

[0068] According to the preparation method described in items 6 and 7, by grouping Hg and V (which can belong to the same group as Hg, and further, Pd if Pd is included as the object element) into the same group (Group 2), and grouping the remaining object elements into other groups (Group 1), it is possible to prevent the concentration of each object element from becoming lower than the actual value, thereby obtaining an analytical verification sample that can be correctly analyzed and verified.

[0069] (Item 8) The method for preparing the sample for analysis verification of the fluorescence X-ray analysis device involved in Item 8 is that, in any one of the preparation methods involved in Items 1 to 3, one of the plurality of groups contains only Hg of the target element.

[0070] According to the preparation method described in item 8, by setting one of the plurality of groups to contain only Hg, whose observed concentration tends to decrease significantly, it is possible to prevent the concentration of Hg from becoming lower than its actual value, thereby obtaining an analytical verification sample that can be correctly analyzed and verified. Furthermore, all target elements other than Hg, including non-essential target elements such as Pd, can belong to the same group, or these target elements other than Hg can be further divided into multiple groups. To reduce labor intensity by minimizing the number of analytical verification operations (measurement using a fluorescence X-ray analysis device), it is preferable that target elements other than Hg belong to the same group.

[0071] (Item 9) The method for preparing the sample for analysis and verification of the fluorescence X-ray analysis device involved in Item 9 is as follows: in any of the preparation methods involved in Items 1 to 8, for each of the plurality of groups having a plurality of the object elements, a plurality of liquids containing one object element belonging to that group are added to different positions of the powder, and the powder is stirred after the plurality of liquids are dried.

[0072] According to the manufacturing method involved in item 9, before drying multiple types of liquids each containing one object element (moreover, the term "multiple" here is different from "multiple" in the number of groups), the concentration of the object element can be more reliably prevented from decreasing because the multiple object elements (which are the same as the quantity of the liquid) do not mix with each other.

[0073] (Item 10) One aspect of the present invention relates to an analytical verification method for a fluorescence X-ray analysis device, wherein multiple analytical verification samples prepared by the manufacturing method of any one of items 1 to 9 are subjected to fluorescence X-ray analysis using a fluorescence X-ray analysis device as the analytical verification object, thereby determining the concentration of the object element and determining whether the difference between the obtained concentration and the predetermined concentration is within a predetermined range.

[0074] According to the analytical verification method described in item 10, by using multiple analytical verification samples prepared by the preparation methods described in any one of items 1 to 9, it is possible to prevent the concentrations of As, Pb, and Hg obtained during analytical verification from being lower than the predetermined concentrations, thereby enabling correct analytical verification.

[0075] Explanation of reference numerals in the attached figures 10… Samples for analytical verification 101, 1011, 1012… Sample 1 for analytical verification Samples 102, 1021, 1022… for the second analytical verification 11…powder 111…First Powder 112…Second Powder 12… The object element contains liquid 121…Cd contains liquid 122…Pb contains liquid 123…As contains liquid 124…Hg contains liquid 125…Co contains liquid 126…V contains liquid 127…Ni contains liquid 128…Pd contains liquid.

Claims

1. A method for preparing samples for analytical verification of a fluorescence X-ray analysis device, characterized in that: The object elements, including Cd, Pb, As, Hg, Co, V, and Ni, are divided into multiple groups such that As and Pb belong to the same group and the As and Pb belong to different groups. For each of the multiple groups, a liquid containing the object element of that group is added to a powder made of a material that does not contain any of the object elements and the mixture is stirred, such that the object elements of that group are at predetermined concentrations.

2. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: Hg and Ni and / or Hg and Co belong to different groups.

3. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: Hg and V belong to the same group.

4. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: The object element also includes Pd.

5. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 4, characterized in that: Hg and Pd belong to the same group.

6. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: The plurality of groups consist of the following two groups: Group 1, consisting of Cd, Pb, As, Co and Ni; and Group 2, consisting of Hg and V.

7. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 6, characterized in that: The object element also includes Pd, which belongs to the second group.

8. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: One of the multiple groups contains only Hg from the object element.

9. The method for preparing samples for analysis and verification of the fluorescence X-ray analysis device as described in claim 1, characterized in that: For each of the multiple groups having multiple object elements, multiple liquids containing one object element belonging to that group are added to different positions of the powder, and the powder is stirred after the multiple liquids are dried.

10. An analytical verification method for a fluorescence X-ray analysis device, characterized in that: For multiple analytical verification samples prepared by the analytical verification sample preparation method of the fluorescence X-ray analysis apparatus according to any one of claims 1 to 9, fluorescence X-ray analysis is performed using the fluorescence X-ray analysis apparatus as the analytical verification object, thereby determining the concentration of the object element and determining whether the difference between the obtained concentration and the predetermined concentration is within a predetermined range.

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