Method and apparatus for determining thickness and solid fractions of a drug tablet using non-invasive

Abstract

The invention relates to a device for obtaining capacitive measurements for determining the relative permittivity and thickness of a pharmaceutical tablet. The invention also relates to a method of determining the relative permittivity and thickness of a pharmaceutical tablet using one or more capacitive sensors. The apparatus and method may be part of a drug tabletting unit or a drug tabletting method.

Description

Technical Field

[0001] The present invention belongs to the technical field of tablet solid fraction. In particular, the present invention relates to process analytical technology, preferably inline analysis, to characterize thickness and solid fraction in solid dosage forms. Moreover, hardness determination is also part of the present invention. Background Art

[0002] The two main quality attributes of pharmaceutical tablets - mechanical strength and dissolution kinetics - are determined by the porosity / solid fraction of the compressed material. During tableting, in addition to the internal control of the tablet press (if available), regular control of tablet characteristics (weight, hardness, thickness and diameter) is performed using equipment such as multifunction testers (online or offline). However, due to the speed of the equipment and the destructive aspect of hardness testing, only a very small part of the batch (about 0.01%) can usually be determined, which lacks batch representativeness. Due to its important role in tablet characterization, it is very desirable to have PAT tools to ensure consistent product quality, especially in design space applications. Moreover, in technologies such as continuous manufacturing, these characteristics are often used in real time to infer other critical quality attributes, such as dissolution properties. Therefore, the availability of continuous and rapid methods to determine these characteristics is a key resource for monitoring and controlling these processes and is an ideal tool to support real-time release applications - existing control strategies can be designed based on the frequency and availability of determination of these parameters. Therefore, there have been many scientific articles aimed at measuring solid fraction in a fast and non-destructive way, such as terahertz imaging (Muller et al. 2012) or Raman spectroscopy (Peeters et al. 2016), but it is not clear whether the limitations of each of these techniques can be overcome and reliable estimates can be provided. An alternative technique that has great potential to provide reliable estimates of solid fraction is electrical capacitance tomography, which has been shown to be accurate and reliable in multiphase flows with lower solid fractions. Obtaining solid fraction from capacitance measurements is not direct, as the capacitance responds to both the volume and mass of the pharmaceutical tablet, so additional information about the sample is usually required.

[0003] In the context of the use of process tomography in the characterization of final dosage forms, a survey of the literature found the following contributions in the field of pharmaceutical processes:

[0004] US4461363 patent relates to a method and apparatus for capacitive weighing of a bounded or unbounded object as it passes between the plates of a capacitor. Although this apparatus can present several configurations for weighing a sample, it does provide information about the solid fraction.

[0005] US5135113 and US5240118 patent applications depict machines for weighing and sorting tablets, particularly at high speed rates. The main purpose of these inventions is to provide a high speed machine for weighing and sorting tablets by capacitive measurement, but without capturing information about the solid fraction.

[0006] Patent US10801986 describes a monitoring sensor sleeve for guiding metered quantities of powder and performing capacitive mass determination therein.

[0007] WO2019057802 and US2020217811 relate to measuring the solid fraction of a drug substance. It also presents the challenge of unknown thickness and solid fraction of a drug substance. These documents propose the use of a separate sensor to measure the thickness of the substance. The use of a separate distance capacitance sensor is not a viable option because for its use, the material composition and density must be exactly the same in all measurements (which is incorrect because density variability between substances is exactly what is being tried to obtain). The results shown are corrected by the thickness of the different tablets, so the thickness and solid fraction measurements proposed in the patents are separate, with the thickness measured at an early stage.

[0008] EP 2 740 671 B1 describes a device for inspecting tablets with a chute and an inclined guide surface, as well as a sensor and a passive piezoelectric bending actuator integrated into the chute for detecting defective tablets.

[0009] JP2009047687A describes a device with both NIR for active ingredient inspection and an array of capacitive sensors for volume inspection. Weight and density can be indirectly inferred from tablet press data and NIR, respectively.

[0010] US10565855B2 employs a device that enables automatic monitoring of the status of the drug content in a blister card by tracking the tablet position via a capacitive sensor.

[0011] US20090314944A1 describes an apparatus for non-destructive imaging of chemical and / or structural features of a pharmaceutical tablet containing an active pharmaceutical ingredient (API) and excipients (fillers) using terahertz radiation.

[0012] DE 2502098 describes the use of capacitance to compare the measured dielectric value of a tablet with a standard value - thereby inferring whether the tablet weight is acceptable. However, this is only a pass or fail method and does not take into account the thickness variations of the multiple tablets being measured.

[0013] In summary, current methods can only provide qualitative measurements of samples or require the use of other techniques to provide quantitative solid fraction measurements. Since robustness is critical in the pharmaceutical industry, it is undesirable to rely on multiple devices and techniques for a single parameter measurement. In contrast to previous methods, the present invention uses only capacitance measurement to provide a quantitative measurement of solid fraction, preferably using a single device to obtain the measurement, thereby allowing a simpler and more robust setup. Summary of the invention

[0014] In a first aspect, the present invention provides an apparatus for obtaining capacitance measurements for determining relative permittivity and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of capacitance sensors in one or more sensing portions, the plurality of capacitance sensors comprising:

[0015] (i) a first capacitance sensor for obtaining a first capacitance measurement, the first capacitance sensor comprising a first pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the first pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, wherein the first capacitance measurement is obtained when a pharmaceutical tablet is positioned in the gap between the planar surfaces of the first pair of conductive elements in a first orientation relative to the planar surfaces of the first pair of conductive elements;

[0016] (ii) a second capacitive sensor for obtaining a second capacitance measurement, the second capacitive sensor comprising a second pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the second pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, wherein the second capacitance measurement is obtained when the pharmaceutical tablet is positioned in the gap between the planar surfaces of the second pair of conductive elements in a second orientation relative to the planar surfaces of the second pair of conductive elements;

[0017] The device is configured so that the first orientation can be perpendicular to the second orientation, so that in one of the first orientation and the second orientation, the thickness of the drug tablet is parallel to the parallel flat surfaces of the pair of conductive elements, and in the other of the first orientation and the second orientation, the thickness of the drug tablet is perpendicular to the parallel flat surfaces of the pair of conductive elements.

[0018] In one example, the arrangement of the parallel flat surfaces of the first pair of conductive elements relative to the parallel flat surfaces of the second pair of conductive elements enables the first orientation to be perpendicular to the second orientation. In particular, the device may include a sensing portion in which the flat surfaces of the first pair of conductive elements are arranged perpendicularly to the flat surfaces of the second pair of conductive elements. Alternatively, the device may include two sensing portions arranged in series, wherein the first pair of conductive elements are arranged in the first sensing portion and the second pair of conductive elements are arranged in the second sensing portion, wherein the second pair of conductive elements are arranged perpendicularly to the first pair of conductive elements.

[0019] In a further example, the device may include two sensing portions arranged in series, wherein a first pair of conductive elements is arranged in the first sensing portion and a second pair of conductive elements is arranged in the second sensing portion, and the device includes a redirecting element to redirect the drug tablet between a first orientation in the first sensing portion and a second orientation in the second sensing portion when the drug tablet is in the device. The redirecting element may, for example, include a funnel.

[0020] In the apparatus, the first pair of conductive elements may be a first pair of parallel plates and the second pair of conductive elements may be a second pair of parallel plates.

[0021] In further embodiments, the apparatus may include a connection for connecting to a controller, or include a controller, wherein the controller is configured to determine the relative permittivity and thickness of the pharmaceutical tablet using the first capacitance measurement and the second capacitance measurement.

[0022] In particular, the controller may include reference data correlating relative dielectric constant to solid fraction for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to determine the solid fraction of the pharmaceutical tablet by comparing with the reference data using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet.

[0023] Additionally or alternatively, the controller includes reference data correlating relative dielectric constant to hardness for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to determine the hardness of the pharmaceutical tablet using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet by comparing with the reference data.

[0024] In an embodiment of the device, in the first pair of conducting elements the conducting elements have planar surfaces of the same dimensions, and / or in the second pair of conducting elements the conducting elements have planar surfaces of the same dimensions.

[0025] In a further embodiment, the device comprises a conduit for a pharmaceutical tablet, in which the one or more sensing portions are arranged, the conduit enabling the pharmaceutical tablet to pass through the device and the one or more sensing portions and enabling the first and second capacitance measurements to be obtained.

[0026] The apparatus may comprise a shield for shielding the plurality of capacitive sensors from fluctuating external conditions, optionally wherein the shield is an electromagnetic shield.

[0027] The apparatus may further include one or more positioning elements to position the drug tablet in the gap between the planar surfaces of the first pair of conductive elements and / or in the gap between the planar surfaces of the second pair of conductive elements.

[0028] In another aspect, the present invention provides a tableting unit for producing a plurality of pharmaceutical tablets, the tableting unit comprising a tablet manufacturing module (e.g., comprising a tablet press) and at least one device as described above, the device being positioned inline downstream of the tablet manufacturing module such that a plurality of pharmaceutical tablets pass through the device to allow first and second capacitance measurements to be obtained. The tableting unit may include a plurality of said devices positioned downstream of the tablet manufacturing module, wherein a plurality of said devices are arranged in series or in parallel to increase throughput and / or the number of pharmaceutical tablets for which capacitance measurements can be obtained.

[0029] A further aspect of the invention is a method of determining the relative dielectric constant and thickness of a pharmaceutical tablet using one or more capacitive sensors, wherein each of the one or more capacitive sensors comprises a pair of conductive elements, each conductive element of the pair of conductive elements having a planar surface, wherein the planar surfaces of the pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, the method comprising:

[0030] (a) obtaining a first differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between planar surfaces of the pair of conductive elements with and without a pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a first orientation in which a thickness of the pharmaceutical tablet is parallel to the planar surfaces of the pair of conductive elements;

[0031] (b) obtaining a second differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between the planar surfaces of the pair of conductive elements with and without the pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a second orientation in which a thickness of the pharmaceutical tablet is perpendicular to the planar surfaces of the pair of conductive elements; and

[0032] (c) determining a relative dielectric constant and a thickness of the pharmaceutical tablet using the first differential capacitance measurement and the second differential capacitance measurement;

[0033] Where (a) and (b) are performed in either order.

[0034] Yet another aspect of the present invention is a method for determining the solid fraction and / or hardness of a pharmaceutical tablet, the method comprising: determining the relative dielectric constant and thickness of the pharmaceutical tablet according to aspects (a) to (c) above; (d) using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet to determine the solid fraction of the pharmaceutical tablet by comparing with reference data, wherein the reference data relates the relative dielectric constant to the solid fraction for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet; and / or (e) using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet to determine the hardness of the pharmaceutical tablet by comparing with reference data, wherein the reference data relates the relative dielectric constant to the hardness for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet.

[0035] In particular, in the above method, one or more of (c) to (e) can be executed on a computer.

[0036] In one embodiment of the above method, a capacitive sensor is used to obtain the first differential capacitance measurement and the second differential capacitance measurement, and the method includes reorienting the pharmaceutical tablet between the first orientation and the second orientation, or vice versa, between the measurements.

[0037] In an alternative embodiment of the above method, the one or more capacitive sensors are a first capacitive sensor for obtaining a first differential capacitive measurement and a second capacitive sensor for obtaining a second differential capacitive measurement, the first capacitive sensor comprising a first pair of conductive elements and the second capacitive sensor comprising a second pair of conductive elements.

[0038] In particular, the first capacitive sensor and the second capacitive sensor may be arranged in one or more sensing portions in the device.

[0039] For example, a first capacitive sensor and a second capacitive sensor are arranged in a sensing portion of the device, wherein the planar surfaces of the first pair of conductive elements are arranged perpendicularly to the planar surfaces of the second pair of conductive elements, and the method includes positioning the pharmaceutical tablet in a first orientation relative to the planar surfaces of the first pair of conductive elements, the first orientation also being the second orientation relative to the planar surfaces of the second pair of conductive elements.

[0040] In another example, a first capacitive sensor is disposed in a first sensing portion and a second capacitive sensor is disposed in a second sensing portion, wherein the method includes reorienting the pharmaceutical tablet between a first orientation and a second orientation or between the second orientation and the first orientation when the pharmaceutical tablet moves between the first sensing portion and the second sensing portion or vice versa.

[0041] In another example, a first capacitive sensor is arranged in a first sensing portion and a second capacitive sensor is arranged in a second sensing portion, wherein planar surfaces of the first pair of conductive elements are arranged perpendicular to planar surfaces of the second pair of conductive elements, and the method includes moving a pharmaceutical tablet between the first sensing portion and the second sensing portion, or moving the pharmaceutical tablet between the second sensing portion and the first sensing portion.

[0042] In an embodiment of the method, the pair of conductive elements is a pair of parallel plates.

[0043] In further embodiments of the method, the pair of conductive elements have planar surfaces of the same dimensions.

[0044] The method may include obtaining capacitance measurements while the pharmaceutical tablet is at rest, optionally while the pharmaceutical tablet is at rest in one or more sensing portions.

[0045] Alternatively, the method may comprise obtaining capacitance measurements as the pharmaceutical tablet moves, optionally wherein the pharmaceutical tablet moves past one or more sensing portions.

[0046] The method may include using an outphasing technique to eliminate interference with the capacitance measurement.

[0047] The method can be implemented inline in a tableting unit.

[0048] In yet another aspect, the present invention provides a pharmaceutical tableting process, comprising producing a pharmaceutical tablet using a tablet manufacturing module and determining the relative dielectric constant and thickness of the pharmaceutical tablet according to the above method. In particular, the tablet manufacturing module may include a tablet press.

[0049] In an additional aspect, the present invention provides the use of the above-mentioned apparatus to determine the relative dielectric constant and thickness of a pharmaceutical tablet. In particular, the use may be the use of determining the relative dielectric constant and thickness according to the above-mentioned method.

[0050] In particular, in one aspect, the present invention discloses an inline, rapid and non-destructive quantitative measurement method and apparatus based on electrical tomography for determining the solid fraction and thickness of a tablet during a pharmaceutical tableting process. Tablet hardness can also be inferred in a non-destructive manner. The apparatus can include (or consist of) a plurality of sensors in one or more sensing portions that can be used to obtain rapid, non-invasive and non-destructive inline measurements that can be used to determine tablet thickness and solid fraction.

[0051] The present invention uses only electrical tomography to determine these quantities and does not require additional equipment and techniques.

[0052] Regarding its application, when installed at the exit of a tablet press, the device of the present invention can ensure the quality of the pharmaceutical tableting process for an entire batch, increase sample representativeness, while reducing the need for destructive offline experiments and facilitating the implementation of real-time releases due to the information it can generate. The device also has the potential to become a key and widespread tool for defining control strategies for multiple applications (e.g., in continuous manufacturing). Destructive and sporadic pharmaceutical tablet analysis can be replaced by non-destructive and high-frequency determination.

[0053] For increased throughput and scale-up, multiple devices can be installed either in series or in parallel to increase batch sample representativeness (ie, the entire batch of samples analyzed). BRIEF DESCRIPTION OF THE DRAWINGS

[0054] To aid understanding of the present disclosure and to show how embodiments may be implemented, reference is made to the accompanying drawings by way of example, in which:

[0055] Figure 1 A representation of a device and dimensions for making multiple measurements in a single part according to an embodiment of the present invention is provided. The representation shows a device (4), a first capacitive sensor having a first pair of conductive elements (1a and 1b), a second capacitive sensor having a second pair of conductive elements (2a and 2b), and a pharmaceutical tablet (3).

[0056] Figure 2 A scheme for performing multiple capacitance measurements in a single section according to an embodiment of the present invention is provided.

[0057] Figure 3 A representation of a device with multiple capacitance measurements in two sensing regions according to an embodiment of the present invention is provided. The representation shows a device (4), a first capacitance sensor (1) with a first pair of conductive elements (1a and 1b), a second capacitance sensor (2) with a second pair of conductive elements (2a and 2b), and a second capacitance sensor (3) with a thickness (d t ) of the pharmaceutical tablet (3).

[0058] Figure 4 A schematic diagram showing a capacitive sensor and a tablet according to an embodiment of the present invention is provided.

[0059] Figure 5 A plot of the calculated relative dielectric constant obtained in Example 1 versus tablet density is provided.

[0060] Figure 6 A plot of the calculated relative dielectric constant obtained in Example 1 versus tablet hardness is provided.

[0061] Figure 7 A plot of the calculated tablet thickness obtained in Example 1 versus the measured tablet thickness is provided.

[0062] Figure 8 A representation of capacitance measurements obtained in Example 2 is provided as a tablet is dynamically passed through the apparatus described herein. DETAILED DESCRIPTION

[0063] The description of the invention provided herein uses the terms "first" and "second", for example, referring to a "first capacitive sensor", "second capacitive sensor", "first capacitive measurement", and "second capacitive measurement". The terms "first" and "second" are used herein for identification purposes only and do not refer to an order of use or the order in which the steps of the described methods are to be taken. In particular, the "first capacitive sensor" and "second capacitive sensor" in the device described herein can be used in any order to obtain capacitive measurements and can be arranged in series in any order in the device, and in the method described herein, the "first capacitive measurement" and "second capacitive measurement" can be obtained in any order.

[0064] The present invention discloses a high-resolution electrical tomography-based device capable of performing a non-destructive inline quantitative method for determining the relative dielectric constant and thickness of pharmaceutical tablets, from which the solids fraction and hardness of the tablet can be inferred, for example in pharmaceutical tableting processes.

[0065] In a first aspect, the present invention provides an apparatus for obtaining capacitance measurements for determining relative permittivity and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of capacitance sensors in one or more sensing portions, the plurality of capacitance sensors comprising:

[0066] (i) a first capacitive sensor for obtaining a first capacitive measurement, the first capacitive sensor comprising a first pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the first pair of conductive elements are arranged in parallel such that a capacitive measurement can be obtained from a gap therebetween, wherein the first capacitive measurement is obtained when a pharmaceutical tablet is positioned in the gap between the planar surfaces of the first pair of conductive elements in a first orientation relative to the planar surfaces of the first pair of conductive elements;

[0067] (ii) a second capacitive sensor for obtaining a second capacitive measurement, the second capacitive sensor comprising a second pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the second pair of conductive elements are arranged in parallel such that a capacitive measurement can be obtained from a gap therebetween, wherein the second capacitive measurement is obtained when the pharmaceutical tablet is positioned in the gap between the planar surfaces of the second pair of conductive elements in a second orientation relative to the planar surfaces of the second pair of conductive elements;

[0068] The device is configured so that the first orientation is perpendicular to the second orientation, so that in one of the first and second orientations, the thickness of the drug tablet is parallel to the parallel flat surfaces of the pair of conductive elements, and in the other of the first and second orientations, the thickness of the drug tablet is perpendicular to the parallel flat surfaces of the pair of conductive elements.

[0069] As described above, the capacitive sensor used in the device includes a pair of conductive elements, each conductive element having a flat surface, wherein the flat surfaces are arranged in parallel with a gap (or operating space) between them, from which a capacitance measurement can be obtained. The conductive elements can be any 3D configuration with a flat surface, but preferably the conductive element pair is two parallel plates.

[0070] The planar surface may have any shape, for example, a rectangular, square, circular or annular shape.

[0071] The planar surfaces of the conductive elements have an area (A) and are arranged in parallel, separated by a distance (d) which defines a gap between the planar surfaces. Preferably, the planar surfaces of the conductive elements have the same dimensions as the planar surfaces of the other conductive element of the same pair.

[0072] Preferably, the area (A) and distance (d) of the first pair of conductive elements are the same as the area (A) and distance (d) of the second pair of conductive elements.

[0073] By minimizing the free space around the pharmaceutical tablet when the pharmaceutical tablet is positioned in the gap in the first and / or second orientation, the accuracy of the measurements obtained by the capacitive sensor may be increased or optimized.

[0074] To obtain a capacitance measurement, the conductive element is connected to a power source so that an electric field is generated in the gap between the planar surfaces of the conductive element and a capacitance measurement is obtained from the gap.

[0075] The apparatus is used to obtain first and second capacitance measurements when the pharmaceutical tablet is in a first orientation relative to the parallel flat surfaces of the first pair of conductive elements and when the pharmaceutical tablet is in a second orientation relative to the parallel flat surfaces of the second pair of conductive elements. In particular, the apparatus is configured such that the first orientation is perpendicular to the second orientation, such that in one of the first and second orientations, the thickness of the pharmaceutical tablet is parallel to the parallel flat surfaces of the pair of conductive elements of the capacitive sensor for obtaining the measurement, and in the other of the first and second orientations, the thickness of the pharmaceutical tablet is perpendicular to the parallel flat surfaces of the pair of conductive elements of the capacitive sensor for obtaining the measurement. In other words, in one of the first and second orientations, the capacitance streamlines are perpendicular to the thickness of the pharmaceutical tablet, and in the other of the first and second orientations, the capacitance streamlines are parallel to the thickness of the pharmaceutical tablet.

[0076] As used herein, the term "perpendicular" refers to 90°±5°, preferably 90°±2°, more preferably 90°±1°, most preferably 90°±0.5°, in order to obtain as accurate a determination of the relative dielectric constant and thickness of the pharmaceutical tablet as possible.

[0077] In particular, some variation around the 90° angle is allowable and this may be due to limitations of sensor / device manufacturing. However, it is believed that the most accurate determination can be obtained with an angle as close to 90° as possible.

[0078] Similarly, as used herein, the term "parallel" includes variations from parallel by ±5°, preferably ±2°, more preferably ±1°, and most preferably ±0.5° from parallel. Again, it is believed that accuracy is improved by keeping such variations as low as possible.

[0079] Figures 1 to 3 An example of a suitable configuration of first and second capacitive sensors in a device to enable these capacitive measurements to be made is shown in .

[0080] In the method of the present invention, as discussed below, two capacitance measurements can be obtained by one capacitance sensor, wherein the orientation of the pharmaceutical tablet relative to the planar surface of the conductive element of the capacitance sensor is changed between a first orientation and a second orientation, or vice versa, between different capacitance measurements. This can be done either manually or using a machine.

[0081] However, the device described herein includes two capacitive sensors, a first capacitive sensor for obtaining a first capacitive measurement and a second capacitive sensor for obtaining a second capacitive measurement.

[0082] Two capacitive sensors can be arranged in parallel in one sensing section, for example Figure 1 and Figure 2 In this arrangement, the device may be box-shaped. In particular, Figure 1 An example of a device with one sensing portion is shown, wherein the parallel planar surfaces of a first pair of conductive elements (1a and 1b) are arranged perpendicular to the parallel planar surfaces of a second pair of conductive elements (2a and 2b). Figure 2 In the measurement 1), the thickness (t) of the drug tablet (3) is perpendicular to the parallel flat surfaces of the first pair of conductive elements, and in the second direction (wherein the Figure 2 In the measurement 2), the thickness (t) of the drug tablet (3) is parallel to the parallel flat surfaces of the second pair of conductive elements.

[0083] Alternatively, two capacitive sensors may be arranged in series in two sensing portions. The sensing portions may be immediately adjacent, or two different sensing portions or regions. Figure 3A schematic diagram of a possible configuration using two different sensing regions is shown in FIG. Figure 3 An example of a device with two sensing portions is shown, wherein the parallel planar surfaces of a first pair of conductive elements (1a and 1b) are arranged perpendicularly to the parallel planar surfaces of a second pair of conductive elements (2a and 2b). In this example, in a first orientation of a pharmaceutical tablet (as shown by the tablet indicated between conductive elements 1a and 1b), the thickness (d t ) is perpendicular to the parallel flat surfaces of the first pair of conductive elements and the capacitance flow lines are perpendicular to the thickness (d t ) are parallel. In the second orientation of the drug tablet (as shown by the tablet indicated between the conductive elements 2a and 2b), the thickness (d t ) are parallel to the parallel flat surfaces of the first pair of conductive elements and the capacitance flow lines are parallel to the thickness (d t )vertical.

[0084] The device may be configured to enable the first and second capacitance measurements to be perpendicular to each other as described above by arranging the parallel planar surfaces of the second conductive element relative to the parallel planar surfaces of the first conductive element. Figure 1 and Figure 3 In the embodiment shown in , the parallel planar surfaces of the first pair of conductive elements can be arranged perpendicular to the parallel planar surfaces of the second pair of conductive elements, for example, the conductive elements of one capacitive sensor are located on each side of the opening or conduit, and the conductive elements of the other capacitive sensor are located at the top and bottom of the opening or conduit.

[0085] Alternatively, where the device includes two sensing portions arranged in series in a first sensing portion and a second sensing portion, the device may be configured to enable the first and second capacitance measurements to be perpendicular to each other by including a redirecting element to redirect the drug tablet between the first sensing portion and the second sensing portion, or vice versa, depending on which sensing portion the drug tablet enters first. (As discussed above, this can be in any order.) The redirecting element may include a funnel or other mechanical component.

[0086] The device can be configured to enable capacitance measurement when the drug tablet is stationary in one or more sensing parts, or when the drug tablet moves through one or more sensing parts. In particular, the device can include a conduit (e.g., a tube) to allow the drug tablet to pass through one or more sensing parts. The conduit can be horizontal, or can be at an angle relative to the ground. For example, the conduit (e.g., a tube) can be horizontal to ensure that the drug tablet is stationary in one or more sensing parts, or can be at an angle relative to the ground to allow the drug tablet to move through one or more sensing parts under the influence of gravity. Preferably, the conduit is at an angle to ensure that the drug tablet moves quickly through one or more sensing parts to ensure high throughput. Alternative components can also be used to move the drug tablet through one or more sensing parts, for example, when the conduit is horizontal. Such components include, for example, a conveyor or a pneumatic system.

[0087] As the pharmaceutical tablet moves through the device, as discussed further below, multiple capacitance measurements may be taken as the pharmaceutical tablet (in either the first orientation or the second orientation) passes through the gap between the planar surfaces of the conductor elements.

[0088] The order of the first and second capacitance measurements is not important, particularly since both are used together to solve the system of equations listed below.

[0089] The device may include a connection for connecting to a controller. In addition, the device may include a controller configured to determine a relative dielectric constant and a thickness of a pharmaceutical tablet using the first and second capacitance measurements obtained using the device. For example, the device may include an integrated chip.

[0090] In particular, the controller may include reference data that relates relative dielectric constants to solid fractions for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet. For example, when the pharmaceutical tablet is produced by a tablet press, the area of ​​the upper surface of the pharmaceutical tablet is known because this is determined by a punch installed in the tablet press, e.g., for a round tablet, the circular surface area of ​​the tablet is known. The reference data may include a collection of data points for pharmaceutical tablets having the same upper surface area and chemical composition as the pharmaceutical tablet but having a range of relative dielectric constants and tablet thicknesses associated with solid fractions and / or hardness. Such reference data sets may be established using existing offline methods. (For example, the thickness of the reference tablet may be determined using a multifunction tester (such as the multifunction tester currently used in commercial pharmaceutical tablet production processes), and the hardness may be determined using conventional destructive testing.)

[0091] The controller may also be configured to use the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet to determine a solid fraction and / or hardness of the pharmaceutical tablet by comparing with reference data.

[0092] The device can be configured to use multiple channels, which allows the use of out-of-phase (OoP) techniques, thereby eliminating any interference, such as the proximity of people either nearby or in contact with the device. Using this technique, the measurements can be asynchronous. The device can include one or more environmental reference sensors to help compensate for environmental changes. The device can also include a shield, optionally an electromagnetic shield, to protect the capacitive sensor from fluctuations in external conditions. The shield can be active or passive. An example of a passive shield is a layer made of a metal such as tin.

[0093] The device may also include a positioning element to position the drug tablet in the gap between the flat surfaces of the first pair of conductive elements and / or in the gap between the flat surfaces of the second pair of conductive elements. The positioning element may be used to ensure that the tablet (unless round) is aligned with the conductive elements of the sensor. In particular, the positioning element may be a funnel or a chute and may ensure that the drug tablet is positioned at a fixed distance from the flat surfaces of the conductive elements.

[0094] In alternative examples, alignment of the tablet with the planar surface of the conductive element may use a force, such as centripetal force or gravity.

[0095] The device may include a positioning sensor to detect the position of the medication tablet. In particular, if alignment cannot be ensured, further tomographic measurements may be used to detect the position of the medication tablet.

[0096] The positioning element may also be a redirecting element as described above. For example, the device may include a first positioning element to ensure that the drug tablet (otherwise in a first orientation) is aligned (straight) relative to the parallel flat surfaces of the conductive elements of the first capacitive sensor in the first sensing portion, and a second positioning element that redirects the drug tablet from the first orientation to the second orientation before the second sensing portion and ensures that the drug tablet in the second orientation is aligned relative to the parallel flat surfaces of the conductive elements of the second capacitive sensor.

[0097] As is known in the art, it is preferred that the apparatus is arranged so that the drug tablet is positioned away from the edge of the conductive element due to the edge effects of capacitance.

[0098] As described above, the device of the present invention has particular inline utility in a pharmaceutical tableting process. Thus, in a further aspect, the present invention provides a tableting unit for producing a plurality of pharmaceutical tablets, the tableting unit comprising a tablet manufacturing module and at least one device as described herein, the device being positioned downstream of the tablet manufacturing module so that a plurality of pharmaceutical tablets pass through the device to allow a first capacitance measurement and a second capacitance measurement to be obtained. The tableting unit may comprise a plurality of devices described herein arranged in series or in parallel. In particular, this will increase throughput and / or the number of pharmaceutical tablets evaluated by the device. Preferably, the tablet manufacturing module is a tablet press.

[0099] The tableting unit may further comprise a sorting component for sorting the pharmaceutical tablets based on a determined thickness, solid fraction and / or hardness.

[0100] The tableting unit may also include a feedback system for adjusting production parameters of the tablet manufacturing module based on the determined thickness, solids fraction and / or hardness.

[0101] The pharmaceutical tablet can have any composition or shape. For example, the pharmaceutical tablet can be round, rectangular, oblong or torpedo-shaped. In a preferred embodiment, the pharmaceutical tablet is round.

[0102] Preferably the pharmaceutical tablet is produced by a tablet press. In particular, as described above, the tablet press produces pharmaceutical tablets having a known surface area (as determined by the shape of the punches mounted in the tablet press), and the method has particular utility in determining the thickness of such tablets.

[0103] The above device can be used to independently perform high-resolution capacitance measurements (either statically or dynamically) of a pharmaceutical tablet (i.e., a target object) located between the conductive elements of the first and second capacitive sensors. Thus, two types of signals are obtained, which can then be correlated to different properties of the tablet - since the relative dielectric constant of the samples is the same, both thickness and solid fraction can be determined (hardness can also be inferred). This design is a key part of the present invention because it allows all necessary information about the tablet to be extracted using a single technique (electrical tomography) without relying on other techniques or additional equipment, resulting in a simpler and more compact device.

[0104] In a further aspect, the present invention provides a method of determining the relative dielectric constant and thickness of a pharmaceutical tablet using one or more capacitive sensors, wherein each of the one or more capacitive sensors comprises a pair of conductive elements, each conductive element in the pair having a planar surface, wherein the planar surfaces of the pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, the method comprising:

[0105] (a) obtaining a first differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between planar surfaces of the pair of conductive elements with and without a pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a first orientation in which a thickness of the pharmaceutical tablet is parallel to the planar surfaces of the pair of conductive elements;

[0106] (b) obtaining a second differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between the planar surfaces of the pair of conductive elements with and without the pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a second orientation in which a thickness of the pharmaceutical tablet is perpendicular to the planar surfaces of the pair of conductive elements; and

[0107] (c) determining a relative dielectric constant and a thickness of the pharmaceutical tablet using the first and second differential capacitance measurements;

[0108] Where (a) and (b) can be performed in either order.

[0109] Another aspect is a method of determining the solid fraction and / or hardness of a pharmaceutical tablet, the method comprising: determining the relative dielectric constant and thickness of the pharmaceutical tablet according to the method of the previous paragraph; and (d) using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet to determine the solid fraction of the pharmaceutical tablet by comparing with reference data, the reference data correlating the relative dielectric constant to the solid fraction for multiple reference tablets having different thicknesses and the same chemical composition and other dimensions as the pharmaceutical tablet; and / or (e) using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet to determine the hardness of the pharmaceutical tablet by comparing with reference data, the reference data correlating the relative dielectric constant to the hardness for multiple reference tablets having different thicknesses and the same chemical composition and other dimensions as the pharmaceutical tablet.

[0110] In a preferred embodiment, one or more of the above steps (c) to (e) are performed on a computer or controller.

[0111] The description above of features of the invention provided by the apparatus also applies to the same features set forth in the method of the invention. However, as also described above, in one embodiment of the method of the invention, a capacitive sensor is used to obtain both the first differential capacitance measurement and the second differential capacitance measurement, wherein the pharmaceutical tablet is moved between the first orientation and the second orientation (or vice versa) between measurements.

[0112] The method may include one or more steps of positioning the drug tablet in the gap between the planar surfaces of the pair of conductive elements. In particular, the positioning step may be used to align the drug tablet with the planar surfaces of the conductive elements of the capacitor(s) so that they are straight. When the drug tablet is round, such positioning is not required to align the tablet.

[0113] In one example of the present invention, the apparatus described above is used to perform the method.

[0114] The method may include using the out-phasing technique as described above to cancel any interference with the capacitance measurement by the external environment of the capacitive sensor. Suitable techniques for determining the level of liquid in a tank or container using capacitive sensing are known in the art.

[0115] In the method, obtaining the capacitance measurement may be performed while the pharmaceutical tablet is stationary in the one or more sensing portions, or while the pharmaceutical tablet is moving through the one or more sensing portions. Preferably, the method is performed while the tablet is moving through the one or more sensing portions, as this provides a higher throughput. When the method is used inline in a pharmaceutical tableting process, a high throughput is necessary.

[0116] In particular, in one embodiment, the method is implemented inline in a tableting unit.

[0117] Thus, in another aspect, the present invention provides a pharmaceutical tableting process comprising producing a pharmaceutical tablet using a tablet manufacturing module and determining the relative dielectric constant and thickness of the pharmaceutical tablet according to the method described herein. Preferably, the tablet manufacturing module comprises a tablet press.

[0118] In the methods described herein, once the solid fraction and / or hardness are determined, this information can be further used to sort the tablets and / or adjust the production parameters of a tablet manufacturing module (e.g., a tablet press) via a feedback loop. Thus, the methods described herein can include the steps of sorting the pharmaceutical tablets according to their determined thickness, solid fraction and / or hardness, and / or adjusting the production parameters of a tablet manufacturing module producing the pharmaceutical tablets in order to modify the thickness, solid fraction and / or hardness of subsequently produced tablets.

[0119] This method is not derived in an obvious way from the prior art, since it is the specific measurement conditions, ie the orientation of the pharmaceutical tablet relative to the flat surface of the conductive element during the first and second capacitance measurements, that allow the thickness to be determined using a tomographic sensor.

[0120] The determination of relative dielectric constant and thickness is further explained below:

[0121] Determination of relative dielectric constant

[0122] Capacitance measurements are useful in this application because their sensors respond to the mass, density and volume of the material present between the plates. Thus, the capacitance of the material located between the parallel plates can be obtained by the difference.

[0123] The capacitance of parallel plates of equal dimensions is described by the following equation:

[0124]

[0125] where ∈ 0 is the dielectric constant of vacuum, ∈ r is the relative permittivity of the medium, A is the area of ​​the plates, and d is the distance between the plates.

[0126] Since the sample only occupies a portion of the gap between the sensor plates, the equations for capacitors in series and parallel need to be applied to get a representative equation for the system. Using a differential measurement between the sensor with and without the sample, the following equation is obtained:

[0127]

[0128] Among them A t is the sample area, d t is the sample thickness, and ∈ r is the relative permittivity of the sample.

[0129] Rearranging Equation 2, a simple calibration can be used to derive the relative dielectric constant, which is directly related to the solids fraction and hardness of the tablet.

[0130]

[0131] This equation is part of the prior art and is also mentioned in US20200217811A1.

[0132] Thickness determination

[0133] The design and properties of the sensor plate are well known and are part of the construction of the device - the gap distance (d) and the vacuum dielectric constant (ε 0 Tablet area (A t ) are also known and depend only on the punches installed in the press and used to make the tablets.

[0134] The thickness of a pharmaceutical tablet is needed to estimate the solid fraction. This value is not constant for all tablets produced (e.g., from a tablet press), as there is a non-negligible variation between tablets. Therefore, the determination of thickness is an important part of the present invention.

[0135] The present invention proposes to use another (second or additional) capacitance measurement in order to be able to estimate the thickness. This allows to extract all the necessary information from the tablet using a single technique without relying on other techniques, resulting in a simpler and more compact device.

[0136] An equation for determining the thickness of a generic tablet can be derived. Thus, taking into account the thickness t and the width b (a second measurement perpendicular to the tablet width) and the length a:

[0137]

[0138] Where ΔC 1 and ΔC 2 are the first and second capacitance measurements, w 1 、w 2 and w 3 is the dimension of the sensor, Φ shape is the tablet form factor*.

[0139] *Shape factor Φ can be added on request shape This shape factor will be the same for every tablet shape and depends only on the equipment used to produce the pharmaceutical tablet (e.g., for round tablets, Φ shape =π / 4). Although b* (the width of the equivalent rectangular tablet) will not have exactly the same value as b (the tablet width of the tablet), it will be proportional to the width, provided a slight correction is incorporated for the roundness of the tablet.

[0140] Similar equations can be obtained for all tablet shapes and sizes.

[0141] Determination of solid fraction and hardness

[0142] The relative dielectric constant and thickness determined for the pharmaceutical tablet are then used to determine the solids fraction and / or hardness of the pharmaceutical tablet.

[0143] For each type of pharmaceutical tablet (having a specific composition and specific dimensions and shape), a reference data set can be created that is correlated with a plurality of reference tablets. This data set relates relative permittivity to solid fraction and / or hardness values ​​for a plurality of reference tablets having different thicknesses (each reference tablet having a different thickness). Thus, the relative permittivity and thickness of the determined pharmaceutical tablet can be used to determine the solid fraction and / or hardness value through correlation with the reference data set.

[0144] The following is for example only and does not limit the present disclosure.

[0145] Example

[0146] Example 1

[0147] Using the prototype of the present invention, two capacitive sensors (similar to Figure 1 ), wherein the parallel plates of the first capacitive sensor are arranged perpendicularly to the parallel plates of the second capacitive sensor. The prototype was tested using placebo tablets. The tablets tested were round, with a mass range between 121 g and 132 g and a thickness range between 3.4 mm and 4.1 mm.

[0148] As previously described, two independent capacitance measurements were made for each tablet using the first and second capacitance sensors, and their thickness and relative dielectric constant were calculated using the equations described previously.

[0149] The data presented ( Figure 5 , Figure 6 and Figure 7 ) shows a good relationship between the predicted and measured properties, which cannot be achieved with a single capacitance measurement. This demonstrates the functionality of the invention, as both tablet solids fraction and hardness correlate well with the relative dielectric constant.

[0150] Example 2

[0151] In another example, a device having two capacitive sensors arranged in two sensing areas in a tube is used (similar to Figure 3 ), wherein the parallel plates of the second capacitive sensor in the second sensing region are arranged perpendicularly to the parallel plates of the first capacitive sensor in the first sensing region. The device is mounted at an angle of approximately 45° to allow the tablet to pass through the device (along the tube) under the effect of gravity. The same tablet as in Example 1 is used. Capacitance measurements from the two capacitive sensors are obtained. Figure 8 An example of capacitance measurements obtained with one tablet is shown. It was observed that a good signal-to-noise ratio and a high analysis frequency (3 ms per measurement point) were achieved, which based on the size of the sensors used in the example allowed approximately 30 stable measurement points per capacitance sensor as the tablet moved through the tube. In addition, signal isolation of the two sensors was observed, which confirms the feasibility of using the apparatus and method described herein inline in a pharmaceutical tableting process to achieve rapid and high-resolution determination of thickness and solids fraction of pharmaceutical tablets produced by a tablet press.

[0152] Additional description of the invention

[0153] 1. An apparatus for determining the solid fraction and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of sensors in one or more sensing portions.

[0154] 2. A method of determining the solids fraction and thickness of a pharmaceutical tablet using electrical tomography, wherein multiple changes in capacitance are measured in one or more sensor areas as the tablet passes between capacitive sensor plates.

[0155] 3. The method of claim 2, wherein the method uses capacitance measurements at different angles to obtain the physical dimensions of the tablet.

[0156] 4. The method of claim 2, wherein tablet hardness measurements are obtained in a rapid and non-destructive manner.

[0157] 5. The method of claim 2, wherein the method determines the thickness and solid fraction of a pharmaceutical tablet using only electrical tomography data.

[0158] 6. The method of claim 2, which can be implemented inline in a tableting unit and wherein the pharmaceutical tablet does not need to be stopped when passing through the tomographic sensor.

[0159] 7. The method of claim 2, which can be scaled up using multiple devices either in series or in parallel to increase throughput and batch sample representativeness.

[0160] 8. The method of claim 2 using multiple channels and out-of-phase (OoP) techniques to eliminate any proximity interference.

[0161] References

[0162] Beck, M and RA Williams. 1995. Process Tomography: Principles, Techniques and Applications. Edited by Butterworth-Heinemann.

[0163] Beck, M and R Williams. 1996. "Process Tomography: A European Innovation and Its Applications." Measurement Science and Technology 7:215.

[0164] Crowe, CT. 2005. Multiphase Flow Handbook. Edited by CT Crowe, E Michaelides, and JD Schwarzkopf. Boca Raton: CRC Press-Taylor & Francis Group.

[0165] Dickin, F, R Waterfall and R Williams. 1992. “Tomographic Imaging of Industrial Process Equipment: Techniques and Applications.” Circuits, Devices and Systems, IEE Proceedings G 139(I): 72 - 82。

[0166] Dyakowski, T and A J Jaworski. 2003. “Non - Invasive Process Imaging - Principles and Applications of Industrial Process Tomography.” Chemical Engineering & Technology 26(6): 697 - 706

[0167] Müller, J et al. 2012 “Prediction of dissolution time and coating thickness of sustained release formulations using Raman spectroscopy and terahertz pulsed imaging”, Eur J. Pharm and Biopharm 80: 690 - 697

[0168] Peeters et al. 2016, “Assessment and prediction of tablet properties using transmission and backscattering Raman spectroscopy and transmission NIR spectroscopy”, Asian J. Pharm Sci. 11: 547 - 558

[0169] Rimpilainen V., 2012, “Electrical tomography imaging in pharmaceutical processes”, Publications of the University of Eastern Finland, Dissertations in Forestry and Natural Sciences, Issue 68

[0170] Bolton G.T., Primrose K.M., 2005, “An Overview of Electrical Tomographic Measurements in Pharmaceutical and Related Application Areas”, AAPS PharmSciTech 2005; 6(2) Article 21

[0171] Ehrhardt N., Montagne M., Berthiaux H., Dalloz-Dubrujeaud B., Gatumel C., 2005, Chemical Engineering and Processing: Process Intensification Vol. 44, No. 2, February 2005, pp. 303 - 313

Claims

1. An apparatus for obtaining capacitance measurements for determining relative permittivity and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of capacitance sensors in one or more sensing portions, the plurality of capacitance sensors comprising: (i) a first capacitance sensor for obtaining a first capacitance measurement, the first capacitance sensor comprising a first pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the first pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, wherein the first capacitance measurement is obtained when a pharmaceutical tablet is positioned in the gap between the planar surfaces of the first pair of conductive elements in a first orientation relative to the planar surfaces of the first pair of conductive elements; (ii) a second capacitive sensor for obtaining a second capacitance measurement, the second capacitive sensor comprising a second pair of conductive elements, each conductive element having a planar surface, wherein the planar surfaces of the second pair of conductive elements are arranged in parallel such that a capacitance measurement can be obtained from a gap therebetween, wherein the second capacitance measurement is obtained when the pharmaceutical tablet is positioned in the gap between the planar surfaces of the second pair of conductive elements in a second orientation relative to the planar surfaces of the second pair of conductive elements; The device is configured so that the first orientation can be perpendicular to the second orientation, so that in one of the first orientation and the second orientation, the thickness of the drug tablet is parallel to the parallel flat surfaces of the pair of conductive elements, and in the other of the first orientation and the second orientation, the thickness of the drug tablet is perpendicular to the parallel flat surfaces of the pair of conductive elements.

2. The apparatus of claim 1, wherein the arrangement of the parallel planar surfaces of the first pair of conductive elements relative to the parallel planar surfaces of the second pair of conductive elements enables the first orientation to be perpendicular to the second orientation.

3. The device of claim 2, wherein the device comprises a sensing portion in which the planar surfaces of the first pair of conductive elements are arranged perpendicular to the planar surfaces of the second pair of conductive elements.

4. The device of claim 2, wherein the device comprises two sensing portions arranged in series, wherein a first pair of conductive elements is arranged in the first sensing portion and a second pair of conductive elements is arranged in the second sensing portion, wherein the second pair of conductive elements is arranged perpendicular to the first pair of conductive elements.

5. The device of claim 1 , wherein the device comprises two sensing portions arranged in series, wherein a first pair of conductive elements are arranged in the first sensing portion and a second pair of conductive elements are arranged in the second sensing portion, and the device comprises a redirecting element to redirect the drug tablet between a first orientation in the first sensing portion and a second orientation in the second sensing portion when the drug tablet is in the device.

6. The apparatus of claim 5, wherein the redirecting element comprises a funnel.

7. An apparatus as claimed in any preceding claim, wherein the first pair of conductive elements is a first pair of parallel plates and the second pair of conductive elements is a second pair of parallel plates.

8. The apparatus of any one of the preceding claims, wherein the apparatus comprises a connection for connecting to a controller, or comprises a controller, wherein the controller is configured to determine the relative permittivity and thickness of the pharmaceutical tablet using the first and second capacitance measurements.

9. The apparatus of claim 8, wherein the controller includes reference data correlating relative permittivity to solid fraction for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to determine the solid fraction of the pharmaceutical tablet by comparing with the reference data using the determined relative permittivity and the determined thickness of the pharmaceutical tablet.

10. An apparatus as claimed in claim 8 or claim 9, wherein the controller includes reference data correlating relative dielectric constant to hardness for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to determine the hardness of the pharmaceutical tablet by comparing with the reference data using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet.

11. The device of any of the preceding claims, wherein in a first pair of conducting elements the conducting elements have planar surfaces of the same dimensions and / or in a second pair of conducting elements the conducting elements have planar surfaces of the same dimensions.

12. The device of any of the preceding claims, comprising a conduit for a pharmaceutical tablet, in which the one or more sensing portions are arranged, the conduit enabling the pharmaceutical tablet to pass through the device and the one or more sensing portions and enabling the first and second capacitance measurements to be obtained.

13. Apparatus as claimed in any preceding claim, comprising a shield for shielding the plurality of capacitive sensors from fluctuating external conditions, optionally wherein the shield is an electromagnetic shield.

14. A device as claimed in any preceding claim, wherein the device comprises one or more positioning elements to position a pharmaceutical tablet in a gap between planar surfaces of a first pair of conductive elements and / or in a gap between planar surfaces of a second pair of conductive elements.

15. A tableting unit for producing a plurality of pharmaceutical tablets, the tableting unit comprising a tablet manufacturing module and at least one apparatus as claimed in any one of claims 1 to 14, the apparatus being positioned inline downstream of the tablet manufacturing module such that the plurality of pharmaceutical tablets pass through the apparatus to allow a first capacitance measurement and a second capacitance measurement to be obtained.

16. A tableting unit as claimed in claim 15, comprising a plurality of devices as claimed in any one of claims 1 to 14 positioned inline downstream of a tablet manufacturing module, wherein the plurality of devices are arranged in series or in parallel to increase throughput and / or the number of pharmaceutical tablets for which capacitance measurements can be obtained.

17. A tableting unit as claimed in claim 15 or claim 16, wherein the tablet making module comprises a tablet press.

18. A method of determining the relative dielectric constant and thickness of a pharmaceutical tablet using one or more capacitive sensors, wherein each of the one or more capacitive sensors comprises a pair of conductive elements, each conductive element of the pair of conductive elements having a planar surface, wherein the planar surfaces of the pair of conductive elements are arranged in parallel so that a capacitance measurement can be obtained from a gap therebetween, the method comprising: (a) obtaining a first differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between planar surfaces of the pair of conductive elements with and without a pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a first orientation in which a thickness of the pharmaceutical tablet is parallel to the planar surfaces of the pair of conductive elements; (b) obtaining a second differential capacitance measurement using one of the one or more capacitance sensors by measuring capacitance between the planar surfaces of the pair of conductive elements with and without the pharmaceutical tablet positioned in the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned in the gap, the pharmaceutical tablet is in a second orientation in which a thickness of the pharmaceutical tablet is perpendicular to the planar surfaces of the pair of conductive elements; as well as (c) determining a relative dielectric constant and a thickness of the pharmaceutical tablet using the first differential capacitance measurement and the second differential capacitance measurement; Where (a) and (b) are performed in either order.

19. A method of determining the solid fraction and / or hardness of a pharmaceutical tablet, the method comprising: Determining the relative dielectric constant and thickness of the pharmaceutical tablet according to (a) to (c) of claim 18; (d) determining a solid fraction of the pharmaceutical tablet using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet by comparison with reference data, wherein the reference data relates the relative dielectric constant to the solid fraction for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet; and / or (e) determining a hardness of the pharmaceutical tablet using the determined relative dielectric constant and the determined thickness of the pharmaceutical tablet by comparison with reference data, wherein the reference data relates the relative dielectric constant to the hardness for a plurality of reference tablets having different thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet.

20. The method of claim 18 or claim 19, wherein one or more of (c) to (e) is performed on a computer.

21. A method as claimed in any one of claims 18 to 20, wherein the first and second differential capacitance measurements are obtained using one capacitive sensor and the method comprises reorienting the pharmaceutical tablet between a first orientation and a second orientation, or vice versa, between measurements.

22. The method of any one of claims 18 to 20, wherein the one or more capacitive sensors are a first capacitive sensor for obtaining a first differential capacitive measurement and a second capacitive sensor for obtaining a second differential capacitive measurement, the first capacitive sensor comprising a first pair of conductive elements and the second capacitive sensor comprising a second pair of conductive elements.

23. The method of claim 22, wherein the first capacitive sensor and the second capacitive sensor are arranged in one or more sensing portions in the device.

24. The method of claim 23, wherein the first capacitive sensor and the second capacitive sensor are arranged in a sensing portion of the device, wherein the planar surfaces of the first pair of conductive elements are arranged perpendicular to the planar surfaces of the second pair of conductive elements, and the method comprises positioning the pharmaceutical tablet in a first orientation relative to the planar surfaces of the first pair of conductive elements, the first orientation also being the second orientation relative to the planar surfaces of the second pair of conductive elements.

25. The method of claim 23, wherein the first capacitive sensor is disposed in the first sensing portion and the second capacitive sensor is disposed in the second sensing portion, wherein the method comprises reorienting the pharmaceutical tablet between a first orientation and a second orientation or between a second orientation and a first orientation when the pharmaceutical tablet moves between the first sensing portion and the second sensing portion or vice versa.

26. The method of claim 23, wherein the first capacitive sensor is arranged in the first sensing portion and the second capacitive sensor is arranged in the second sensing portion, wherein the planar surfaces of the first pair of conductive elements are arranged perpendicular to the planar surfaces of the second pair of conductive elements, and the method includes moving a pharmaceutical tablet between the first sensing portion and the second sensing portion, or moving the pharmaceutical tablet between the second sensing portion and the first sensing portion.

27. A method as claimed in any one of claims 18 to 26, wherein the pair of conductive elements is a pair of parallel plates.

28. A method as claimed in any one of claims 18 to 27, wherein the pair of conductive elements have planar surfaces of the same dimensions.

29. A method as claimed in any one of claims 18 to 28 comprising obtaining capacitance measurements while the pharmaceutical tablet is at rest.

30. A method as claimed in any one of claims 18 to 28 comprising obtaining capacitance measurements while the pharmaceutical tablet is moving.

31. A method as claimed in any one of claims 18 to 30, comprising using an outphasing technique to eliminate interference with capacitance measurements.

32. The method of any one of claims 18 to 31 , wherein the method is carried out inline in a tableting unit.

33. A pharmaceutical tableting process comprising producing pharmaceutical tablets using a tablet manufacturing module and determining the relative dielectric constant and thickness of the pharmaceutical tablets according to the method of any one of claims 18 to 32.

34. A pharmaceutical tableting process as claimed in claim 33, wherein the tablet manufacturing module comprises a tablet press.

35. Use of the apparatus of any one of claims 1 to 17 for determining the relative dielectric constant and thickness of a pharmaceutical tablet.

36. Use of a device as claimed in claim 35, wherein the relative permittivity and the thickness are determined according to the method of any one of claims 18 to 34.

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