X-ray diffraction apparatus and method for analyzing encapsulated samples

Abstract

The present invention relates to a method and an X-ray diffraction apparatus for angular dispersion X-ray diffraction analysis of an analyte (sample) ("encapsulated sample") confined in a package. In one embodiment, a method includes arranging a first primary X-ray optic between an X-ray source and an encapsulated sample to focus X-rays from the X-ray source into a focused X-ray beam of converged or parallel X-rays and direct the focused X-ray beam toward the encapsulated sample; and arranging a first secondary X-ray optic between the encapsulated sample and the X-ray detector. The encapsulated sample is irradiated with a focused X-ray beam of converged or parallel X-ray beams by an X-ray source, the X-rays having an energy greater than about 9 keV while the analyte is confined in the package. The first secondary X-ray optic is configured such that a first portion of the diffracted X-rays passes therethrough to be detected by the X-ray detector and a second portion of the diffracted X-rays is prevented from being detected by the X-ray detector, with the first portion of the diffracted X-rays coming from an area within the package.

Description

Technical Field

[0001] The present invention relates to an X-ray diffraction apparatus for analyzing packaged samples and a method for analyzing packaged samples by X-ray diffraction analysis. In particular, the present invention provides for convenient and improved analysis of packaged samples, particularly packaged samples containing a small amount of crystalline material, such as pharmaceutical samples containing primarily amorphous material, or samples having a mixture of phases. Background Art

[0002] Generally speaking, X-ray diffraction analysis is used to analyze products by identifying the crystalline components present in the sample. X-ray diffraction analysis can be used to test samples in the form of powders, lyophilized powders, tablets, liquids, or semisolid formulations. For example, in the pharmaceutical field, X-ray diffraction analysis can be used to test the amorphous state of products such as vaccines. Even the presence of a small amount of crystalline components can also damage the stability of the vaccine, so it is desirable to be able to detect the presence of crystallinity in an originally amorphous matrix.

[0003] Ideally, during X-ray diffraction analysis, analyze the sample without any type of packaging interfering with the incident and / or diffracted X-rays. If there is packaging, then packaging can absorb and attenuate some X-rays incident on the sample / scattered by the sample and / or packaging can serve as a background scattering source. This can make it difficult to use the data obtained by X-ray diffraction analysis to identify the component in the sample, particularly when the sample comprises only a small amount of crystalline material or a low concentration of the crystalline minority phase. In some cases, the problem associated with the existence of packaging—particularly being difficult to distinguish between the signal from the crystalline material and the signal from the packaging—may completely prevent the crystalline component present in the identification sample. Glass, metal and plastic packaging have significant X-ray absorption / attenuation conventionally, and are also significant background scattering sources. Encapsulated samples can be larger than the sample specifically prepared for X-ray diffraction analysis. Explanation of the data obtained from large encapsulated samples also may be difficult, because the diffraction signal may experience the tailing (for example, peak broadening or deformation) of the diffraction signal.

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

[0005] Therefore, it is 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 is desirable to provide an X-ray diffraction apparatus with high specificity that facilitates safe, efficient, and convenient analysis of packaged samples. It is also desirable to provide a safe, efficient, and convenient method for analyzing packaged samples with high specificity. Summary of the Invention

[0006] According to one aspect of the present invention, there is provided a method for angular dispersive X-ray diffraction analysis of a packaged sample, wherein the packaged sample comprises an analyte confined in a package, the method comprising: arranging a first primary X-ray optics between the X-ray source and the packaged sample to focus X-rays from the X-ray source into a focused X-ray beam of convergent or parallel X-rays and directing the focused X-ray beam toward the packaged sample; disposing a first secondary X-ray optical device between the packaged sample and the X-ray detector; irradiating the packaged sample using an X-ray source with a focused X-ray beam of convergent or parallel X-rays having an energy greater than about 9 keV while the analyte is confined within the package; The first secondary X-ray optical device is configured so that a first portion of the diffracted X-rays passes therethrough to be detected by the X-ray detector and a second portion of the diffracted X-rays is blocked from being detected by the X-ray detector, wherein the first portion of the diffracted X-rays comes from an area substantially within the package.

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

[0008] Generally speaking, X-ray diffraction analysis is performed on a sample (analyte) that has been specifically prepared for the purpose of performing the analysis and that minimizes any external influences (e.g., minimizing any contribution of the sample holder / container to background scattering or X-ray absorption or attenuation, and controlling the volume / format of the sample to minimize / eliminate diffraction signal tailing). In this regard, and in the context of this specification, "packaged sample" (and variants thereof) refers to an analyte that is confined in a package (i.e., it is not a sample that has been specifically prepared for the purpose of performing the analysis: the packaging may always contribute to background scattering and / or X-ray absorption or attenuation; and the volume / format of the analyte may result in diffraction signal tailing).

[0009] As used herein, "analyte" refers to the substance being analyzed (also referred to herein as a "sample"), and the fact that the analyte is "confined in a package" refers to the fact that the contents of the package (i.e., the analyte / sample) may not be directly accessible and / or processed for analysis. This may be due to any of a number of reasons, such as: the analyte / sample may be harmful / toxic; access to the analyte / sample may render any tamper-evident features of the package ineffective; if accessed, the analyte / sample may no longer be saleable; if exposed to ambient atmosphere / conditions, the analyte / sample may alter. In some cases, "confined" may mean that the analyte is (usually) sealed in an inaccessible package (e.g., a battery), or it may mean that the analyte is accessible and sealed in a package (e.g., a pharmaceutical product). As used herein, "packaging" may refer to any material used to contain the analyte, including but not limited to glass, metal, plastic, or any combination thereof. In contrast to samples prepared specifically for the purpose of analysis (e.g., glass capillaries with very thin (<0.5 mm) walls), the packaging may be opaque to the eye and / or may be only translucent to X-rays.

[0010] As will be understood by those skilled in the art, the area of ​​the packaged sample being analyzed is defined by the region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam as detected by the X-ray detector (i.e., the first portion of the diffracted X-rays). This region can be changed / moved by modifying one or more of the first primary X-ray optics, the sample holder (and therefore the position of the packaged sample), or the first secondary X-ray optics. Doing so changes / moves the position (position 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 being analyzed). In this way, the area being analyzed can be changed / moved to accommodate the type / format of the packaged sample. In other words, changing the proportion of diffracted X-rays detected (or detectable) by the X-ray detector limits the acceptance at the X-ray detector, thereby changing / moving the region from which the first portion of the diffracted X-rays is detected. Furthermore, by ensuring that the first portion of the diffracted X-rays comes from an area substantially within the package, the effect of the packaging on the detected X-ray signal can be reduced.

[0011] Of the X-rays diffracted by the packaged sample, only a first portion of the diffracted X-rays passes through the first secondary X-ray optics and reaches the X-ray detector and is detected by the X-ray detector. The first portion of the diffracted X-rays originates from an area substantially within the package—that is, all or a majority (e.g., equal to or greater than 50%, 60%, 70%, 80%, 90%, or 95%) of the first portion of the diffracted X-rays originate from an area of ​​the packaged sample within the package. "Area of ​​the packaged sample within the package" refers to an area within the package that does not substantially include the package.

[0012] The X-ray beam can be substantially monochromatic. That is, the X-rays have energies within an energy range of ±0.5 keV. For example, the X-ray beam can have energies between 16.9 keV and 17.9 keV (for molybdenum, which has a characteristic energy of 17.44 keV). It will be understood that other X-ray sources will have different energy ranges that are considered monochromatic. For example, an X-ray beam from a gallium source (which has a characteristic energy of 9.2 keV) can have energies within an energy range of 8.7 keV and 9.7 keV.

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

[0014] In some embodiments, all or a majority (e.g., equal to or greater than 50%, 60%, 70%, 80%, 90%, or 95%) of the diffracted X-rays that pass through the first secondary X-ray optics 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 optics and reach the X-ray detector, some (e.g., equal to or less than 49%) of the diffracted X-rays may be from regions within the package that do not include the analyte and / or regions that include the package.

[0015] The second portion of the X-rays may comprise X-rays diffracted by the packaging.Thus, the first secondary X-ray optics may be configured to block at least some of the X-rays diffracted by the packaging from reaching and being detected by the X-ray detector.

[0016] The method may further include arranging a second primary X-ray optic between the first primary X-ray optic and the packaged sample, wherein the second primary X-ray optic and the first secondary X-ray optic are configured to form an analysis intersection region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam, wherein the analysis intersection region is positioned in an area inside the package. Thus, the diffracted X-rays that pass through the first secondary optic to be detected by the X-ray detector may come from an area inside the package (i.e., an area of ​​the packaged sample that does not include the package).

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

[0018] In embodiments comprising a second primary X-ray optics, preferably both the first secondary X-ray optics and the second primary X-ray optics are collimators with a slit-shaped aperture.

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

[0020] The package may include a cavity in which the analyte is retained, and a portion of the cavity may be free of the analyte. The method may further include adjusting a position of the packaged sample and / or the first secondary X-ray optics such that an analysis intersection region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is positioned in the portion of the cavity in which the analyte is retained, rather than in a portion of the cavity in which the analyte is absent.

[0021] The packaging may comprise glass, metal and / or plastic.The analyte may comprise an amorphous organic material.

[0022] The X-ray source may include an anode. The anode may include a material having an atomic number equal to or greater than 31, 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, there is provided an X-ray diffraction apparatus for angular dispersive X-ray diffraction analysis of a packaged sample, the X-ray diffraction apparatus comprising: a sample support for supporting a packaged sample comprising an analyte confined within a 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 an incident beam path; a first primary X-ray optics arranged in an incident beam path, wherein the first primary X-ray optics is arranged to focus the incident X-rays into a converging or parallel X-ray beam and to direct the X-ray beam towards the packaged sample; an X-ray detector arranged to receive diffracted X-rays from the packaged sample; and a first secondary X-ray optical device arranged 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 prevent a second portion of the diffracted X-rays from being detected by the X-ray detector, wherein the first secondary X-ray optical device is configured such that the first portion of the diffracted X-rays comes from an area substantially within the package.

[0024] The first secondary X-ray optics may be arranged to prevent at least some of the diffracted X-rays from reaching an active part of the X-ray detector.

[0025] The X-ray diffraction apparatus may also include encapsulating the sample.

[0026] With this arrangement, the area of ​​the packaged sample being 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 diffracted X-rays) as detected by the X-ray detector. This region can be changed / moved by modifying one or more of the first primary X-ray optics, the sample holder (and therefore the position of the packaged sample), or the first secondary X-ray optics. Thus, the region from which the first portion of diffracted X-rays originate can be adjusted by moving the position of the packaged sample.

[0027] In some embodiments, the X-ray diffraction apparatus can be arranged to perform X-ray analysis in a transmission geometry. In such embodiments, the X-ray source is arranged to direct X-rays toward an incident surface of the packaged sample, and the X-ray detector is arranged to receive X-rays that exit the packaged sample through another surface of the packaged sample.

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

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

[0030] By reducing the region from which the first portion of the diffracted X-rays originate to originate substantially within the analyte, not only is the effect of the packaging on the detected X-ray signal reduced (or substantially minimized), but also the effect of any space within the packaging that does not contain the analyte (e.g., air or other materials or substances within the packaging that are not considered analytes) is reduced. Similarly, by achieving a reduced region of analyte to be analyzed, the apparatus can also be used to analyze non-uniform analytes. For example, different portions of the analyte can be analyzed by configuring the first secondary X-ray optics to allow diffracted X-rays corresponding to different portions of the analyte to reach the X-ray detector (e.g., different portions of a battery—such as a cathode, anode, or electrodes—can be analyzed).

[0031] The X-ray diffraction analysis apparatus can be adjusted to change the region from which the first portion of the diffracted X-rays come—for example, by modifying one or more of the first primary X-ray optical device, the sample holder (and therefore the position of the encapsulated sample), or the first secondary X-ray optical device.

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

[0033] The X-ray diffraction apparatus may further include a second primary X-ray optic disposed between the first primary X-ray optic and the packaged sample, wherein the second primary X-ray optic and the first secondary X-ray optic are configured to form an analysis intersection region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam, wherein the analysis intersection region is positioned in an area within the package. The “area within the package” refers to an area within the package that substantially excludes the package.

[0034] The first secondary X-ray optical device of the X-ray diffraction analysis equipment can be a collimator. The collimator may include a slit-shaped aperture having an aspect ratio greater than 5. The collimator can be positioned closer to the packaged sample than it is to the X-ray detector. Positioning the collimator closer to the packaged sample than to the X-ray detector minimizes the area of ​​the packaged sample being analyzed (i.e., by changing the acceptance angle, thereby limiting the proportion of diffracted X-rays that reach the X-ray detector). Reducing the aperture size of the collimator can additionally or alternatively further limit the proportion of diffracted X-rays that reach the X-ray detector. When one or both of these modifications to the overall area / volume of the area of ​​the packaged sample being analyzed is combined with moving / modifying the incident X-ray beam (e.g., by modifying the first primary X-ray optical device), this can result in a positioning shift of the area of ​​the packaged sample being analyzed (e.g., further within the package to capture more analytes).

[0035] By positioning the collimator closer to the packaged sample than to the X-ray detector, a slit collimator can be used in combination with a one-dimensional or two-dimensional X-ray detector. The ratio of the distance between the sample and the collimator to the distance between the collimator and the X-ray detector can thus be equal to or less than 0.1 or less than 0.025. The distance between the packaged sample and the collimator can be a distance along a straight line extending from the second surface of the packaged sample to the sample-facing surface of the collimator, wherein the straight line is perpendicular to the sample-facing surface of the collimator.

[0036] In other embodiments, the first secondary X-ray optical device can be any optical device that limits the acceptance of X-rays from the sample, such as an X-ray mirror, a monochromator, etc., which can be configured so that the first portion of the diffracted X-rays (i.e., the portion of the diffracted X-rays detected by the X-ray detector) comes from an area substantially within the package.

[0037] The X-ray diffraction apparatus may include a goniometer, wherein the X-ray detector is arranged to rotate about an axis of the goniometer. The axis of the goniometer lies in an axial plane of the X-ray diffraction apparatus. A first secondary X-ray optic (e.g., a one-dimensional slit collimator) may limit the divergence of the X-ray beam in an equatorial plane of the X-ray diffraction apparatus. The equatorial plane is a plane perpendicular to the axial plane of the X-ray diffraction apparatus.

[0038] The X-ray source may comprise an anode. The anode may comprise a material having an atomic number equal to or greater than 31 and / or the primary X-ray optics may be a monochromator arranged to direct a substantially monochromatic X-ray beam towards the encapsulated sample.

[0039] The X-ray source may be configured to selectively irradiate the packaged sample with characteristic X-rays having an energy greater than or equal to about 9 keV. For example, the X-ray source may include a filter configured to attenuate X-rays having an energy less than 9 keV.

[0040] The 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 including a plurality of detection elements for detecting X-rays, and the X-ray diffraction device may also include a controller configured to select which of the detection elements contribute to generating the detection signal.

[0041] In this way, it is possible to control which portion of the X-ray detector is used to detect X-rays, which can help the user ensure that X-rays diffracted from the package do not substantially contribute to the detection signal.

[0042] The X-ray source may be arranged to irradiate an incident surface of the packaged sample at an incident angle ω, and the X-ray detector may be arranged to receive diffracted X-rays at a diffraction angle 2θ.

[0043] The X-ray diffraction apparatus may further comprise second secondary X-ray optics for changing the divergence of the diffracted X-rays, wherein the second secondary X-ray optics is arranged between the first secondary X-ray optics and the X-ray detector. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Embodiments of the present invention will now be described by way of example with reference to the accompanying drawings, in which: Figure 1A is a schematic diagram illustrating an example of a packaged sample; Figure 1B is a schematic diagram illustrating another example of a package sample; Figure 2 is a schematic diagram illustrating an X-ray diffraction apparatus for analyzing a packaged sample according to an embodiment of the present invention; Figure 3 is a schematic diagram illustrating an X-ray diffraction apparatus for analyzing a packaged sample according to another embodiment of the present invention; Figure 4 is a schematic diagram illustrating an X-ray diffraction apparatus for analyzing a packaged sample according to another embodiment of the present invention; Figure 5 A method of X-ray analysis according to one or more embodiments of the present invention is illustrated; and Figure 6 A method of X-ray analysis according to one or more embodiments of the present invention is illustrated.

[0045] It should be noted that these drawings are schematic and not drawn to scale. For clarity and convenience in the drawings, the relative sizes and proportions of parts of these drawings are exaggerated or reduced in size. DETAILED DESCRIPTION

[0046] Figure 1A and Figure 1B Examples of packaged samples 1 , 11 are shown, respectively. In each example, the packaged sample 1 , 11 comprises a package 2 and an analyte 3 held within the package 2.

[0047] exist Figure 1A In the present invention, a packaged sample 1 includes a package in the form of a glass vial 2, which holds an 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 example, the pharmaceutical product primarily comprises an amorphous matrix of organic material. The pharmaceutical product can be subjected to X-ray diffraction analysis to determine whether there are crystalline components in the analyte. The glass vial used to hold the pharmaceutical sample typically has a diameter of at least 5 mm and a wall thickness of at least 1 mm. The glass vial is translucent to X-rays and is a significant potential source of X-ray scattering.

[0048] exist Figure 1B In the figure, packaged sample 11 is a battery cell. The left side of the battery shows the packaging 2 (i.e., the battery housing), while the packaging is omitted on the right side to illustrate the internal structure. X-ray diffraction analysis can be used to monitor battery degradation by analyzing the underlying crystal structure of the battery's internal structure, such as the electrodes and / or electrolyte during charging cycles.

[0049] Generally speaking, 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. For batteries, the analyte cannot be removed from the packaging without damaging the battery. In addition, removing the analyte may release toxic substances into the environment. In the case of pharmaceutical products, removing the analyte from the glass vial may release toxic substances into the environment, compromise the integrity of the pharmaceutical product, or have some other effect on the sample (e.g., mechanical impact on the sample may induce recrystallization of amorphous materials, polymorphic phase transitions, and / or the introduction of defects - in addition, it may generally be desirable to avoid contact with the external atmosphere) that may prevent the sale of the product. Although reference Figure 1A and Figure 1BTwo specific examples of packaged samples are discussed, but one of ordinary skill in the art will understand that analysis of other sample types (such as polycrystalline samples) may also or alternatively be analyzed, other types of analysis (such as polymorph analysis) may be performed, and depending on the sample being analyzed, different packaging types may block direct access to the sample.

[0050] Figure 2 An X-ray diffraction apparatus 200 is shown for analyzing a packaged sample 201, such as one of the packaged samples shown in FIG. Figure 2 In the embodiment, the packaged sample 201 includes a package 202 and an analyte 203. For example, the package 202 is a glass vial partially filled with the analyte 203, such as Figure 1A shown.

[0051] refer to Figure 2 , the X-ray diffraction apparatus 200 is arranged to perform angular dispersive X-ray diffraction analysis in transmission geometry. In angular dispersive X-ray diffraction analysis, X-rays scattered by different crystal planes of the sample are recorded by a detector at different angles. The X-ray diffraction apparatus 200 comprises 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 comprises an array of detection elements, i.e. it is a one-dimensional (1D) or two-dimensional (2D) X-ray detector. In Figure 2 In FIG, a goniometer circle is illustrated, wherein the packaged sample 201 is positioned at the center of the goniometer circle. The axis of the goniometer, about which the X-ray detector 207 rotates, extends into the plane of the page. 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 can be a clamp for holding the packaged sample 201. Although Figure 2 The X-ray diffraction apparatus 200 is depicted as being arranged to perform angular dispersive X-ray diffraction analysis in transmission geometry, but it will be appreciated that in an alternative arrangement the X-ray diffraction apparatus may be arranged to perform angular dispersive X-ray diffraction analysis in reflection geometry.

[0052] The X-ray source 204 is an X-ray tube configured to generate X-rays. A first primary X-ray optics 208 is arranged between the X-ray source 204 and the sample support 205 to form a converging incident X-ray beam 211. Figure 2 , the first primary X-ray optics 208 is shown as comprising an elliptical gradient X-ray mirror configured to receive X-rays from the X-ray source 204 and reflect a substantially monochromatic, convergent X-ray beam toward the packaged sample 201. It should be understood that other first primary X-ray optics may alternatively be implemented. Similarly, although Figure 2The first primary X-ray optics is shown forming a converging incident X-ray beam, but it will be appreciated that the first primary X-ray optics may alternatively be configured to form a substantially parallel X-ray beam.

[0053] An incident X-ray beam 211 strikes 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 exit the packaged sample 201 through the other surface of the packaged sample 201. Some of the incident X-rays pass through the packaged sample 201 without deviation toward the beam stop 206. Some of the incident X-rays are diffracted by the crystalline components of the analyte 203 at an angle 2θ, and some may be scattered by the package 202 (thus contributing to "background scatter"). Some X-rays may be scattered by unoccupied portions of the package where the analyte 203 is not present (these X-rays are scattered in the unoccupied portions of the package). Figure 2 (not shown in the example).

[0054] The X-ray detector 207 is arranged to receive X-rays diffracted at an angle 2θ by the analyte 203. To detect the presence of crystalline components in the analyte 203, the X-ray detector 207 is rotated about the axis of the goniometer to different 2θ angles and records the X-ray intensity at each of the different 2θ positions.

[0055] In an embodiment of the present invention, and as Figure 2 As shown, the first secondary X-ray optical device 221 is arranged between the packaged sample 201 and the X-ray detector 207 (note that the term "primary X-ray optical device" refers to an optical device with the incident beam side between the X-ray source and the sample, while the first secondary X-ray optical device is arranged on the diffracted beam side between the sample and the X-ray detector). Figure 2 In , the first secondary X-ray optics 221 is a one-dimensional slit collimator arranged to limit the beam divergence in the equatorial plane of the X-ray diffraction apparatus 200. The collimator 221 comprises a slit-shaped aperture having an aspect ratio of at least 5. The collimator 221 is arranged very close to the packaged sample 201, on the diffracted beam side of the X-ray diffraction apparatus. The collimator 221 is positioned to receive X-rays diffracted by the analyte 203 at an angle 2θ and to allow only some of the X-rays diffracted by the analyte at an angle 2θ to pass towards the X-ray detector 207. In Figure 2 , only the diffracted X-rays that are able to pass through the slit of the collimator 221 (and form the diffracted X-ray beam 223) are illustrated. In this way, the X-ray detector 207 receives only the diffracted X-rays originating from the portion 225 of the analyte 203 defined by both the incident beam and the diffracted beam, while the X-rays originating from other portions of the packaged sample directed toward the X-ray detector are blocked by the collimator 221 before they reach the X-ray detector 207.

[0056] To prevent some of the X-rays diffracted by the analyte 203 at 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 that is "seen" by the X-ray detector 207, scattering from sources other than the analyte (such as the interior walls of the package, which can cause background scattering) can be significantly limited. The collimator 221 is positioned closer to the sample support 205 (and the packaged sample 201) than it is 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 equal to or less than 0.1, and preferably equal to or less than 0.025.

[0057] In some X-ray diffraction devices, the beam conditioner may be positioned close to the X-ray detector to reduce the amount of background scatter (e.g., from the measurement environment, the X-ray diffraction device, etc.) received by the X-ray detector 207. Note that in these arrangements, the beam conditioner is sized and positioned to allow the entire diffracted X-ray beam to reach the X-ray detector (in the absence of the collimator 221). In other words, the beam conditioner is positioned very close to the X-ray detector to maximize the proportion of detected X-rays corresponding to X-rays diffracted by the analyte by reducing background scatter in the device.

[0058] In contrast, the collimator 221 is arranged to block X-rays diffracted at 2θ that 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 effect of X-rays scattered from the sample package 202 on the detected signal.

[0059] In some embodiments, the X-ray source 204 generates X-rays using an anode comprising a material having an atomic number equal to or greater than 31 (gallium), such as silver (atomic number 47). The inventors have discovered that, in an X-ray diffraction apparatus arranged in a transmission geometry, combining an X-ray source 204 having such an anode with a collimator 221 arranged close to the packaged sample 201 can help ensure that the X-ray detector 207 receives appropriately high intensities of diffracted X-rays from a portion 225 of the analyte 203 while minimizing any contribution from the package 202. Furthermore, the inventors have discovered that this particular arrangement facilitates the effective detection and identification of crystalline components present in a packaged sample, particularly where only minor amounts of crystalline material are present in a predominantly amorphous sample.

[0060] In some embodiments, the collimator 221 can be less than 15 mm from the axis of the goniometer (i.e., from the center of the sample). The width of the slit can be equal to or less than 5 mm. For example, the slit can be 5 mm from the center of the goniometer circle, and the width of the slit can be about 1 mm.

[0061] The X-ray diffraction apparatus 200 also includes a controller 226 configured to control the X-ray detector 207. The controller 226 can be configured to control the active area of ​​the X-ray detector 207 based on the position and slit width of the collimator 221. The active area of ​​the X-ray detector 207 includes a plurality of detector elements, such as pixels. In some embodiments, the controller 226 is configured to control which detector elements of the active area of ​​the X-ray detector 207 are enabled to generate a signal based on the position and slit width of the collimator 221. That is, the controller 226 is configured to control which detector elements of the active area of ​​the X-ray detector are enabled to generate a signal based on information related to the position and slit width of the collimator 221. Thus, the controller 226 can select the active area of ​​the X-ray detector 207 that corresponds to the diffracted X-rays from the portion 225 of the analyte 203 that have passed through the collimator 221. This can help further reduce the amount of background scatter present in the diffraction pattern. Additionally, by controlling the active area of ​​the X-ray detector to determine which detector elements are configured to generate signals in response to incident X-rays, the portion of the sample "seen" by the X-ray detector can be further controlled.

[0062] By changing the configuration of the X-ray diffraction apparatus, for example by changing the position of the sample (using the sample stage) and / or changing the configuration of the first primary X-ray optical device and / or the first secondary X-ray optical device, the portion 225 of the analyte 203 defined by the incident beam and the diffracted beam can be moved / modified.

[0063] Figure 3 Another embodiment of the X-ray diffraction apparatus 300 is illustrated. In this embodiment, in addition to Figure 2 In addition to the components shown, the X-ray diffraction apparatus further includes a second secondary X-ray optical device 328, which is arranged in the diffracted X-ray beam 323 between the collimator 321 and the X-ray detector 307. The second secondary X-ray optical device 328 can be a beam conditioner for blocking at least some X-rays in the equatorial plane. For example, the second secondary X-ray optical device 328 can be an equatorial divergence slit or a parallel plate collimator.

[0064] Figure 2 and Figure 3 The X-ray diffraction apparatus exemplified in may additionally comprise a Soller slit collimator and / or an aperture arranged between the first primary X-ray optics and the sample support for limiting the axial divergence of the incident X-ray beam. Additionally or alternatively, Figure 2 and Figure 3The X-ray diffraction apparatus exemplified in FIG may comprise a Soller slit collimator and / or an aperture arranged between the sample support and the X-ray detector for limiting the axial divergence of the diffracted X-ray beam. The axial divergence is the distance from the axis about which the X-ray detector rotates (in FIG. Figure 2 and Figure 3 divergence of the axis extending into the plane of the page).

[0065] Figure 4 Another embodiment of an X-ray diffraction apparatus 400 according to an embodiment of the present invention is illustrated. The X-ray diffraction apparatus comprises an X-ray source 404 and a first primary X-ray optics 408 arranged to irradiate a packaged sample 401 with an incident beam of converging X-rays. A beam stop 406 is arranged to absorb at least some of the X-rays that pass directly through the packaged sample 401. The packaged sample comprises a package 402 and an analyte 403. A second primary X-ray optics 427 is arranged between the first primary X-ray optics 408 and the packaged sample 401. The second primary X-ray optics 427 and the first secondary X-ray optics 421 are configured to define an analysis intersection region 425 formed by the intersection of the incident X-ray beam and the diffracted X-ray beam, wherein the analysis intersection region is positioned in a region of the packaged sample within the package.

[0066] In some embodiments, both the second primary X-ray optics 427 and the first secondary X-ray optics 421 are collimators (e.g., collimating slits). The aperture size and position of the collimators are selected so as to select a specific area of ​​the packaged sample 401 for analysis. Figure 4 , the collimator is configured such that a region of the packaged sample that includes substantially only the analyte 403 is selected for analysis (i.e., the analysis intersection region includes substantially only the analyte). The configuration of the second primary X-ray optics 427 and the first secondary X-ray optics 421 can be adjusted to change the position of the analysis intersection region 425. For example, in some embodiments, the analysis intersection region can define a volume where a majority of the volume is occupied by the analyte and a smaller portion of the volume is occupied by packaging / other material (e.g., air).

[0067] The X-ray detector 407 is arranged to receive diffracted X-rays from the encapsulated sample 401. The X-ray detector 407 is a position sensitive detector. That is, the X-ray detector comprises a plurality of detection elements (e.g. in a ID or 2D array). In general, the active area of the X-ray detector is defined by the detection elements configured to produce a signal in response to incident X-rays. The controller 426 is configured to control the X-ray detector 407. The controller 426 can be configured to control the active area of the X-ray detector 207 based on the position of the collimators 421, 427 and the slit width. In this way, the controller 426 can select the active area of the X-ray detector 407 corresponding to diffracted X-rays originating from the analysis intersection region. This can help to further reduce the amount of background scatter present in the diffraction pattern.

[0068] Although Figure 4 The arrangement is shown in which the X-ray source 404 and the first primary X-ray optics 408 are arranged to irradiate the encapsulated sample 401 with a converging beam of incident X-rays, it will be understood that the incident beam can instead be a parallel beam of X-rays.

[0069] Referring Figure 5 In accordance with embodiments of the application, there is provided a method of analysing an encapsulated sample by X-ray diffraction analysis. The method can be performed using an X-ray diffraction apparatus as described in connection with any of Figure 2 、 Figure 3 and Figure 4 In one embodiment, the method comprises, in an arranging step 501, arranging a first secondary X-ray optic between the encapsulated sample and an X-ray detector.

[0070] In an irradiating step 503, the encapsulated sample is irradiated with a converging or parallel beam of incident X-rays. The X-ray source irradiates the encapsulated sample with a beam of incident X-rays having an energy of at least about 9 keV. In some embodiments, the X-ray source, the encapsulated sample and the X-ray detector are arranged to perform X-ray diffraction analysis of the encapsulated sample in transmission geometry. That is, the diffracted X-rays exit the sample from a portion of the encapsulated sample opposite the irradiated surface of the sample in the direction of the incident X-ray beam.

[0071] In an X-ray optics configuration step 505, the X-ray optics are configured to block a plurality of X-rays diffracted by the analyte from reaching the X-ray detector. By blocking X-rays from the packaged sample that would otherwise be detected by the X-ray detector, the X-ray optics limit the portion of the sample observed by the X-ray detector. The inventors have recognized that by positioning a collimator close to the packaged sample and irradiating the sample with an X-ray source configured to emit X-rays having an energy of at least 17 keV, good X-ray diffraction analysis results can be obtained even for packaged samples. In particular, by performing the X-ray diffraction analysis in this manner, the X-ray analysis results obtained have a reduced effect from background scatter sources that would otherwise make it difficult to distinguish between low-intensity diffraction peaks and scatter from the packaging / other background scatter sources.

[0072] It should be understood that although the X-ray optics configuration step 505 is shown as occurring after the irradiation step 503, the X-ray optics configuration step 505 may occur before the irradiation step 503, or these steps may occur (or begin) substantially simultaneously.

[0073] In some embodiments, the X-ray optics 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 equal to or less than 0.1, and preferably equal to or less than 0.025.

[0074] In some embodiments, the packaged sample includes a container, and the analyte partially fills the container (e.g., Figure 2 In these embodiments, the arranging step of the method may further include adjusting the position of the packaged sample and / or the collimator so that the analysis intersection region (e.g., Figure 2 The portion 225 in the cavity is positioned in the portion of the cavity where the analyte is held, rather than in the portion of the cavity where there is no analyte. In this way, detection of X-ray scattering from the empty portion of the container is minimized / avoided.

[0075] In some embodiments, the method includes controlling the size of the active portion of the X-ray detector by selecting which portions of the active portion of the X-ray detector contribute to detecting X-rays. The size of the active portion can be electronically controlled to match the size of the diffracted X-ray beam selected by the collimator. This can help further avoid / reduce the presence of background scatter in the diffraction pattern.

[0076] Figure 6 A method for analyzing X-ray diffraction analysis of packaged samples is illustrated. This method can be used, for example, Figure 4In the arrangement step 601 , the second primary X-ray optical device and the first secondary X-ray optical device are arranged on the incident X-ray beam side and the diffracted X-ray beam side of the packaged sample, respectively.

[0077] In an X-ray optics configuration step 603, the second primary X-ray optics and the first secondary X-ray optics are configured to define an analysis intersection region. That is, the second primary X-ray optics and the first secondary X-ray optics are positioned relative to the rest of the X-ray diffraction apparatus (e.g., the X-ray source, the first primary X-ray optics, the packaged sample, and the X-ray detector)—and the associated dimensions of the second primary X-ray optics and the first secondary X-ray optics, such as the collimation slit dimensions, are optionally selected to define the analysis intersection region. The analysis intersection region is positioned in the region of the packaged sample within the package (i.e., the analysis intersection region does not include the package). The analysis intersection region is formed by the intersection of the incident X-ray beam and the diffracted X-ray beam.

[0078] In some embodiments, the packaged sample defines a cavity in a "package" region of the packaged sample (as opposed to a packaging region of the packaged sample where the packaging is present). The cavity includes an analyte region and an analyte-free region. The analytical intersection region may be formed in both the analyte region and the analyte-free region. Alternatively, the analytical intersection region may be formed only in the analyte region (e.g., Figure 2 、 Figure 3 and Figure 4 depicted).

[0079] In an irradiation step 605, the packaged sample is irradiated with incident X-rays. The incident X-rays are directed from an X-ray source via a first primary X-ray optical device and a second primary X-ray optical device toward the sample. The incident X-rays are diffracted and / or scattered by the sample. A first portion of the diffracted X-rays passes through the first secondary X-ray optical device to be detected by an X-ray detector. The first portion of the diffracted X-rays are X-rays from an analysis intersection region defined by the second primary X-ray optical device and the first secondary X-ray optical device. A second portion of the diffracted X-rays is blocked from being detected by the X-ray detector. The second portion of the diffracted X-rays are X-rays outside the analysis intersection region defined by the second primary X-ray optical device and the first secondary X-ray optical device. For example, the first portion of the diffracted X-rays comes from an area within the package, and the second portion of the diffracted X-rays comes from the package area (the area where the package is present).

[0080] In some embodiments, the method further comprises an adjustment step 607, wherein the position 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 is adjusted such that an analysis intersection region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is repositioned. For example, the adjustment step 607 can comprise changing the position of the analysis intersection region such that it is formed in a portion of the cavity in which the analyte is held, rather than in a portion of the cavity in which the analyte is absent.

[0081] Those skilled in the art will appreciate that the embodiments described above are illustrative of the present invention and that modifications may be made to these embodiments without departing from the scope of the claims.

[0082] although Figure 2 and Figure 3 The encapsulated sample is shown to include a package partially filled with the analyte, but the package may alternatively be completely filled with the analyte.

[0083] The encapsulated sample does not necessarily have to be a glass vial or battery holding a pharmaceutical product. X-ray diffraction equipment is applicable to the analysis of any core-shell structure, wherein the core is the analyte and the shell is the packaging. Examples of encapsulated samples include any sample held in a container comprising a package that can scatter and / or absorb X-rays. For example, the analyte is held in a plastic, metal or glass container. The analyte can be a powder, lyophilized powder, tablet, liquid or semi-solid formulation. In another example, the encapsulated sample can be a device containing the analyte, such as an electrochemical cell.

[0084] The sample support may not be a fixture. In some embodiments, the sample support may be a platform on which the packaged sample is supported. In some embodiments, the sample support may be motorized to rotate the sample (to improve scattering statistics) or to provide automatic exchange of samples.

[0085] In some embodiments, the collimator is not a one-dimensional slit. The collimator may alternatively include an aperture shaped to limit 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.

[0086] In some embodiments, the primary X-ray optics is not an elliptical gradient X-ray mirror. It can instead be another type of X-ray optics for providing a converging or parallel X-ray beam. For example, the primary X-ray optics can include a curved crystal monochromator for producing a converging beam, or a parabolic gradient X-ray mirror for producing a parallel beam. Alternatively, the primary X-ray optics can include a combination of a flat gradient X-ray mirror and a narrow slit to form a narrow quasi-parallel beam.

[0087] The anode of the X-ray source does not necessarily have to comprise silver. The anode can comprise any material capable of producing an X-ray beam having an energy greater than 9 keV or greater than 17 keV. For example, the anode can comprise gallium (atomic number 31), molybdenum (atomic number 42), or any other material having an atomic number equal to or greater than 31.

[0088] In some embodiments, the X-ray diffraction apparatus does not include secondary X-ray optics.

[0089] When the collimator has a slit-shaped aperture, the aspect ratio of the aperture may be at least 2, or preferably at least 5.

[0090] In some embodiments, the size of the active area of ​​the X-ray detector can be adjusted based on the size / configuration of the first secondary X-ray optics and the X-ray detector. The adjustment can be determined according to a formula, where the size of the first secondary X-ray optics (e.g., slit size) and the size of the X-ray detector and their relative positions are parameters. In some embodiments, the X-ray diffraction apparatus is not configured to adjust the size of the active area based on the size of the first secondary X-ray optics and the X-ray detector. The adjustment can be determined (according to the formula) and performed manually by an operator.

[0091] The primary X-ray optics may comprise an optical filter in combination with the X-ray optics for forming a converging X-ray beam.

[0092] In some embodiments, the secondary X-ray optics is not positioned closer to the X-ray sample than to the X-ray detector.

Claims

1. A method for angular dispersive X-ray diffraction analysis of a packaged sample, wherein the packaged sample comprises an analyte confined in a package, the method comprising: arranging a first primary X-ray optical device between an X-ray source and the packaged sample to focus X-rays from the X-ray source into a focused X-ray beam of convergent or parallel X-rays and directing the focused X-ray beam toward the packaged sample; disposing a first secondary X-ray optical device between the packaged sample and the X-ray detector; irradiating the packaged sample with the focused X-ray beam of the convergent or parallel X-rays using the X-ray source, the X-rays having an energy greater than about 9 keV while the analyte is confined within the package; The first secondary X-ray optical device is configured so that a first portion of diffracted X-rays passes therethrough to be detected by the X-ray detector and a second portion of diffracted X-rays is blocked from being detected by the X-ray detector, wherein the first portion of diffracted X-rays comes from an area substantially within the package. 2 . The method of claim 1 , wherein the first secondary X-ray optics is configured such that the first portion of diffracted X-rays is from a region within the analyte.

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

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

5. The method according to any one of claims 1 to 4, wherein the first secondary X-ray optics is a collimator. 6 . The method of claim 5 , further comprising controlling an active area of ​​the X-ray detector based on a size of an aperture of the collimator and a position of the collimator relative to the packaged sample and the X-ray detector.

7. A method according to any one of claims 1 to 6, wherein the package includes a cavity in which the analyte is retained and a portion of the cavity is free of the analyte, the method further comprising adjusting the position of the packaged sample and / or the first secondary X-ray optical device so that the analysis intersection region formed by the intersection of the incident X-ray beam and the diffracted X-ray beam is positioned in the portion of the cavity that retains the analyte, rather than in the portion of the cavity that is free of the analyte.

8. The method of any one of claims 1 to 7, wherein the X-ray source comprises an anode comprising a material having an atomic number equal to or greater than 31, and the package comprises a wall having a thickness of at least about 1 mm.

9. An X-ray diffraction apparatus for performing angular dispersive X-ray diffraction analysis on a packaged sample, the X-ray diffraction apparatus comprising: a sample support for supporting the packaged sample, the packaged sample comprising an analyte confined in a 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 an incident beam path; a first primary X-ray optics arranged in the incident beam path, wherein the first primary X-ray optics is arranged to focus the incident X-rays into a converging or parallel X-ray beam and to direct the X-ray beam towards the packaged sample; an X-ray detector arranged to receive diffracted X-rays from the packaged sample; and a first secondary X-ray optic arranged 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, wherein the first secondary X-ray optics is configured such that the first portion of diffracted X-rays comes from a region substantially within the package.

10. An X-ray diffraction apparatus according to claim 9, wherein the first secondary X-ray optics is configured such that the first portion of diffracted X-rays is from a region within the analyte.

11. The X-ray diffraction apparatus according to claim 9 or claim 10, further comprising a second primary X-ray optical device arranged between the first primary X-ray optical device and the packaged sample, wherein the second primary X-ray optical device and the first secondary X-ray optical device are configured to form an analysis intersection region, the analysis intersection region being formed by the intersection of the incident X-ray beam and the diffracted X-ray beam, wherein the analysis intersection region is positioned in an area within the package.

12. X-ray diffraction apparatus according to any one of claims 9 to 11, wherein the first secondary X-ray optics is a collimator.

13. An X-ray diffraction apparatus according to any one of claims 9 to 12, wherein the X-ray source comprises an anode comprising a material having an atomic number equal to or greater than 31, and / or wherein the primary X-ray optics is a monochromator arranged to direct a substantially monochromatic X-ray beam towards the encapsulated sample.

14. An X-ray diffraction device according to any one of claims 9 to 13, wherein 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 diffraction device further includes a controller configured to select which of the detection elements contribute to generating the detection signal.

15. The X-ray diffraction apparatus 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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