X-ray diffractometer and method for analyzing packaged samples

Abstract

The present invention relates to a method and an X-ray diffractometer for angle-dispersive X-ray diffraction analysis of an analyte (sample) ("packaged sample") enclosed in a package. The method includes arranging a first primary X-ray optical system between an X-ray source and a packaged sample to focus X-rays from an X-ray source to form a focused X-ray beam of focused or parallel X-rays and direct the focused X-ray beam towards the packaged sample, and arranging a first secondary X-ray optical system between the packaged sample and an X-ray detector. The packaged sample is irradiated by the X-ray source with a focused X-ray beam of focused or parallel X-rays, which are X-rays having an energy greater than about 9 keV, while the analyte is enclosed in the package. The first secondary X-ray optical system is configured such that a first portion of the diffracted X-rays passes through it and is detected by the X-ray detector, while a second portion of the diffracted X-rays is prevented from being detected by the X-ray detector, the first portion of the diffracted X-rays originating from a region within the package.

Description

Technical Field

[0001] The present invention relates to an X-ray diffractometer for analyzing a packaged sample, and a method for analyzing a packaged sample by X-ray diffraction analysis. In particular, the present invention relates to providing a simple and improved analysis of a packaged sample containing a small amount of crystalline material, such as a packaged sample containing a pharmaceutical sample mainly composed of an amorphous material or a sample containing a phase mixture.

Background Art

[0002] Generally, X-ray diffraction analysis is used to analyze a product by identifying the crystalline components present in the sample. Samples in the form of powders, lyophilized powders, tablets, liquids or semi-solid preparations can be tested using X-ray diffraction analysis. For example, in the field of pharmaceuticals, X-ray diffraction analysis may be used to test the amorphous state of products such as vaccines. Since the presence of even a small amount of crystalline components can compromise the stability of a vaccine, it is desirable to be able to detect the presence of crystals within the otherwise amorphous matrix.

[0003] Ideally, during X-ray diffraction analysis, the sample should be analyzed without any packaging that interferes with the incident and / or diffracted X-rays. If packaging is present, it may absorb and attenuate some of the X-rays incident on / scattered by the sample and / or act as a source of background scattering. This can make it difficult to identify components in the sample using data obtained by X-ray diffraction analysis, especially if the sample contains only small amounts of crystalline material or low concentrations of minority crystalline phases. In some cases, problems associated with the presence of packaging, particularly the difficulty in distinguishing signals from crystalline material from signals from the packaging, can completely prevent the identification of crystalline components present in the sample. Glass, metal, and plastic packaging typically absorb / attenuate X-rays significantly and are also a major source of background scattering. Packaged samples may be larger than samples specifically prepared for X-ray diffraction analysis. Furthermore, interpreting data from large packaged samples can be difficult because the diffraction signal may be affected by smearing (e.g., peak broadening or deformation).

[0004] Removing a sample from its packaging is inconvenient, increases the time required for sample preparation, and is not cost-effective. In some cases, removing a sample from its packaging may be dangerous and require expensive handling (e.g., if the sample contains toxic and / or radioactive materials, or if the contents of the packaging are unknown), which can further increase the time, inconvenience, and cost associated with performing X-ray diffraction analysis of the sample. Furthermore, removing a sample from its packaging may alter or damage the sample (e.g., analysis of lyophilized powder or battery), or otherwise complicate the measurement process (e.g., exposure to air may be unacceptable for lyophilized powder, amorphous samples at risk of recrystallization, or samples where exposure to air may cause polymorphic phase transitions).

[0005] Therefore, it would be desirable to provide an X-ray diffraction apparatus that facilitates the collection of relatively easy-to-interpret X-ray diffraction analysis data. In particular, it would be desirable to provide an X-ray diffraction apparatus that facilitates safe, effective, and simple analysis of packaged samples with high specificity. It would also be desirable to provide a safe, effective, and simple method for analyzing packaged samples with high specificity. [Overview of the Initiative]

[0006] According to one aspect of the present invention, a method of angle-dispersive X-ray diffraction analysis for analyzing a packaged sample is provided, wherein the packaged sample comprises an analyte enclosed within a package, and the method is as follows: To focus X-rays from an X-ray source to form a focused X-ray beam of focused or parallel X-rays, and to direct the focused X-ray beam towards the packaged sample, a first primary X-ray optical system is placed between the X-ray source and the packaged sample. The first secondary X-ray optical system is placed between the packaged sample and the X-ray detector, While the analyte is sealed within the package, an X-ray source is used to irradiate the packaged sample with a focused X-ray beam of focused or parallel X-rays, which have an energy greater than approximately 9 keV. The first secondary X-ray optical system is configured such that a first portion of the diffracted X-rays passes through it and is detected by an X-ray detector, while a second portion of the diffracted X-rays is prevented from being detected by the X-ray detector, wherein the first portion of the diffracted X-rays substantially originates from a region within the packaging.

[0007] The X-ray source may irradiate the packaged sample with a focused X-ray beam at an incident angle ω relative to the incident surface of the packaged sample.

[0008] Generally speaking, X-ray diffraction analysis is performed on a sample (analyte) that has been specially prepared for the purpose of performing the analysis and minimizing external influences (e.g., minimizing background scattering or contribution to X-ray absorption or attenuation by the sample holder / container, and controlling the volume / shape of the sample to minimize / eliminate smearing of the diffraction signal). In this regard, and in the context of this specification, “packaged sample” (and its variations) refers to an analyte enclosed within a package (i.e., not a sample specially prepared for the purpose of performing the analysis, where the packaging can always contribute to background scattering and / or X-ray absorption or attenuation, and the volume / shape of the analyte can cause smearing of the diffraction signal).

[0009] As used herein, “analyte” means the material being analyzed (also referred to herein as “sample”), and “the analyte is “sealed in packaging” means that the contents of the packaging (i.e., the analyte / sample) are not directly accessible and / or may not be able to be processed for analysis. This could be due to one of many reasons, for example, if the analyte / sample is hazardous / toxic, if accessing the analyte / sample would disable the tamper-evident features of the packaging, if accessing the analyte / sample would make it unsaleable, or if the analyte / sample would deteriorate when exposed to the surrounding atmosphere / conditions. In some instances, “sealed” may mean that the analyte is sealed within packaging so that it is (generally) inaccessible (e.g., a battery), or that it is sealed within packaging so that it is accessible (e.g., a pharmaceutical product). As used herein, “packaging” may mean any material used to contain the analyte, including but not limited to glass, metal, plastic, or any combination thereof. In contrast to samples specially prepared for analysis (e.g., glass capillaries with very thin walls (less than 0.5 mm)), the packaging may be opaque to the naked eye and / or semi-transparent to X-rays only.

[0010] As those skilled in the art will understand, the region of the packaged sample to be analyzed is defined by the region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam (i.e., the first portion of the diffracted X-rays) detected by the X-ray detector. This region can be modified / shifted by changing one or more of the first primary X-ray optics, the sample holder (and thus the position of the packaged sample), or the first secondary X-ray optics. This changes / shifts the position (location and / or volume) of the region formed by the intersection of the incident X-ray beam and the first portion of the diffracted X-rays detected by the X-ray detector (i.e., the region of the packaged sample to be analyzed). In this way, the region to be analyzed can be modified / shifted to correspond to the type / shape of the packaged sample. In other words, by changing the proportion of diffracted X-rays detected (or detectable) by the X-ray detector, reception by the X-ray detector is limited, thereby changing / shifting the region in which the first portion of the diffracted X-rays is detected. Furthermore, the influence of the packaging on the detected X-ray signal can be reduced by ensuring that the first portion of the diffracted X-rays substantially originates from the region within the packaging.

[0011] Of the X-rays diffracted by the packaged sample, only the first portion of the diffracted X-rays passes through the first secondary X-ray optics and reaches the X-ray detector for detection. The first portion of the diffracted X-rays substantially originates from the region within the packaging; that is, all or most of the X-rays in the first portion of the diffracted X-rays (e.g., 50%, 60%, 70%, 80%, 90%, or 95% or more) originate from the region of the packaged sample within the packaging. The "region of the packaged sample within the packaging" refers to the region inside the packaging that substantially excludes the packaging.

[0012] An X-ray beam may be substantially monochromatic; that is, the X-rays have an energy within a range of ±0.5 keV. For example, an X-ray beam may have an energy range of 16.9 keV to 17.9 keV (in the case of molybdenum, whose characteristic energy is 17.44 keV). It will be understood that other X-ray sources have different energy ranges in order to be considered monochromatic. For example, an X-ray beam from a gallium source (with a characteristic energy of 9.2 keV) may have an energy range of 8.7 keV to 9.7 keV.

[0013] The first secondary X-ray optical system may be configured such that the first portion of the diffracted X-rays originates from a region within the analyte.

[0014] In some embodiments, all or most (e.g., 50%, 60%, 70%, 80%, 90%, or 95% or more) of the diffracted X-rays that pass through the first secondary X-ray optical system and reach the X-ray detector are diffracted X-rays from regions within the analyte. Of the diffracted X-rays that pass through the first secondary X-ray optical system and reach the X-ray detector, a portion of the diffracted X-rays (e.g., 49% or less) may originate from regions inside the packaging that do not contain the analyte and / or regions that include the packaging.

[0015] The second portion of the X-rays may include X-rays diffracted by the packaging. Therefore, the first secondary X-ray optical system may be configured to prevent at least a portion of the X-rays diffracted by the packaging from reaching the X-ray detector and being detected by it.

[0016] The method may further include arranging a second primary X-ray optical system between a first primary X-ray optical system and a packaged sample, wherein the second primary X-ray optical system and the first secondary X-ray optical system are configured to form an analytical intersection formed by the intersection of an incident X-ray beam and a diffracted X-ray beam, and the analytical intersection is located in a region within the packaging. Thus, the diffracted X-rays that pass through the first secondary optical system and are detected by the X-ray detector may originate from a region within the packaging (i.e., a region of the packaged sample excluding the packaging).

[0017] The first secondary X-ray optical system may be a collimator. The collimator has a slit-shaped aperture which may have an aspect ratio greater than 5. The ratio of the distance from the packaged sample to the collimator to the distance from the collimator to the X-ray detector may be 0.1 or less, and preferably less than 0.025.

[0018] In embodiments including a second primary X-ray optical system, preferably both the first secondary X-ray optical system and the second primary X-ray optical system are collimators having slit-shaped apertures.

[0019] The method may further include controlling the effective area of ​​the X-ray detector based on the size of the collimator aperture and the position of the collimator relative to the packaged sample and the X-ray detector.

[0020] The packaging may include a cavity in which the analyte is held, with a portion of the cavity not containing the analyte. The method may further include positioning the packaged sample and / or the first secondary X-ray optical system such that the analytical intersection formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is located in the portion of the cavity in which the analyte is held, rather than in the portion of the cavity not containing the analyte.

[0021] The packaging may include glass, metal, and / or plastic. The material being analyzed may include amorphous organic materials.

[0022] The X-ray source may include an anode. The anode may include a material having an atomic number of 31 or higher, and the packaging may include a wall having a thickness of at least about 1 mm.

[0023] According to another aspect of the present invention, an X-ray diffractometer for angle-dispersive X-ray diffraction analysis of a packaged sample is provided, and the X-ray diffractometer is A sample support for supporting a packaged sample, wherein the packaged sample includes the analyte enclosed within the package; An X-ray source for irradiating an incident X-ray onto a packaged sample, wherein the incident X-ray is directed along an incident beam path toward the packaged sample, the X-ray source, and A first primary X-ray optical system disposed in the incident beam path, wherein the first primary X-ray optical system focuses the incident X-ray to form a converging X-ray beam or a parallel X-ray beam, and is disposed so as to direct the X-ray beam toward the packaged sample, the first primary X-ray optical system; and An X-ray detector disposed so as to receive diffracted X-rays from the packaged sample; and A first secondary X-ray optical system disposed between the sample support and the X-ray detector to allow a first portion of the diffracted X-rays to reach the X-ray detector and to prevent a second portion of the diffracted X-rays from being detected by the X-ray detector, The first secondary X-ray optical system is configured such that the first portion of the diffracted X-rays substantially originates from a region within the packaging.

[0024] The first secondary X-ray optical system may be configured to prevent at least a portion of the diffracted X-rays from reaching the active portion of the X-ray detector.

[0025] The X-ray diffractometer may further include a packaged sample.

[0026] With this arrangement, the region of the packaged sample to be analyzed is defined by the region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam detected by the X-ray detector (i.e., the first portion of the diffracted X-rays). This region can be changed / moved by changing one or more of the first primary X-ray optical system, the sample holder (and thus the position of the packaged sample), or the first secondary X-ray optical system. Therefore, by moving the position of the packaged sample, it is possible to adjust the region from which the first portion of the diffracted X-rays originates.

[0027] In some embodiments, the X-ray diffractometer may be configured to perform X-ray analysis in transmission geometry. In such embodiments, the X-ray source is arranged to direct X-rays at the incident surface of the packaged sample, and the X-ray detector is arranged to receive X-rays exiting the packaged sample from another surface of the packaged sample.

[0028] In some other embodiments, the X-ray diffractometer may be configured to perform X-ray analysis in reflection geometry. In such embodiments, the X-ray source is arranged to direct X-rays at the incident surface of the packaged sample, and the X-ray detector is arranged to receive X-rays reflected by the crystal lattice.

[0029] The first secondary X-ray optical system may be configured such that a first portion of the diffracted X-rays originates from a region within the analyte.

[0030] By reducing the region from which the first portion of the diffracted X-rays originates to substantially originate within the analyte, not only is the effect of the packaging on the detected X-ray signal reduced (or substantially minimized), but also, for example, the effect from spaces within the packaging that do not contain the analyte (such as air, or other materials or substances located within the packaging that are not considered the analyte) is reduced. Similarly, by enabling the analysis of a reduced region of the analyte, this apparatus may be useful for the analysis of non-uniform analytes. For example, by configuring the first secondary X-ray optical system such that diffracted X-rays corresponding to different portions of the analyte (such as different portions of a battery, for example the cathode, anode, electrodes, etc.) reach the X-ray detector, different portions of the analyte can be analyzed.

[0031] The X-ray diffraction analyzer can be adjusted to change the region from which the first portion of the diffracted X-rays originates, for example, by changing one or more of the first primary X-ray optical system, the sample holder (and thus the position of the packaged sample), or the first secondary X-ray optical system.

[0032] The second portion of the X-rays may include X-rays diffracted by the packaging process.

[0033] The X-ray diffractometer may further include a second primary X-ray optical system positioned between a first primary X-ray optical system and a packaged sample, wherein the second primary X-ray optical system and the first secondary X-ray optical system are configured to form an analytical intersection formed by the intersection of an incident X-ray beam and a diffracted X-ray beam, and the analytical intersection is located in a region within the package.

[0034] "The area within the packaging" refers to the area inside the packaging, excluding the packaging itself.

[0035] The first secondary X-ray optical system of an X-ray diffraction analyzer may be a collimator. The collimator may include a slit-shaped aperture with an aspect ratio greater than 5. The collimator may be positioned closer to the packaged sample than the X-ray detector. By positioning the collimator closer to the packaged sample than the X-ray detector, the area of ​​the packaged sample to be analyzed is minimized (i.e., the proportion of diffracted X-rays reaching the X-ray detector is limited by changing the receiving angle). The proportion of diffracted X-rays reaching the X-ray detector can be further limited, either additionally or alternatively, by reducing the size of the collimator aperture. Combining one or both of these changes to the total area / volume of the area of ​​the packaged sample to be analyzed with movement / modification of the incident X-ray beam (e.g., by changing the first primary X-ray optical system) may result in a shift in the placement of the area of ​​the packaged sample to be analyzed (e.g., moving deeper into the packaging to capture more analytes).

[0036] By positioning the collimator closer to the packaged sample than the X-ray detector, the slit collimator can be used in combination with a one-dimensional or two-dimensional X-ray detector. Therefore, the ratio of the distance between the sample and the collimator to the distance between the collimator and the X-ray detector may be 0.1 or less, or less than 0.025. The distance between the packaged sample and the collimator may be the distance along a straight line extending from the second surface of the packaged sample to the sample-facing surface of the collimator, where the straight line is perpendicular to the sample-facing surface of the collimator.

[0037] In other embodiments, the first secondary X-ray optical system may be any optical system that limits the reception of X-rays from the sample, such as an X-ray mirror or monochromator, and these optical systems may be configured such that the first portion of the diffracted X-rays (i.e., the portion of the diffracted X-rays detected by the X-ray detector) substantially originates from a region within the packaging.

[0038] The X-ray diffractometer may include a goniometer, and the X-ray detector is positioned to rotate about the axis of the goniometer. The axis of the goniometer lies in the axial plane of the X-ray diffractometer. A first secondary X-ray optical system (e.g., a one-dimensional slit collimator) can limit the divergence of the X-ray beam in the equatorial plane of the X-ray diffractometer. The equatorial plane is a plane perpendicular to the axial plane of the X-ray diffractometer.

[0039] The X-ray source may include an anode. The anode may include a material having an atomic number of 31 or greater, and / or the primary X-ray optics may be a monochromator configured to direct a substantially monochromatic X-ray beam onto the packaged sample.

[0040] The X-ray source may be configured to selectively irradiate the packaged sample with characteristic X-rays having an energy of approximately 9 keV or higher. For example, the X-ray source may include a filter configured to attenuate X-rays having an energy of less than 9 keV.

[0041] An X-ray detector may have an effective portion for generating a detection signal in response to X-rays incident on the effective portion, the effective portion may include a plurality of detection elements for detecting X-rays, and the X-ray diffractometer may further include a controller configured to select which detection elements contribute to generating the detection signal.

[0042] In this way, it is possible to control which part of the X-ray detector is used for X-ray detection, thereby ensuring that X-rays diffracted from the packaging do not substantially contribute to the detection signal.

[0043] The X-ray source may be positioned to irradiate the incident surface of the packaged sample at an incident angle ω, and the X-ray detector may be positioned to receive the diffracted X-rays at a diffraction angle 2θ.

[0044] The X-ray diffractometer may further include a second secondary X-ray optical system for modifying the divergence of diffracted X-rays, the second secondary X-ray optical system being positioned between the first secondary X-ray optical system and the X-ray detector.

[0045] Hereinafter, embodiments of the present invention will be described as examples with reference to the attached drawings. [Brief explanation of the drawing]

[0046] [Figure 1] Figure 1A is a schematic diagram showing an example of a packaged sample. Figure 1B is a schematic diagram showing another example of a packaged sample. [Figure 2] This is a schematic diagram showing an X-ray diffractometer for analyzing packaged samples according to one embodiment of the present invention. [Figure 3] This is a schematic diagram showing an X-ray diffractometer for analyzing a packaged sample according to another embodiment of the present invention. [Figure 4] This is a schematic diagram showing an X-ray diffractometer for analyzing a packaged sample according to another embodiment of the present invention. [Figure 5] The present invention illustrates a method for X-ray analysis according to one or more embodiments. [Figure 6]The present invention illustrates a method for X-ray analysis according to one or more embodiments. [Modes for carrying out the invention]

[0047] Please note that these diagrams are schematic and not drawn to scale. The relative dimensions and proportions of the parts in these diagrams are exaggerated or reduced for clarity and convenience in the drawings. Detailed explanation

[0048] Figures 1A and 1B show examples of packaged samples 1 and 11, respectively. In each example, packaged samples 1 and 11 include a package 2 and the analyte 3 held within the package 2.

[0049] In Figure 1A, the packaged sample 1 includes packaging in the form of a glass vial 2 that holds the analyte 3, such as a pharmaceutical product. The glass vial includes a container and a lid, and the container is partially filled with the pharmaceutical product. In this embodiment, the pharmaceutical product mainly consists of an amorphous matrix of organic material. By performing X-ray diffraction analysis on the pharmaceutical product, it is possible to determine whether crystalline components are present in the analyte. Glass vials for holding pharmaceutical samples typically have a diameter of at least 5 mm and a wall thickness of at least 1 mm. Glass vials are semi-transparent to X-rays and are a significant potential source of X-ray scattering.

[0050] In Figure 1B, the packaged sample 11 is a battery cell. The packaging 2 (i.e., the battery case) is shown on the left side of the battery, while the packaging is omitted on the right side to depict the internal structure. X-ray diffraction analysis can be used to monitor battery degradation by analyzing the underlying crystal structure of the cell's internal structure, for example, by analyzing the electrodes and / or electrolyte during a charging cycle.

[0051] In general, for packaged samples (including both types of packaged samples), it may be useful to be able to evaluate the analyte without removing it from the packaging. In the case of batteries, it is not possible to remove the analyte from the packaging without damaging the battery. Furthermore, removing the analyte may release toxic materials into the environment. In the case of pharmaceuticals, removing the analyte from a glass vial may release toxic materials into the environment, impair the integrity of the pharmaceutical, or have other effects on the sample (for example, mechanical effects on the sample may cause recrystallization of amorphous materials, polymorphic phase transitions, and / or the introduction of defects, and it is generally desirable to avoid contact with the external atmosphere), which may hinder the sale of the product. Two specific examples of packaged samples will be described with reference to Figures 1A and 1B, but those skilled in the art will understand that the analysis of other sample types (such as polycrystalline samples) can be performed alternatively or additionally, that other types of analysis (such as polymorphism analysis) can be performed, and that different packaging types may prevent direct access to the sample depending on the sample being analyzed.

[0052] Figure 2 shows an X-ray diffractometer 200 for analyzing a packaged sample 201, such as one of the packaged samples shown in Figure 1. In Figure 2, the packaged sample 201 includes a package 202 and the analyte 203. For example, as shown in Figure 1A, the package 202 is a glass vial in which the analyte 203 is partially filled.

[0053] Referring to Figure 2, the X-ray diffractometer 200 is configured to perform angle-dispersive X-ray diffraction analysis in transmission geometry. In angle-dispersive X-ray diffraction analysis, X-rays scattered by different crystal planes of the sample are recorded by the detector at different angles. The X-ray diffractometer 200 includes an X-ray source 204, a sample support 205, a beam stop 206, an X-ray detector 207, and a goniometer 219. The X-ray detector 207 includes an array of detection elements; that is, it is a one-dimensional (1D) or two-dimensional (2D) X-ray detector. Figure 2 shows a goniometer circle, with the packaged sample 201 located at the center of the goniometer circle. The axis of the goniometer, from which the X-ray detector 207 rotates, extends in the plane of the paper. The sample support 205 holds the packaged sample 201 between the X-ray source 204 and the X-ray detector 207 at the center of the goniometer circle. For example, the sample support may be a clamp for holding the packaged sample 201. Figure 2 shows the X-ray diffractometer 200 configured to perform angle-dispersive X-ray diffraction analysis in transmission geometry, but it should be understood that in alternative arrangements, the X-ray diffractometer may be configured to perform angle-dispersive X-ray diffraction analysis in reflection geometry.

[0054] The X-ray source 204 is an X-ray tube configured to generate X-rays. The first primary X-ray optics system 208 is positioned between the X-ray source 204 and the sample support 205 to form a focused incident X-ray beam 211. In Figure 2, the first primary X-ray optics system 208 is shown to include an elliptical grading X-ray mirror, which is configured to receive X-rays from the X-ray source 204 and reflect a substantially monochromatic, focused X-ray beam toward the packaged sample 201. It will be understood that other first primary X-ray optics systems may be implemented instead. Similarly, while Figure 2 shows the first primary X-ray optics system forming a focused incident X-ray beam, it will be understood that the first primary X-ray optics system may instead be configured to form a substantially parallel X-ray beam.

[0055] The incident X-ray beam 211 irradiates the packaged sample 201 at an angle ω to the incident surface of the packaged sample 201. The incident X-rays pass through the packaged sample 201 and are emitted from another side of the packaged sample 201. A portion of the incident X-rays passes through the packaged sample 201 without deflection and heads towards the beam stop 206. A portion of the incident X-rays may be diffracted at an angle 2θ by the crystalline components of the material to be analyzed 203, and a portion may be scattered by the packaging 202 (thus contributing to "background scattering"). A portion of the X-rays may be scattered by empty portions of the packaging where the material to be analyzed 203 is not present (these X-rays are not shown in Figure 2).

[0056] The X-ray detector 207 is positioned to receive X-rays diffracted by the material to be analyzed 203 at an angle of 2θ. To detect whether crystalline components are present in the material to be analyzed 203, the X-ray detector 207 is rotated around the axis of the goniometer to different angles of 2θ, and the intensity of the X-rays at each of the different 2θ positions is recorded.

[0057] In embodiments of the present invention, as shown in Figure 2, the first secondary X-ray optical system 221 is positioned between the packaged sample 201 and the X-ray detector 207 (note that the term "primary X-ray optical system" refers to the optical system between the incident beam-side X-ray source and the sample, while the first secondary X-ray optical system is positioned between the diffracted beam-side sample and the X-ray detector). In Figure 2, the first secondary X-ray optical system 221 is a one-dimensional slit collimator positioned to limit the beam divergence in the equatorial plane of the X-ray diffractometer 200. The collimator 221 includes a slit-shaped opening having an aspect ratio of at least 5. The collimator 221 is positioned on the diffracted beam side of the X-ray diffractometer in very close proximity to the packaged sample 201. The collimator 221 receives X-rays diffracted by the analyte 203 at an angle of 2θ and is positioned to allow only a portion of the X-rays diffracted by the analyte at an angle of 2θ to pass toward the X-ray detector 207. Figure 2 shows only the diffracted X-rays (and thus the diffracted X-ray beam 223) that can pass through the slit of the collimator 221. In this way, only the diffracted X-rays originating from portion 225 of the analyte 203 sandwiched between the incident beam and the diffracted beam are received by the X-ray detector 207, while X-rays originating from other parts of the packaged sample heading toward the X-ray detector are blocked by the collimator 221 before reaching the X-ray detector 207.

[0058] To prevent some of the X-rays diffracted by the analyte 203 at an angle 2θ from reaching the X-ray detector 207, the collimator 221 is positioned very close to the packaged sample 201. By limiting the portion of the analyte "seen" by the X-ray detector 207, it is possible to significantly limit scattering from sources other than the analyte (e.g., on the inner wall of the packaging, which could cause background scattering). The collimator 221 is positioned closer to the sample support 205 (and the packaged sample 201) than to the X-ray detector 207. In some embodiments, the ratio of the distance between the sample support 205 and the collimator 221 to the distance between the collimator 221 and the X-ray detector 207 is 0.1 or less, preferably 0.025 or less.

[0059] In some X-ray diffractometers, a beam conditioner may be placed close to the X-ray detector 207 to reduce the amount of background scattering (e.g., from the measurement environment, the X-ray diffractometer, etc.) received by the X-ray detector 207. In these arrangements, the beam conditioner is sized and positioned so that the entire diffracted X-ray beam reaches the X-ray detector (in the absence of a collimator 221). In other words, the beam conditioner is placed very close to the X-ray detector to maximize the proportion of detected X-rays corresponding to the X-rays diffracted by the analyte by reducing background scattering within the instrument.

[0060] In contrast, the collimator 221 is positioned to block the X-rays diffracted at 2θ, which would otherwise be detected by the X-ray detector 207, from reaching the X-ray detector 207. In this way, a portion of the analyte is analyzed while reducing / avoiding the contribution of scattered X-rays from the sample packaging 202 to the detection signal.

[0061] In some embodiments, the X-ray source 204 generates X-rays using an anode containing a material with an atomic number of 31 (gallium) or higher, such as silver (atomic number 47). The inventors found that by combining the X-ray source 204 having such an anode with a collimator 221 positioned near the packaged sample 201 in an X-ray diffractometer arranged in transmission geometry, it is possible to ensure that the X-ray detector 207 receives sufficiently high-intensity diffracted X-rays from a portion 225 of the analyte 203 while minimizing contributions from the packaging 202. Furthermore, the inventors found that this particular arrangement facilitates the effective detection and identification of crystalline components present in the packaged sample, especially when only small amounts of crystalline material are present in a predominantly amorphous sample.

[0062] In some embodiments, the collimator 221 may be located less than 15 mm away from the axis of the goniometer (i.e., the center of the sample). The width of the slit may be 5 mm or less. For example, the slit may be located only 5 mm away from the center of the goniometer circle, and the width of the slit may be about 1 mm.

[0063] The X-ray diffractometer 200 further includes a controller 226 configured to control the X-ray detector 207. The controller 226 may be configured to control the effective area of ​​the X-ray detector 207 based on the position of the collimator 221 and the slit width. The effective area of ​​the X-ray detector 207 includes a plurality of detection elements, such as pixels. In some embodiments, the controller 226 is configured to control which detection elements in the effective area of ​​the X-ray detector 207 can generate a signal, based on the position of the collimator 221 and the slit width. That is, the controller 226 is configured to control which detection elements in the effective area of ​​the X-ray detector are configured to generate a signal, based on information regarding the position of the collimator 221 and the slit width. Thus, the controller 226 can select the effective area of ​​the X-ray detector 207 that corresponds to the diffracted X-rays originating from a portion 225 of the analyte 203 passing through the collimator 221. This may help to further reduce the amount of background scattering present in the diffraction pattern. Furthermore, by controlling the effective area of ​​the X-ray detector and determining which detection elements are configured to generate a signal in response to incident X-rays, it becomes possible to further control the portion of the sample that is "seen" by the X-ray detector.

[0064] The portion 225 of the object to be analyzed 203 sandwiched between the incident beam and the diffracted beam can be moved / changed by changing the configuration of the X-ray diffractometer, for example, by changing the position of the sample (using a sample stage) and / or by changing the configuration of the first primary X-ray optical system and / or the first secondary X-ray optical system.

[0065] Figure 3 shows another embodiment of the X-ray diffractometer 300. In this embodiment, in addition to the components shown in Figure 2, the X-ray diffractometer includes a second secondary X-ray optical system 328 positioned within the diffracted X-ray beam 323 between the collimator 321 and the X-ray detector 307. The second secondary X-ray optical system 328 may also be a beam conditioner for blocking at least a portion of the X-rays in the equatorial plane. For example, the second secondary X-ray optical system 328 may be an equatorial divergent slit or a parallel plate collimator.

[0066] The X-ray diffractometers shown in Figures 2 and 3 may further include a solar slit collimator and / or aperture positioned between the first primary X-ray optical system and the sample support to limit the axial divergence of the incident X-ray beam. Additionally or alternatively, the X-ray diffractometers shown in Figures 2 and 3 may include a solar slit collimator and / or aperture positioned between the sample support and the X-ray detector to limit the axial divergence of the diffracted X-ray beam. Axial divergence is the divergence from the axis of rotation of the X-ray detector (an axis extending in the plane of the paper in Figures 2 and 3).

[0067] Figure 4 shows another embodiment of the X-ray diffractometer 400 according to one embodiment of the present invention. The X-ray diffractometer includes an X-ray source 404 and a first primary X-ray optical system 408 positioned to irradiate a packaged sample 401 with a focused X-ray incident beam. A beam stop 406 is positioned to absorb at least a portion of the X-rays that directly pass through the packaged sample 401. The packaged sample includes a package 402 and an object to be analyzed 403. A second primary X-ray optical system 427 is positioned between the first primary X-ray optical system 408 and the packaged sample 401. The second primary X-ray optical system 427 and the first secondary X-ray optical system 421 are configured to define an analysis intersection 425 formed by the intersection of the incident X-ray beam and the diffracted X-ray beam, the analysis intersection located in the region of the packaged sample within the packaging.

[0068] In some embodiments, both the second primary X-ray optics system 427 and the first secondary X-ray optics system 421 are collimators (e.g., collimation slits). The aperture dimensions and position of the collimators are chosen to select a specific region of the packaged sample 401 for analysis. In Figure 4, the collimators are configured such that a region of the packaged sample containing substantially only the analyte 403 is selected for analysis (i.e., the analysis crossover contains substantially only the analyte). The configurations of the second primary X-ray optics system 427 and the first secondary X-ray optics system 421 can be adjusted to change the position of the analysis crossover 425. For example, in some embodiments, the analysis crossover can define a volume, the majority of which is occupied by the analyte and a small portion of which is occupied by packaging / other materials (e.g., air).

[0069] The X-ray detector 407 is positioned to receive diffracted X-rays from the packaged sample 401. The X-ray detector 407 is a position-sensitive detector; that is, the X-ray detector includes multiple detection elements (e.g., in a 1D or 2D array). Generally, the effective area of ​​the X-ray detector is defined by detection elements configured to generate a signal in response to incident X-rays. The controller 426 is configured to control the X-ray detector 407. The controller 426 may be configured to control the effective area of ​​the X-ray detector 407 based on the positions of the collimators 421 and 427 and the slit width. In this way, the controller 426 can select the effective area of ​​the X-ray detector 407 corresponding to the diffracted X-rays originating from the analysis crossover. This can help further reduce the amount of background scattering present in the diffraction pattern.

[0070] Figure 4 shows a configuration in which the X-ray source 404 and the first primary X-ray optics system 408 are arranged to irradiate the packaged sample 401 with a focused X-ray incident beam, although it will be understood that the incident beam may instead be a parallel X-ray beam.

[0071] Referring to Figure 5, one embodiment of the present invention provides a method for analyzing a packaged sample by X-ray diffraction analysis. The method may be performed using an X-ray diffractometer described in relation to any one of Figures 2, 3, and 4, or using a different X-ray diffractometer. In one embodiment, the method includes, in a setup step 501, arranging a first secondary X-ray optical system between the packaged sample and an X-ray detector.

[0072] In irradiation step 503, the packaged sample is irradiated with a focused or parallel incident X-ray beam. The X-ray source irradiates the packaged sample with an incident beam of X-rays having an energy of at least about 9 keV. In some embodiments, the X-ray source, the packaged sample, and the X-ray detector are arranged to perform X-ray diffraction analysis of the packaged sample in transmission geometry. That is, the diffracted X-rays exit the sample from the portion of the packaged sample opposite the irradiated surface of the sample, along the direction of the incident X-ray beam.

[0073] In X-ray optical system configuration step 505, the X-ray optical system is configured to block multiple X-rays diffracted by the analyte from reaching the X-ray detector. The X-ray optical system limits the portion of the sample visible to the X-ray detector by blocking X-rays from the packaged sample that would otherwise have been detected by the X-ray detector. The inventors have found that good X-ray diffraction analysis results can be obtained even with a packaged sample by placing a collimator close to the packaged sample and irradiating the sample with an X-ray source configured to emit X-rays at an energy of at least 17 keV. In particular, by performing X-ray diffraction analysis in this manner, the resulting X-ray analysis results have a reduced contribution from background scattering sources; otherwise, it would be difficult to distinguish low-intensity diffraction peaks from scattering from the packaging / other background scattering sources.

[0074] Although the X-ray optical system configuration step 505 is shown as being performed after the irradiation step 503, it should be understood that the X-ray optical system configuration step 505 may be performed before the irradiation step 503, or these steps may be performed (or initiated) substantially simultaneously.

[0075] In some embodiments, the X-ray optical system is a collimator (e.g., a collimating slit), and the distance from the packaged sample to the collimator is shorter than the distance from the collimator to the X-ray detector. For example, the ratio of the distance from the analyte to the collimator to the distance from the collimator to the X-ray detector is 0.1 or less, preferably less than 0.025.

[0076] In some embodiments, the packaged sample includes a container, and the analyte partially fills the container (for example, as shown in Figure 2). In these embodiments, the positioning step of the method may further include positioning the packaged sample and / or collimator such that the analytical intersection (e.g., portion 225 in Figure 2) formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is located in the portion of the cavity where the analyte is held, and not in the portion of the cavity that does not contain the analyte. In this way, detection of X-ray scattering from the empty portion of the container is minimized / avoided.

[0077] In some embodiments, the method includes controlling the size of the effective portion of the X-ray detector by selecting which portion of the effective portion of the X-ray detector contributes to X-ray detection. The size of the effective portion can be electronically controlled to match the size of the diffracted X-ray beam selected by the collimator. This helps to further avoid / reduce the presence of background scattering in the diffraction pattern.

[0078] Figure 6 shows a method of X-ray diffraction analysis for analyzing a packaged sample. The method may be performed, for example, using the X-ray diffractometer shown in Figure 4. In the setup step 601, the second primary X-ray optical system and the first secondary X-ray optical system are positioned on the incident X-ray beam side and the diffracted X-ray beam side of the packaged sample, respectively.

[0079] In X-ray optical system configuration step 603, the second primary X-ray optical system and the first secondary X-ray optical system are configured to define the analytical intersection. That is, the second primary X-ray optical system and the first secondary X-ray optical system are positioned to define the analytical intersection with respect to the rest of the X-ray diffractometer (e.g., the X-ray source, the first primary X-ray optical system, the packaged sample, and the X-ray detector), and the relevant dimensions of the second primary X-ray optical system and the first secondary X-ray optical system (e.g., the dimensions of the collimating slit) are optionally selected. The analytical intersection is located in the region of the packaged sample within the packaging (i.e., the analytical intersection does not include the packaging). The analytical intersection is formed by the intersection of the incident X-ray beam and the diffracted X-ray beam.

[0080] In some embodiments, a packaged sample defines a cavity in the "packaged" region of the packaged sample (as opposed to the packaging region where the packaging exists). The cavity includes an analyte region and an analyte-free region. The analytical crossover may be formed in both the analyte region and the analyte-free region. Alternatively, the analytical crossover may be formed only in the analyte region (as shown in Figures 2, 3, and 4).

[0081] In irradiation step 605, the packaged sample is irradiated with incident X-rays. The incident X-rays are directed from the X-ray source to the sample via the first primary X-ray optical system and the second primary X-ray optical system. The incident X-rays are diffracted and / or scattered by the sample. The first portion of the diffracted X-rays passes through the first secondary X-ray optical system and is detected by the X-ray detector. The first portion of the diffracted X-rays is the X-rays from the analytical crossover defined by the second primary X-ray optical system and the first secondary X-ray optical system. The second portion of the diffracted X-rays is prevented from being detected by the X-ray detector. The second portion of the diffracted X-rays is the X-rays from outside the analytical crossover defined by the second primary X-ray optical system and the first secondary X-ray optical system. For example, the first portion of the diffracted X-rays originates from a region within the packaging, and the second portion of the diffracted X-rays originates from the packaging region (the region where the packaging exists).

[0082] In some embodiments, the method further includes a tuning step 607, in which the positions of the packaged sample and / or the first secondary X-ray optics and / or the first primary X-ray optics and / or the second primary X-ray optics are adjusted so that the analytical intersection formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is repositioned. For example, tuning step 607 may include changing the position of the analytical intersection so that it is formed in the portion of the cavity where the analyte is held, and not in the portion of the cavity that does not contain the analyte.

[0083] Those skilled in the art will understand that the embodiments described above are illustrative of the present invention and that modifications can be made to these embodiments without departing from the scope of the claims.

[0084] Figures 2 and 3 show packaged samples, including packaging partially filled with the analyte; however, the packaging may instead be completely filled with the analyte.

[0085] Packaged samples do not necessarily have to be glass vials that hold pharmaceuticals or batteries. X-ray diffractometers are suitable for use in the analysis of any core-shell structure in which the core is the analyte and the shell is the packaging. Examples of packaged samples include any sample held in a container that includes packaging capable of scattering and / or absorbing X-rays. For example, the analyte held in a plastic, metal, or glass container. The analyte may be a powder, lyophilized powder, tablet, liquid, or semi-solid formulation. In another example, the packaged sample may be a device containing the analyte, such as an electrochemical cell.

[0086] The sample support does not have to be a clamp. In some embodiments, the sample support may be a stage on which a packaged sample is supported. In some embodiments, the sample support may be motorized to rotate the sample (to improve scattering statistics) or to allow for automatic sample exchange.

[0087] In some embodiments, the collimator is not a one-dimensional slit. Instead, the collimator may include an aperture shaped to restrict the diffracted X-ray beam in two dimensions. Alternatively, the collimator may be a combination of a parallel plate collimator, an X-ray mirror, or a one-dimensional slit.

[0088] In some embodiments, the primary X-ray optical system is not an elliptical grading X-ray mirror. Instead, it may be another type of X-ray optical system for providing a focused X-ray beam or a parallel X-ray beam. For example, the primary X-ray optical system may include a curved crystal monochromator for generating a focused beam, or a parabolic grading X-ray mirror for generating a parallel beam. Alternatively, the primary X-ray optical system may include a combination of a planar grading X-ray mirror and a narrow slit for forming a narrow quasi-parallel beam.

[0089] The anode of an X-ray source does not necessarily have to contain silver. The anode may contain any material capable of generating an X-ray beam with an energy greater than 9 keV or greater than 17 keV. For example, the anode may contain gallium (atomic number 31), molybdenum (atomic number 42), or any other material with an atomic number greater than or equal to 31.

[0090] In some embodiments, the X-ray diffractometer does not include a secondary X-ray optical system.

[0091] If the collimator has a slit-shaped opening, the aspect ratio of the opening may be at least 2, preferably at least 5.

[0092] In some embodiments, the size of the effective area of ​​the X-ray detector can be adjusted based on the dimensions / configuration of the first secondary X-ray optics and the X-ray detector. This adjustment may be determined according to a formula that parameters the dimensions of the first secondary X-ray optics (e.g., slit dimensions) and the X-ray detector, as well as their relative positions. In some embodiments, the X-ray diffractometer is not configured to adjust the size of the effective area based on the dimensions of the first secondary X-ray optics and the X-ray detector. The adjustment is determined (according to a formula) and may be performed manually by the operator.

[0093] The primary X-ray optical system may include a filter combined with an X-ray optical system for forming a focused X-ray beam.

[0094] In some embodiments, the distance between the secondary X-ray optical element and the X-ray sample is never shorter than the distance between the secondary X-ray optical element and the X-ray detector.

Claims

1. An angle-dispersive X-ray diffraction method for analyzing a packaged sample, wherein the packaged sample comprises an analyte enclosed within a package, and the method is: To focus X-rays from an X-ray source to form a focused X-ray beam of focused or parallel X-rays, and to direct the focused X-ray beam towards the packaged sample, a first primary X-ray optical system is placed between the X-ray source and the packaged sample. The first secondary X-ray optical system is placed between the packaged sample and the X-ray detector, While the object to be analyzed is sealed within the packaging, the packaged sample is irradiated with a focused X-ray beam, which is a focused X-ray beam or parallel X-ray beam having an energy greater than approximately 9 keV, using the X-ray source. The method comprising configuring the first secondary X-ray optical system such that a first portion of diffracted X-rays passes through it and is detected by the X-ray detector, while a second portion of diffracted X-rays is prevented from being detected by the X-ray detector, wherein the first portion of diffracted X-rays substantially originates from a region within the packaging.

2. The method according to claim 1, wherein the first secondary X-ray optical system is configured such that the first portion of the diffracted X-rays originates from a region within the object to be analyzed.

3. The method according to claim 1 or 2, wherein the second portion of the X-rays includes X-rays diffracted by the packaging.

4. The method according to any one of claims 1 to 3, further comprising arranging a second primary X-ray optical system between the first primary X-ray optical system and the packaged sample, wherein the second primary X-ray optical system and the first secondary X-ray optical system are configured to form an analytical intersection formed by the intersection of an incident X-ray beam and a diffracted X-ray beam, and the analytical intersection is located in a region within the packaging.

5. The method according to any one of claims 1 to 4, wherein the first secondary X-ray optical system is a collimator.

6. The method of claim 5, further comprising controlling the effective area of ​​the X-ray detector based on the size of the collimator's aperture and the position of the collimator relative to the packaged sample and the X-ray detector.

7. The method according to any one of claims 1 to 6, wherein the packaging includes a cavity in which the analyte is held, a portion of the cavity not containing the analyte, and the method further includes positioning the packaged sample and / or the first secondary X-ray optical system such that the analytical intersection formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is located in the portion of the cavity in which the analyte is held, rather than in the portion of the cavity not containing the analyte.

8. The method according to any one of claims 1 to 7, wherein the X-ray source includes an anode, the anode includes a material having an atomic number of 31 or more, and the packaging includes a wall having a thickness of at least about 1 mm.

9. An X-ray diffractometer for angle-dispersive X-ray diffraction analysis of packaged samples, A sample support for supporting the packaged sample, wherein the packaged sample includes the analyte enclosed within the package; An X-ray source for irradiating the packaged sample with incident X-rays, wherein the incident X-rays are directed toward the packaged sample along the incident beam path, A first primary X-ray optical system arranged in the incident beam path, wherein the first primary X-ray optical system is arranged to focus the incident X-rays to form a focused X-ray beam or a parallel X-ray beam, and directs the X-ray beam toward the packaged sample, An X-ray detector positioned to receive diffracted X-rays from the packaged sample, The system includes a first secondary X-ray optical system positioned between the sample support and the X-ray detector to allow a first portion of the diffracted X-rays to reach the X-ray detector and to prevent a second portion of the diffracted X-rays from being detected by the X-ray detector, The X-ray diffractometer is configured such that the first secondary X-ray optical system is substantially derived from a region within the packaging.

10. The X-ray diffractometer according to claim 9, wherein the first secondary X-ray optical system is configured such that the first portion of the diffracted X-rays originates from a region within the object to be analyzed.

11. The X-ray diffractometer according to claim 9 or 10, further comprising a second primary X-ray optical system disposed between the first primary X-ray optical system and the packaged sample, wherein the second primary X-ray optical system and the first secondary X-ray optical system are configured to form an analytical intersection formed by the intersection of an incident X-ray beam and a diffracted X-ray beam, and the analytical intersection is located in a region within the packaging.

12. The X-ray diffractometer according to any one of claims 9 to 11, wherein the first secondary X-ray optical system is a collimator.

13. The X-ray diffractometer according to any one of claims 9 to 12, wherein the X-ray source includes an anode, the anode includes a material having an atomic number of 31 or more, and / or the primary X-ray optical system is a monochromator arranged to direct a substantially monochromatic X-ray beam onto the packaged sample.

14. The X-ray detector has an effective portion for generating a detection signal in response to X-rays incident on the effective portion, the effective portion includes a plurality of detection elements for detecting X-rays, and the X-ray diffractometer further includes a controller configured to select which of the detection elements contributes to generating the detection signal, according to any one of claims 9 to 13.

15. The X-ray diffractometer according to any one of claims 7 to 14, wherein the X-ray source is arranged to irradiate the incident surface of the packaged sample at an incident angle ω, and the X-ray detector is arranged to receive diffracted X-rays at a diffraction angle 2θ.

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