Fluorescent x-ray analysis sample preparation tool and fluorescent x-ray analysis

Abstract

A sample preparation tool (10) for X-ray fluorescence analysis is a tool for preparing a sample for X-ray fluorescence analysis by pulverizing a solid pharmaceutical product (91) to be analyzed into a powder, and is provided with: a pulverizing container (11) for accommodating the solid pharmaceutical product (91); and a pulverizing member (12) that can be housed in the pulverizing container (11) together with the solid pharmaceutical product (91), the inner surfaces (131, 132) of the pulverizing container (11) and the surface (133) of the pulverizing member (12) being made of a material that has lipophobicity, is harder than the solid pharmaceutical product (91), does not contain Cd, Pb, As, Hg, Co, V, or Ni, and has a thickness of 10-30 [mu] m. Or the pharmaceutical composition does not contain impurity elements specified by the element impurity management guidance principle in pharmaceutical preparations published by the technical requirements of human medicines on international coordination affairs.

Description

Technical Field

[0001] This invention relates to an apparatus for preparing samples for fluorescence X-ray analysis, and more particularly to an apparatus for pulverizing solid pharmaceutical substances as the subject of analysis into powder. Furthermore, this invention also relates to a method for preparing samples for fluorescence X-ray analysis using said apparatus. Background Technology

[0002] If harmful metallic elements are mixed into pharmaceuticals or food as impurities, they may pose health hazards to people who ingest these products or foods. Therefore, standards have been established to limit the concentration of specific metallic elements. Particularly in the pharmaceutical field, the International Council for Harmonization 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 intake levels for 24 metallic elements, and the permissible concentration for each pharmaceutical preparation is determined based on these levels. These 24 metallic elements are divided into four categories (Category 1, Category 2A, Category 2B, and Category 3) according to 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 products 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 products, may be contaminated in pharmaceuticals from substances used in manufacturing processes, such as catalysts. Category 3, although considered less toxic than the aforementioned 17 elements, is frequently used for screening-based risk assessment using fluorescence X-ray analysis.

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

[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. In response, it has recently been proposed to use fluorescence X-ray analysis, which requires simpler sample pretreatment, for the concentration analysis of the target element (Non-Patent Literature 2). In fluorescence X-ray analysis, sample pretreatment only requires pulverizing the pharmaceutical product into a uniform powder.

[0006] Existing technical documents Non-patent literature Non-Patent Literature 1: Ichinose Takayuki et al., “Pharmaceutical Elemental Impurities Guidelines (ICH Q3D) and ICP-MS: Current Status 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 20, 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 When performing fluorescence X-ray analysis on powders obtained from pulverized pharmaceutical products, the detected concentration of elements originally present in the pharmaceutical product may sometimes be lower than the actual concentration, depending on the equipment used during pulverization. In such cases, even if the detected concentration of the target element, which should not be present in the pharmaceutical product, is below the benchmark value, the reliability of the analysis may be questionable.

[0007] The technical problem to be solved by the present invention is to provide a sample preparation apparatus for fluorescent X-ray analysis that can prepare powder samples for high-reliability fluorescent X-ray analysis, and a sample preparation method for fluorescent X-ray analysis using the apparatus.

[0008] Solution to the above technical problems The sample preparation apparatus for fluorescence X-ray analysis, which is made in accordance with the present invention to solve the above-mentioned technical problems, is an apparatus for pulverizing solid pharmaceutical products as the subject of analysis into powder to prepare samples for fluorescence X-ray analysis. Its characteristics are as follows: It comprises: a pulverizing container for containing the solid pharmaceutical product; and a pulverizing component that can be contained within the pulverizing container together with the solid pharmaceutical product. The inner surface of the pulverizing container and the surface of the pulverizing component are made of a material that is oleophobic, harder than the solid pharmaceutical product, and free of Cd, Pb, As, Hg, Co, V and Ni, or free of the impurity elements specified in the guidelines for elemental impurity management in pharmaceutical preparations published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

[0009] The present invention relates to a method for preparing samples for fluorescence X-ray analysis, which involves using the aforementioned sample preparation apparatus for fluorescence X-ray analysis to pulverize a solid pharmaceutical product, the object of analysis, into powder, thereby preparing a sample for fluorescence X-ray analysis. The method is characterized by... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated or rotated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

[0010] Invention Effects Many solid pharmaceutical tablets or granules have coatings applied to their surfaces to suppress bitterness or off-flavors and to adjust drug dissolution time. Some of these coatings contain oils or organic components. If a solid pharmaceutical product with an oil- or organic coating is pulverized, a portion of the oil or organic component of the coating adheres to the pulverizing apparatus, and consequently, a portion of the element being evaluated may also adhere to the apparatus along with the oil. As a result, the concentration of the element being evaluated in the pulverized powder becomes lower than the concentration of these elements in the original solid pharmaceutical product, making accurate evaluation impossible. Therefore, in the sample preparation apparatus for fluorescence X-ray analysis involved in this invention, by using an oleophobic material for the inner surface of the pulverizing container and the surface of the pulverizing component, the adhesion of the oil from the coating and the element being evaluated to these inner and outer surfaces can be suppressed. This allows for accurate determination of the concentration of the element being evaluated, enabling highly reliable fluorescence X-ray analysis.

[0011] Furthermore, if the inner surface of the pulverizing container and the surface of the pulverizing components are softer than the solid pharmaceutical product being analyzed, the solid pharmaceutical product cannot be pulverized. Therefore, a material harder than the solid pharmaceutical product is used on these inner and outer surfaces. In particular, in the case of cryogenic pulverization, where the sample preparation apparatus for fluorescence X-ray analysis of the present invention and the solid pharmaceutical product are cooled to below -100°C to pulverize the solid pharmaceutical product, a material harder than the solid pharmaceutical product during freezing is used.

[0012] Furthermore, if the inner surface of the pulverizing container and the surface of the pulverizing components contain the element being evaluated, this element may be introduced into the pulverized powder from these surfaces. Therefore, the materials used for these inner surfaces and surfaces must be free of at least the essential evaluation elements for pharmaceuticals, namely Cd, Pb, As, Hg, Co, V, and Ni, or the impurity elements specified in the guidelines for elemental impurity management in pharmaceutical preparations published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Moreover, when other elements are included as evaluation targets, materials that also do not contain these elements must be used. Attached Figure Description

[0013] 【 Figure 1 [Image showing a schematic cross-sectional view of one embodiment of the sample preparation apparatus for fluorescence X-ray analysis according to the present invention.]

[0014] 【 Figure 2 [Image showing a schematic cross-sectional view of a modified example of the sample preparation apparatus for fluorescence X-ray analysis according to this embodiment.]

[0015] 【 Figure 3 [Image showing a schematic cross-sectional view of other variations of the sample preparation apparatus for fluorescence X-ray analysis according to this embodiment.]

[0016] 【 Figure 4 The following diagram illustrates the method of using the sample preparation apparatus for fluorescence X-ray analysis and the method of preparing a sample for fluorescence X-ray analysis according to this embodiment. (a) is a diagram showing the process of housing the pulverizing component and the solid pharmaceutical product in the pulverizing container; (b) is a diagram showing the process of cooling the sample preparation apparatus for fluorescence X-ray analysis and the solid pharmaceutical product to below -100°C; (c) is a diagram showing the process of applying vibration to the sample preparation apparatus for fluorescence X-ray analysis; and (d) is a diagram showing the powder of the obtained sample for fluorescence X-ray analysis.

[0017] 【 Figure 5 The image indicates a fluorescence X-ray spectrum obtained for a first solid pharmaceutical product prepared using the fluorescence X-ray analysis sample preparation apparatus (a) of this embodiment, the fluorescence X-ray analysis sample preparation apparatus (b) of Comparative Example 1, and the commercially available mortar and pestle (c) of Comparative Example 2.

[0018] 【 Figure 6 The image indicates a fluorescence X-ray spectrum obtained by using the fluorescence X-ray analysis sample preparation apparatus (a) of this embodiment, the fluorescence X-ray analysis sample preparation apparatus (b) of Comparative Example 1, and the commercially available mortar and pestle (c) of Comparative Example 2 for a second solid pharmaceutical product. Detailed Implementation

[0019] use Figures 1-6 This invention describes the embodiments of the sample preparation apparatus and method for fluorescence X-ray analysis involved in this invention.

[0020] (1) Composition of the sample preparation apparatus for fluorescence X-ray analysis in this embodiment The sample preparation apparatus 10 for fluorescence X-ray analysis in this embodiment is an apparatus used to pulverize solid pharmaceutical products such as tablets or granules when performing fluorescence X-ray analysis on such solid pharmaceutical products. Figure 1 As shown, it includes a crushing container 11 and a crushing component (impactor) 12.

[0021] The crushing container 11 consists of a body 111 and a lid 112. The body 111 is cylindrical in shape, closed at one end and open at the other. However, the shape of the body 111 is not limited to this; it can also be any shape such as a sphere or a cuboid. The lid 112 is installed at the other end of the body 111 to close the opening of the body 111. The lid 112 can be installed, for example, by screwing an external thread on the other end of the body 111 into an internal thread on the inner surface of the lid 112, but other methods can also be used.

[0022] The crushing component 12 is a component with dimensions that allow it to be housed within the main body 111 of the crushing container 11. The crushing component 12 can take the shape of a cylinder, an elliptical cylinder, a polygonal prism, a cuboid, a sphere, or an ellipsoid. Furthermore, there can be only one crushing component 12, or multiple crushing components can be used. Figure 1 A crushing component 12 is shown, consisting of a cylindrical component that is slightly shorter in length and slightly smaller in diameter than the space within the main body 111. Figure 2 The crushing component 12 is shown, which consists of multiple cylindrical parts that are much shorter in length and much smaller in diameter than the space within the main body 111.

[0023] The inner surface 131 of the main body 111 of the pulverizing container 11, the inner surface 132 of the cover 112, and the outer surface 133 of the pulverizing component 12 are all made of an oleophobic material. Since the surfaces listed here are the surfaces that come into contact with the solid pharmaceutical product to be pulverized and the pulverized powder, these surfaces are collectively referred to as "contact surfaces 13" below. Each component of the main body 111, cover 112, and pulverizing component 12 may be made entirely of an oleophobic material, not just on the contact surfaces 13. On the other hand, non-oleophobic materials may also be used for the parts of these components other than the contact surfaces. As an example, a component with a coating 14 made of an oleophobic material applied to the contact surfaces 13 of a component made of a non-oleophobic material can be described. Figure 3 ).

[0024] Furthermore, since the seven elements Cd, Pb, As, and Hg, which belong to Category 1 in the ICH Q3D Elemental Impurities Guidelines, and Co, V, and Ni, which belong to Category 2A, must be evaluated when assessing the concentration of metal elements in solid pharmaceutical products, the materials used for the contact surfaces must be free of these seven elements in order to prevent them from contaminating the sample. Alternatively, the material of the contact surface may be free of the 24 elements specified in the ICH-Q3D Elemental Impurity Guidelines (in addition to the 7 elements mentioned above, it also includes 10 elements belonging to Category 2B: Tl (thallium), Au (gold), Pd, Ir (iridium), Os (osmium), Rh (rhodium), Ru (ruthenium), Se (selenium), Ag (silver), and Pt (platinum), and 7 elements belonging to Category 3: Li (lithium), Sb (antimony), Ba (barium), Mo (molybdenum), Cu (copper), Sn (tin), and Cr (chromium)).

[0025] Furthermore, in order to reliably pulverize solid pharmaceuticals while preventing damage to the contact surface 13, the material of the contact surface 13 is made of a material with a higher hardness than the solid pharmaceuticals being pulverized.

[0026] Here, polytetrafluoroethylene (PTFE), known as "Teflon" (a registered trademark), is cited as an example of an oleophobic material. Furthermore, zirconium oxide (ZrO2) is known as an oleophobic material in ceramic materials. Both PTFE and zirconium oxide meet the requirements of being free of the aforementioned seven elements or the 24 elements specified in the ICH-Q3D elemental impurity guideline. PTFE is superior in terms of oleophobicity, but zirconium oxide is higher in terms of hardness. When the hardness of the solid pharmaceutical product to be pulverized is lower than that of PTFE, PTFE is preferred as the material for the contact surface. On the other hand, when the hardness of the solid pharmaceutical product to be pulverized is higher than that of PTFE, zirconium oxide is preferred as the material for the contact surface cannot be PTFE.

[0027] For example, since multilayer coated tablets with multiple coating layers having different dissolution rates tend to have high hardness, it is preferable to use a sample preparation apparatus 10 for fluorescence X-ray analysis with a zirconia contact surface 13. On the other hand, granules or film-coated tablets with only one coating layer generally do not have very high hardness, so it is preferable to use a sample preparation apparatus 10 for fluorescence X-ray analysis with a PTFE contact surface 13.

[0028] Of course, materials other than PTFE and zirconium oxide can also be used in the material of the contact surface 13, as long as the material is oleophobic, does not contain the seven essential assessment elements or the 24 elements that require risk assessment in the ICH-Q3D element impurity guidelines, and meets the hardness requirements.

[0029] Preferably, the contact surface 13 is ground during the preparation of the sample preparation apparatus 10 for fluorescence X-ray analysis to minimize its surface roughness. For example, the maximum height difference on the contact surface 13 is less than 100 μm, preferably less than 10 μm. When the height difference on the contact surface 13 is less than 10 μm, the surface roughness is so small that it is imperceptible to a person when rubbing the contact surface 13 with their fingers.

[0030] In the contact surface 13, the bottom surface 1311 of the main body 111 of the crushing container 11 and the inner surface 132 of the cover 112 are preferably concave curved surfaces, and when the crushing component 12 is rod-shaped, the two end faces 1331 of the crushing component 12 are preferably convex curved surfaces (see reference). Figure 1 (etc.). Therefore, compared to cases where all surfaces are flat, the material being crushed moves more easily laterally during crushing, thus resulting in more uniform crushing.

[0031] (2) The method of using the sample preparation apparatus for fluorescence X-ray analysis in this embodiment, and the structure of the sample preparation method for fluorescence X-ray analysis in this embodiment. The sample preparation apparatus 10 for fluorescence X-ray analysis of this embodiment can be used to implement the sample preparation method for fluorescence X-ray analysis of this embodiment. In this embodiment, a solid pharmaceutical product 91 containing an oil-based coating agent is used to prepare a sample for fluorescence X-ray analysis.

[0032] First, after accommodating the pulverizing component 12 and the solid pharmaceutical product 91 to be analyzed in the main body 111 of the pulverizing container 11, the cover 112 is installed on the main body 111. Figure 4 (a)).

[0033] Next, by immersing the pulverizing container 11, which houses the pulverizing component 12 and the solid pharmaceutical product 91, in liquid nitrogen 93, the sample preparation apparatus 10 for fluorescence X-ray analysis and the solid pharmaceutical product 91 are cooled to below -100°C. Figure 4 (b)

[0034] Next, while maintaining the temperature of the sample preparation apparatus 10 for fluorescence X-ray analysis and the solid pharmaceutical product 91 below -100°C (before the temperature naturally rises above -100°C), a centrifugal force based on vibration and / or rotation is applied to the pulverizing container 11. Figure 4 (c)). Vibration or rotation can be applied using a centrifugal grinder or a commercially available grinder that swings the grinding container 11 in a figure-eight shape. By applying centrifugal force based on vibration or rotation to the grinding container 11, the solid pharmaceutical product 91 inside the grinding container 11, while sandwiched between the inner surfaces 131, 132 of the grinding container 11 and the outer surface 133 of the grinding component 12, is subjected to impact forces from the grinding component 12 due to its impact, and also to reaction forces from the inner surfaces 131, 132 of the grinding container 11. Under these forces, the solid pharmaceutical product 91 is pulverized, yielding a sample 92 for fluorescent X-ray analysis as powder. Figure 4 (d)

[0035] (3) Effects of the sample preparation apparatus and sample preparation method for fluorescence X-ray analysis in this embodiment Since the solid pharmaceutical product 91, which is the object to be pulverized in this embodiment, contains a coating agent containing oil, it is assumed that when the solid pharmaceutical product 91 is pulverized, a portion of this oil adheres to the contact surface 13 of the sample preparation apparatus 10 for fluorescence X-ray analysis. Consequently, a portion of the analyte element may also adhere to the contact surface 13 along with the oil, thus preventing it from being included in the powder of the sample 92 for fluorescence X-ray analysis. However, in the sample preparation apparatus 10 for fluorescence X-ray analysis of this embodiment, since the contact surface 13 is made of an oleophobic material, the adhesion of such oil or a portion of the analyte element to the contact surface 13 can be suppressed, and these oils or analyte elements are included in the powder of the sample 92 for fluorescence X-ray analysis obtained by pulverizing the solid pharmaceutical product 91. As a result, the sample preparation apparatus 10 for fluorescence X-ray analysis and the sample preparation method for fluorescence X-ray analysis of this embodiment facilitate accurate performance of fluorescence X-ray analysis.

[0036] Furthermore, in the sample preparation apparatus 10 for fluorescence X-ray analysis in this embodiment, the contact surface 13 does not have a height difference of more than 100 μm (preferably, it does not have a height difference of more than 10 μm), which also helps to prevent the oil or part of the analyte element of the solid pharmaceutical 91 from adhering to the contact surface 13.

[0037] Furthermore, the low temperature of the sample preparation apparatus 10 for fluorescence X-ray analysis and the solid pharmaceutical product 91, below -100°C, helps to prevent the adhesion of oils or analyte elements from the solid pharmaceutical product 91 to the contact surface 13 of the sample preparation apparatus 10. Additionally, cooling to such a low temperature makes the material easier to pulverize, regardless of whether it contains oils or grease.

[0038] Although the focus so far has been on the oils contained in the solid pharmaceutical product 91, the sample preparation apparatus 10 for fluorescence X-ray analysis of this embodiment also has the advantage of preventing these elements from being mixed into the sample 92 for fluorescence X-ray analysis as impurities because the material of the contact surface 13 does not contain the seven elements consisting of Cd, Pb, As, Hg, Co, V and Ni or the 24 elements specified in the ICH-Q3D elemental impurity guideline.

[0039] (4) Experiments on fluorescent X-ray analysis samples prepared using the sample preparation apparatus and method for fluorescent X-ray analysis according to this embodiment. Next, the preparation of a fluorescent X-ray analysis sample 92 using the sample preparation apparatus and method for fluorescent X-ray analysis according to this embodiment will be described, and the experimental results of fluorescent X-ray analysis of the obtained fluorescent X-ray analysis sample 92 will be explained.

[0040] As the sample preparation apparatus 10 for fluorescence X-ray analysis in this embodiment, a pulverizing container 11 and a pulverizing component 12 were prepared, both made of PTFE, and the contact surface 13 was ground until no unevenness could be felt when rubbed with a finger. The solid pharmaceutical product 91 used tablets coated with an agent containing hydroxypropyl methylcellulose (HPMC), titanium dioxide (TiO2), ferric oxide (Fe2O3), and polyethylene glycol 400 (polyethylene glycol with a number average molecular weight of approximately 400). Multiple tablets, totaling 18g, were prepared, divided into three groups, and each group was pulverized independently.

[0041] Comparative experiments were conducted using the fluorescence X-ray analysis sample preparation apparatus 10 and the apparatuses described in Comparative Examples 1 and 2 below. In Comparative Example 1, a fluorescence X-ray analysis sample preparation apparatus was used, with a pulverizing container made of polycarbonate (PC) and a pulverizing component made of agate. Similar to this embodiment, in the fluorescence X-ray analysis sample preparation apparatus of Comparative Example 1, an apparatus was used where the contact surface 13 was imperceptible even when rubbed with a finger. Furthermore, as Comparative Example 2, commercially available agate mortars and pestles were used. Regarding the inner surfaces of these mortars and the surface of the pestle, an apparatus was used where the imperfections were imperceptible even when rubbed with a finger.

[0042] In this experiment, two types of solid pharmaceutical tablets containing oil-based coatings were prepared. The first solid pharmaceutical tablet was coated with an agent comprising HPMC, carnauba wax, and titanium dioxide, the coating comprising approximately 5% of the tablet's total weight. The second solid pharmaceutical tablet was coated with an agent comprising HPMC, titanium dioxide, ferric oxide, and alcohols, the coating comprising approximately 1% of the tablet's total weight. Among the components of these coatings, HPMC and carnauba wax are organic and oil-based ingredients, respectively.

[0043] Multiple first solid pharmaceutical products, totaling 6g, were prepared and divided into two equal groups (3g each). Each group was then independently pulverized. In this embodiment, after containing the pulverizing component 12 and the first solid pharmaceutical products in the pulverizing container 11 and thoroughly cooling them with liquid nitrogen, a rotary and vibratory pulverizing device capable of pulverizing the material by applying a large centrifugal force was immediately used. The operation of applying vibration at 2800 rpm for 10 seconds was repeated three times. Afterward, for each of the two groups, the powder sample was recovered from the pulverizing container 11 and subjected to fluorescence X-ray analysis (first time). Subsequently, fluorescence X-ray analysis was performed after stirring the powder sample (second time), and then after stirring the powder sample with a mortar and pestle (third time). The fluorescence X-ray analysis used an EDX-7000 fluorescence X-ray analyzer manufactured by Shimadzu Corporation.

[0044] Furthermore, the purpose of stirring the powder sample here is to alter the portion of the powder sample that has been irradiated with X-rays to generate fluorescent X-rays. If the solid pharmaceutical product is not sufficiently pulverized, the concentration of the coating agent will vary depending on the localized areas of irradiation, resulting in different amounts of the coating agent within the powder sample. Therefore, the smaller the deviation in the elemental concentrations within the coating agent obtained from three fluorescent X-ray analyses, the more thoroughly the solid pharmaceutical product has been pulverized. Since the powder sample is stirred for this purpose, almost no pressure needs to be applied to the powder sample from the stirring apparatus; therefore, the grease contained in the coating agent will hardly adhere to the apparatus and can be ignored.

[0045] In Comparative Example 1, except that the set speed of the rotary and vibratory pulverizer was changed to 2500 rpm, the two groups of samples were subjected to three fluorescence X-ray analyses using the same method as in this embodiment. In Comparative Example 2, without cooling, multiple first solid pharmaceutical particles were divided into two groups at room temperature, and each group was pulverized and stirred for 30 minutes using a mortar and pestle to prepare a powder sample, which was then subjected to fluorescence X-ray analysis (first analysis). Subsequently, as in this embodiment, fluorescence X-ray analysis was performed after stirring the powder sample (second analysis), and then after stirring the powder sample again (third analysis).

[0046] Multiple second solid pharmaceutical samples, totaling 6g, were prepared and subjected to pulverization and fluorescence X-ray analysis using the same method as the first solid pharmaceutical sample, except for the following points. In this embodiment, the set rotation speed of the rotary and vibratory pulverizer was changed to 3000 rpm, and the pulverization time per cycle was changed to 20 seconds. In Comparative Example 1, the number of operations using the rotary and vibratory pulverizer at 2500 rpm for 10 seconds (these rotation speeds and times are the same as in the case of the first solid pharmaceutical sample) was changed to 4. These changes were made considering that the second solid pharmaceutical sample is harder than the first solid pharmaceutical sample, and taking into account the strength of the sample preparation equipment used for fluorescence X-ray analysis, either by increasing the parameters of a single pulverization process (in this embodiment) or by increasing the number of pulverization processes (in Comparative Example 1).

[0047] In the above experiment, two groups of samples underwent three fluorescence X-ray analysis measurements, totaling six measurements, and the result was calculated as the average peak area of ​​the six measurements. Higher peak intensities of the elements contained in the coating agent, and smaller deviations for each measured sample, mean that the coating agent is less likely to adhere to the sample preparation equipment used for fluorescence X-ray analysis, allowing for more accurate analysis.

[0048] The experimental results are shown below. First, the spectra obtained by fluorescence X-ray analysis, which represent the relationship between energy and intensity, are shown for the first solid pharmaceutical product. Figure 5 Regarding the second solid pharmaceutical product, Figure 6 In these figures, for each solid pharmaceutical product, six spectra obtained from three separate fluorescence X-ray analyses of the two groups of samples in this embodiment, Comparative Example 1, and Comparative Example 2 are displayed overlaid. Figure 5 and Figure 6 In the obtained spectra, peaks of Kα and Kβ lines of Ti, derived from titanium dioxide contained in the coating agents of various solid pharmaceutical products, were visible, but peaks of the 24 evaluation elements specified in ICH Q3D were not observed. Therefore, we will focus on the Ti peaks in the following sections, while also paying close attention to the background, instead focusing on those evaluation elements.

[0049] In this embodiment, no significant differences were observed between the six spectra, either in the Ti peak or the background. In contrast, in Comparative Example 2, not only were significant differences observed in the Ti peak between the six spectra, but the fluorescence X-ray intensity was also lower than in this embodiment and Comparative Example 1. On the other hand, in Comparative Example 1, no significant differences were observed in the six spectra by visual inspection alone.

[0050] Therefore, for this embodiment, Comparative Example 1, and Comparative Example 2, the Kα line intensities of Ti obtained from the six spectra were determined. To assess data bias in each example, the intensity obtained in the first analysis of one of the two sample groups was set to 100, and the intensities of the remaining five samples were displayed. Furthermore, the average value and coefficient of variation of these six intensities are also shown. The coefficient of variation is the value obtained by dividing the standard deviation by the average value. The results are shown in Table 1 for the first solid pharmaceutical product and in Table 2 for the second solid pharmaceutical product.

[0051] Table 1

[0052] Table 2

[0053] Comparative Example 2 showed significant intensity deviations between the six measurements, with coefficients of variation reaching high values ​​of 20% (first solid pharmaceutical product) and 91.9% (second solid pharmaceutical product). This indicates that the solid pharmaceutical product containing the coating agent could not be sufficiently pulverized in Comparative Example 2, resulting in localized portions of the powder with either more or less coating agent.

[0054] Comparing this embodiment with Comparative Example 1, it is evident that the average intensity of this embodiment is higher, and the deviation (coefficient of variation) also shows a smaller value. This indicates that the coating agent of the solid pharmaceutical product is less likely to adhere to the contact surface of the sample preparation apparatus for fluorescence X-ray analysis. In this experiment, the concentration of Ti (titanium) contained in the coating agent was measured. However, it can be considered that, assuming the first / second solid pharmaceutical product being analyzed contains the evaluation element specified in ICH Q3D, this embodiment is more effective in suppressing such evaluation elements from adhering to the contact surface of the sample preparation apparatus for fluorescence X-ray analysis along with the oil in the coating agent. Furthermore, the coefficient of variation of this embodiment is lower than that of Comparative Example 1, indicating that the solid pharmaceutical product is more uniformly pulverized.

[0055] The experiment described above can also be used to determine the uniformity of the obtained fluorescence X-ray analysis samples 92, and further to determine the conformity of the fluorescence X-ray analysis sample preparation apparatus 10 (especially the material of the contact surface 13) of this embodiment. That is, both the method for confirming the uniformity of fluorescence X-ray analysis samples and the method for determining the conformity of the fluorescence X-ray analysis sample preparation apparatus of this embodiment include the following steps: First, multiple groups of solid pharmaceutical products 91 are prepared, and fluorescence X-ray analysis samples 92 are prepared for each group using the fluorescence X-ray analysis sample preparation apparatus 10 of this embodiment and the fluorescence X-ray analysis sample preparation method of this embodiment. Next, fluorescence X-ray analysis is performed on each obtained fluorescence X-ray analysis sample 92 to obtain a spectrum representing the relationship between wavelength or energy and intensity. If the shape and background of the multiple spectra obtained are consistent within a predetermined error range, it can be determined that the fluorescence X-ray analysis sample 92 is uniform, and the fluorescence X-ray analysis sample preparation apparatus 10 is conformable.

[0056] The embodiments of the sample preparation apparatus and method for fluorescence X-ray analysis according to the present invention have been described above. However, it should be noted that the present invention is not limited to the above embodiments and various modifications can be made.

[0057] [plan] It will be apparent to those skilled in the art that the above exemplary embodiments are specific examples of the following solutions.

[0058] (Item 1) One aspect of the present invention relates to a sample preparation apparatus for fluorescence X-ray analysis, which is an apparatus for pulverizing a solid pharmaceutical product as the object of analysis into powder to prepare a sample for fluorescence X-ray analysis, characterized in that... It comprises: a pulverizing container for containing the solid pharmaceutical product; and a pulverizing component that can be contained within the pulverizing container together with the solid pharmaceutical product. The inner surface of the pulverizing container and the surface of the pulverizing component are made of a material that is oleophobic, harder than the solid pharmaceutical product, and free of Cd, Pb, As, Hg, Co, V and Ni, or free of the impurity elements specified in the guidelines for elemental impurity management in pharmaceutical preparations published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

[0059] In many solid pharmaceutical tablets or granules, a coating agent is applied to the surface for purposes such as suppressing bitterness or off-flavors and adjusting drug dissolution time. Some of these coating agents contain oils. If a solid pharmaceutical product with an oil-containing coating is pulverized, a portion of the oil from the coating agent will adhere to the pulverizing apparatus, and consequently, a portion of the element to be evaluated may also adhere to the apparatus along with the oil. As a result, the concentration of the element to be evaluated in the pulverized powder will become lower than the concentration of these elements in the original solid pharmaceutical product, making accurate evaluation impossible. Therefore, in the sample preparation apparatus for fluorescence X-ray analysis described in claim 1, by using an oleophobic material on the inner surface of the pulverizing container and the surface of the pulverizing component, the adhesion of the oil from the coating agent and the element to be evaluated to these inner and outer surfaces can be suppressed, thus enabling accurate determination of the concentration of the element to be evaluated and allowing for highly reliable fluorescence X-ray analysis.

[0060] Furthermore, if the inner surface of the pulverizing container and the surface of the pulverizing components are softer than the solid pharmaceutical product being analyzed, the solid pharmaceutical product cannot be pulverized. Therefore, a material harder than the solid pharmaceutical product is used on these inner and outer surfaces. In particular, in cryogenic pulverization, where the sample preparation apparatus for fluorescence X-ray analysis and the solid pharmaceutical product described in paragraph 1 are cooled to below -100°C for pulverization, a material harder than the solid pharmaceutical product is used when frozen.

[0061] Furthermore, if the inner surface of the pulverizing container and the surface of the pulverizing components contain the element being evaluated, this element may be introduced into the pulverized powder from these surfaces. Therefore, the materials used for these inner surfaces and surfaces must be free of at least the essential evaluation elements for pharmaceuticals, namely Cd, Pb, As, Hg, Co, V, and Ni, or the impurity elements specified in the guidelines for elemental impurity management in pharmaceutical preparations published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Additionally, when elements other than these essential elements are included in the evaluation, materials that also do not contain these elements should be used.

[0062] (Item 2) The sample preparation apparatus for fluorescence X-ray analysis involved in Item 2 is the apparatus involved in Item 1, wherein the inner surface and the surface have the following surface roughness: the maximum height difference formed on the inner surface and the surface is less than 100 μm.

[0063] (Item 3) The sample preparation apparatus for fluorescence X-ray analysis mentioned in Item 3 is the apparatus mentioned in Item 2, wherein the maximum height difference is less than 10 μm.

[0064] According to the sample preparation apparatus for fluorescence X-ray analysis mentioned in items 2 and 3, by smoothing the inner surface of the pulverizing container and the surface of the pulverizing components, it is possible to further suppress the adhesion of coating agents, oils, and evaluation elements to these inner and outer surfaces.

[0065] (Item 4) The sample preparation apparatus for fluorescence X-ray analysis mentioned in Item 4 is the apparatus mentioned in any one of Items 1 to 3, wherein the material is polytetrafluoroethylene.

[0066] According to the sample preparation apparatus for fluorescence X-ray analysis involved in item 4, by using a highly oleophobic material, namely polytetrafluoroethylene, on the inner surface of the crushing container and the surface of the crushing components, it is possible to further suppress the adhesion of coating agents and evaluation elements to these inner and outer surfaces.

[0067] (Item 5) The sample preparation apparatus for fluorescence X-ray analysis mentioned in Item 5 is the apparatus mentioned in any one of Items 1 to 3, wherein the material is zirconium oxide.

[0068] According to the sample preparation apparatus for fluorescence X-ray analysis involved in item 5, by using a high-hardness material, namely oleophobic zirconium oxide from ceramics, on the inner surface of the crushing container and the surface of the crushing components, hard solid pharmaceutical products can be crushed while inhibiting the adhesion of coating agents and evaluation elements to these inner and outer surfaces.

[0069] (Item 6) One aspect of the present invention relates to a method for preparing a sample for fluorescence X-ray analysis, which involves using the sample preparation apparatus for fluorescence X-ray analysis described in any one of items 1 to 5 to pulverize a solid pharmaceutical product as the object of analysis into powder, thereby preparing a sample for fluorescence X-ray analysis, characterized in that... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated or rotated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

[0070] According to the sample preparation method for fluorescence X-ray analysis described in item 6, by using the sample preparation apparatus for fluorescence X-ray analysis described in any one of items 1 to 5 to pulverize solid pharmaceutical products into powder to prepare samples for fluorescence X-ray analysis, it is possible to suppress the adhesion of coating oils and evaluation elements to the inner surface of the pulverizing container and the surface of the pulverizing components, thereby accurately obtaining the concentration of the evaluation elements and enabling highly reliable fluorescence X-ray analysis.

[0071] (Item 7) The sample preparation method for fluorescence X-ray analysis involved in Item 7 is that, in the preparation method involved in Item 6, the temperature of the sample preparation apparatus for fluorescence X-ray analysis and the solid pharmaceutical product when the vibration is applied to the pulverizing container is below -100°C.

[0072] According to the sample preparation method for fluorescence X-ray analysis involved in item 7, by pulverizing solid pharmaceutical products at a low temperature below -100°C, it is possible to further inhibit the adhesion of coating oils and evaluation elements to the inner surface of the pulverizing container and the surface of the pulverizing components, while the solid pharmaceutical products become easier to pulverize due to embrittlement.

[0073] (Item 8) Item 8 relates to a method for preparing a sample for fluorescence X-ray analysis, which uses the sample preparation apparatus for fluorescence X-ray analysis described in Item 4, and prepares the sample for fluorescence X-ray analysis by pulverizing a solid pharmaceutical product having only one coating layer, which is the object of analysis, into powder, characterized in that... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

[0074] According to the sample preparation method for fluorescence X-ray analysis involved in item 8, for solid pharmaceutical products with relatively low hardness due to having only one coating layer, the sample preparation apparatus for fluorescence X-ray analysis involved in item 4, which is made of polytetrafluoroethylene for the inner surface of the pulverizing container and the surface of the pulverizing component, is used for pulverization, thereby further suppressing the adhesion of the coating agent oil and the evaluation target element on these inner and outer surfaces.

[0075] (Item 9) Item 9 relates to a method for preparing samples for fluorescence X-ray analysis, which uses the sample preparation apparatus for fluorescence X-ray analysis described in Item 5, and prepares the sample for fluorescence X-ray analysis by pulverizing a solid pharmaceutical product with multiple coating layers, which is the object of analysis, into powder, characterized in that... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

[0076] According to the sample preparation method for fluorescence X-ray analysis involved in item 9, for solid pharmaceutical products with high hardness due to having multiple coating layers, the sample preparation apparatus for fluorescence X-ray analysis involved in item 5, which uses zirconium oxide as the material for the inner surface of the pulverizing container and the surface of the pulverizing component, can be used to pulverize the solid pharmaceutical product while inhibiting the adhesion of coating oils and evaluation elements to these inner and outer surfaces.

[0077] (Item 10) The method for determining the homogeneity of a sample for fluorescence X-ray analysis, as per Item 10, is a method for determining the homogeneity of a sample for fluorescence X-ray analysis prepared by any one of the sample preparation methods per Item 6 to Item 9, characterized in that... Prepare multiple groups of the aforementioned solid pharmaceutical products, and for each group of solid pharmaceutical products, prepare a sample for fluorescence X-ray analysis using any one of the sample preparation methods for fluorescence X-ray analysis described in items 6 to 9. By performing fluorescence X-ray analysis on the samples obtained from each of the aforementioned groups, spectra were acquired as curves representing the relationship between wavelength or energy and intensity. If the shape and background of the multiple spectra obtained from each group are consistent within a predetermined error range, the sample for fluorescence X-ray analysis is determined to be homogeneous.

[0078] (Item 11) The method for determining the conformity of sample preparation apparatus for fluorescence X-ray analysis involved in Item 11 is a method for determining the conformity of sample preparation apparatus for fluorescence X-ray analysis involved in any one of Items 1 to 5, characterized in that, Prepare multiple sets of the aforementioned solid pharmaceutical products, and prepare fluorescent X-ray analysis samples for each set of solid pharmaceutical products using any of the sample preparation apparatus for fluorescent X-ray analysis described in items 1 to 5. By performing fluorescence X-ray analysis on the samples obtained from each of the aforementioned groups, spectra were acquired as curves representing the relationship between wavelength or energy and intensity. If the shape and background of the multiple spectra obtained from each group are consistent within a predetermined error range, the sample preparation apparatus for fluorescence X-ray analysis is deemed to be qualified.

[0079] According to the method for determining the homogeneity of samples for fluorescence X-ray analysis involved in item 10, the homogeneity of the samples for fluorescence X-ray analysis can be confirmed based on the shape and background of the spectra obtained by performing fluorescence X-ray analysis on multiple samples for fluorescence X-ray analysis prepared from multiple groups of prepared solid pharmaceutical products using the sample preparation methods for fluorescence X-ray analysis involved in any one of items 6 to 9. Furthermore, according to the method for determining the conformity of apparatus for preparing samples for fluorescence X-ray analysis involved in item 11, the conformity of the apparatus for preparing samples for fluorescence X-ray analysis (particularly the material of the inner surface of the pulverizing container and the surface of the pulverizing components) can be confirmed based on the shape of the spectra obtained by performing fluorescence X-ray analysis on multiple samples for fluorescence X-ray analysis, using the same method as the method for determining the homogeneity of samples for fluorescence X-ray analysis involved in item 10.

[0080] Explanation of reference numerals in the attached figures 10…Sample preparation apparatus for fluorescence X-ray analysis 11… Crushing Container 111…The main body of the crushing container 112…Lid of the crusher container 12… Crushing components 13…Contact Surface 131…Inner surface of the crushing container body 1311… Bottom surface of the main body of the crushing container 132…Inner surface of the crusher container lid 133…Outside of the crushing component 1331… Both ends of the crushing component 14… Coating on the contact surface 91…Solid pharmaceutical products 92…Samples for fluorescence X-ray analysis 93…Liquid nitrogen.

Claims

1. A sample preparation apparatus for fluorescence X-ray analysis, characterized in that it is used to pulverize a solid pharmaceutical product, the object of analysis, into powder to prepare a sample for fluorescence X-ray analysis. It comprises: a pulverizing container for containing the solid pharmaceutical product; and a pulverizing component that can be contained within the pulverizing container together with the solid pharmaceutical product. The inner surface of the pulverizing container and the surface of the pulverizing component are made of a material that is oleophobic, harder than the solid pharmaceutical product, and free of Cd, Pb, As, Hg, Co, V and Ni, or free of the impurity elements specified in the guidelines for elemental impurity management in pharmaceutical preparations published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

2. The sample preparation apparatus for fluorescence X-ray analysis according to claim 1, characterized in that, The inner surface and the surface have the following surface roughness: the maximum height difference formed on the inner surface and the surface is less than 100 μm.

3. The sample preparation apparatus for fluorescence X-ray analysis according to claim 2, characterized in that, The maximum height difference is less than 10 μm.

4. The sample preparation apparatus for fluorescence X-ray analysis according to claim 1, characterized in that, The material is polytetrafluoroethylene.

5. The sample preparation apparatus for fluorescence X-ray analysis according to claim 1, characterized in that, The material is zirconium oxide.

6. A method for preparing a sample for fluorescence X-ray analysis, comprising using the sample preparation apparatus for fluorescence X-ray analysis as described in claim 1 to pulverize a solid pharmaceutical product as the object of analysis into powder, thereby preparing a sample for fluorescence X-ray analysis, characterized in that, After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated or rotated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

7. The sample preparation method for fluorescence X-ray analysis according to claim 6, characterized in that, The temperature of the sample preparation apparatus for fluorescence X-ray analysis and the solid pharmaceutical product when the vibration is applied to the pulverizing container is below -100°C.

8. A method for preparing a sample for fluorescence X-ray analysis, using the sample preparation apparatus for fluorescence X-ray analysis as described in claim 4, wherein a solid pharmaceutical product having only one coating layer, which is the object of analysis, is pulverized into powder to prepare a sample for fluorescence X-ray analysis, characterized in that... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

9. A method for preparing a sample for fluorescence X-ray analysis, using the sample preparation apparatus for fluorescence X-ray analysis as described in claim 5, wherein a solid pharmaceutical product having multiple coating layers, which is the object of analysis, is pulverized into powder to prepare a sample for fluorescence X-ray analysis, characterized in that... After the solid medicine and the pulverizing component are contained in the pulverizing container, the pulverizing component is vibrated to cause the pulverizing component to strike the solid medicine sandwiched between the pulverizing component and the inner surface of the pulverizing container, thereby pulverizing the solid medicine.

10. A method for determining the homogeneity of a sample for fluorescence X-ray analysis, comprising determining the homogeneity of a sample for fluorescence X-ray analysis prepared by the sample preparation method for fluorescence X-ray analysis according to claim 6, characterized in that, Prepare multiple groups of the aforementioned solid pharmaceutical products, and prepare fluorescent X-ray analysis samples for each group of solid pharmaceutical products using the sample preparation method for fluorescent X-ray analysis as described in claim 6. By performing fluorescence X-ray analysis on the samples obtained from each of the aforementioned groups, spectra were acquired as curves representing the relationship between wavelength or energy and intensity. If the shape and background of the multiple spectra obtained from each group are consistent within a predetermined error range, the sample for fluorescence X-ray analysis is determined to be homogeneous.

11. A method for determining the conformity of a sample preparation apparatus for fluorescence X-ray analysis, comprising a method for determining the conformity of the sample preparation apparatus for fluorescence X-ray analysis as described in claim 1, characterized in that, Prepare multiple sets of the aforementioned solid pharmaceutical products, and prepare fluorescent X-ray analysis samples for each set of solid pharmaceutical products using the sample preparation apparatus for fluorescent X-ray analysis as described in claim 1. By performing fluorescence X-ray analysis on the samples obtained from each of the aforementioned groups, spectra were acquired as curves representing the relationship between wavelength or energy and intensity. If the shape and background of the multiple spectra obtained from each group are consistent within a predetermined error range, the sample preparation apparatus for fluorescence X-ray analysis is deemed to be qualified.

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