Method and apparatus for determining the thickness and solids fraction of pharmaceutical tablets using non-invasive process electrical tomography

Abstract

The present invention relates to an apparatus for obtaining capacitance measurement values for use in determining the relative permittivity and thickness of pharmaceutical tablets. The present invention further relates to a method for determining the relative permittivity and thickness of pharmaceutical tablets using one or more capacitance sensors. The apparatus and method may be part of a pharmaceutical tablet forming unit or a pharmaceutical tablet forming method.

Description

Technical Field

[0001] The present invention belongs to the technical field of tablet solid fraction. Specifically, the present invention relates to process analytical technology, preferably in-line, for characterizing the thickness and solid fraction in solid dosage forms. Further, hardness measurement is also part of the present invention.

Background Art

[0002] Two main quality characteristics of pharmaceutical tablets - mechanical strength and dissolution kinetics - are governed by the porosity / solid fraction of the compressed material. During tableting, periodic control of tablet characteristics (weight, hardness, thickness and diameter), along with in-process controls of the tablet press (if available), is performed using an instrument such as a multi-tester (either on- or off-line). However, due to the speed of the instrument and the destructive nature of the hardness test, typically only a very small fraction (about 0.01%) of the batch can be determined, which lacks batch representativeness. Due to its important role in tablet characterization, especially in the context of design space applications, it is highly desirable to have PAT tools in place to ensure product quality consistency. Furthermore, in technologies such as continuous manufacturing, these characteristics are frequently used in real-time to infer other important quality attributes such as dissolution performance. Therefore, the availability of continuous and high-speed methods for determining these characteristics is an important resource for monitoring and controlling these processes, an ideal tool for supporting real-time release applications, and an in-process control strategy can be designed based on the availability and frequency of determination of these parameters. As a result, there are numerous scientific papers aimed at measuring the solid fraction by high-speed and non-destructive methods such as terahertz imaging (Muller et al. 2012) or Raman spectroscopy (Peeters et al. 2016), but it is not clear whether they can provide reliable estimates beyond the limitations of each of these technologies. An alternative technology with great potential for providing reliable estimates of the solid fraction is electrical capacitance tomography, which has already been demonstrated to be accurate and reliable in multiphase flows at lower solid fractions. Since capacitance responds to both the volume and mass of the pharmaceutical tablet, it is not straightforward to obtain the solid fraction from capacitance measurements, and therefore additional information about the sample is usually required.

[0003] In the context of using process tomography for the characterization of the final dosage form, a literature survey has identified the following contributions in the field of pharmaceutical processes.

[0004] U.S. Patent No. 4,461,363 relates to a method and apparatus for capacitance measurement of bounded or unbounded objects as they pass between the plates of a capacitor. This apparatus can present several configurations for the purpose of weighing samples, but provides information regarding the solids fraction.

[0005] U.S. Patent Application Publication Nos. 5,135,113 and 5,240,118 show machines for weighing and classifying tablets, particularly at high speed. The main object of these inventions is to provide a high-speed machine for weighing and classifying tablets by capacitance measurement, but information regarding the solids fraction is not captured.

[0006] U.S. Patent No. 10,801,986 shows a monitoring sensor sleeve that channels a measured amount of powder and is used herein for capacitive mass determination.

[0007] WO2019057802 and US2020217811 relate to measuring the solids fraction of pharmaceutical substances. They also present the problems of unknown thickness and solids fraction of pharmaceutical substances. These documents propose using a separate sensor to measure the thickness of the substance. Using a separated distance capacitance sensor is not a viable option because the material composition and density have to be exactly the same across all measurements for its use (this is not true as density variability across substances is what is being sought). The results shown are corrected for the thickness of different tablets, and thus the thickness and solids fraction measurements proposed in this patent are separated and the thickness is measured at an earlier stage.

[0008] EP2407818B1 describes an apparatus for inspecting tablets, comprising a chute, an inclined guide surface, a sensor incorporated in the chute for detecting defective tablets, and a passive piezoelectric bending actuator.

[0009] JP2009047687A describes an apparatus having both NIR for active ingredient inspection and an array of capacitance sensors for inspecting volume. Weight and density can be indirectly inferred from tablet press data and NIR respectively.

[0010] US10565855B2 employs an apparatus that enables automatic monitoring of the state of the drug contents of a blister card through a capacitance sensor by tracking the position of the tablets.

[0011] US20090314944A1 shows an apparatus that uses terahertz radiation non-destructive imaging of the chemical and / or structural characteristics of pharmaceutical tablets containing pharmaceutical active ingredients (API) and excipients (fillers).

[0012] DE2502098 describes using capacitance to compare the measured dielectric value of a tablet with a standard value, thus inferring whether the tablet weight is acceptable. However, this is simply a pass or fail method and does not take into account the variation in the thickness of multiple tablets being measured.

[0013] Furthermore, US7956623B2 describes a container filling machine that includes a sensing device for detecting the integrity of separate articles for personal treatment to be packaged in a container.

[0014] In summary, current methods can only perform qualitative measurements of samples or need to rely on other techniques to perform quantitative solid fraction measurements. Since robustness is important in the pharmaceutical industry, it is not desirable to rely on multiple devices and techniques for single parameter measurements. In contrast to the conventional methods, the present invention provides a quantitative measurement of the solid fraction using only capacitance measurements preferably obtained using a single device, enabling a simpler and more robust instrument.

Summary of the Invention

[0015] In a first aspect, the present invention provides an apparatus for obtaining capacitance measurement values for use in determining the relative permittivity and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of capacitance sensors within one or more sensing sections, the plurality of capacitance sensors comprising: (i) a first capacitance sensor for obtaining a first capacitance measurement value, the first capacitance sensor comprising a first pair of conductive elements each having a flat surface, the flat surfaces of the first pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the first capacitance measurement value being obtained when the pharmaceutical tablet is positioned in the gap between the flat surfaces of the first pair of conductive elements in a first orientation with respect to the flat surfaces of the first pair of conductive elements; (ii) a second capacitance sensor for obtaining a second capacitance measurement value, the second capacitance sensor comprising a second pair of conductive elements each having a flat surface, the flat surfaces of the second pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the second capacitance measurement value being obtained when the pharmaceutical tablet is positioned in the gap between the flat surfaces of the second pair of conductive elements in a second orientation with respect to the flat surfaces of the second pair of conductive elements; The apparatus is configured to enable the first orientation to be 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, 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.

[0016] In one example, the arrangement of the parallel flat surfaces of the first pair of conductive elements with respect to the parallel flat surfaces of the second pair of conductive elements allows the first orientation to be perpendicular to the second orientation. In particular, the device may comprise one sensing section in which the flat surfaces of the first pair of conductive elements are arranged perpendicular to the flat surfaces of the second pair of conductive elements. Alternatively, the device may comprise two sensing parts arranged in series, the first pair of conductive elements being arranged in the first sensing part, the second pair of conductive elements being arranged in the second sensing part, and the second pair of conductive elements being arranged perpendicular to the first pair of conductive elements.

[0017] In a further example, the device may comprise two detection parts arranged in series, the first pair of conductive elements being arranged in the first detection part, the second pair of conductive elements being arranged in the second detection part, and the device comprising a reorientation element for reorienting the pharmaceutical tablet between the first orientation in the first detection part and the second orientation in the second detection part when the device is within the device. The reorientation element can include, for example, a funnel.

[0018] In this device, the first pair of conductive elements are the first pair of parallel plates and the second pair of conductive elements are the second pair of parallel plates.

[0019] In a further embodiment, the device may comprise a connection for connection to a controller or may comprise a controller, the controller being configured to use the first and second capacitance measurements to determine the relative permittivity and thickness of the pharmaceutical tablet.

[0020] In particular, the controller can include reference data correlating the relative permittivity with the solids fraction for a plurality of reference tablets of various thicknesses having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to determine the solids fraction of the pharmaceutical tablet using the determined relative permittivity and determined thickness of the pharmaceutical tablet by comparison with the reference data.

[0021] Additionally, or alternatively, the controller includes reference data correlating the relative permittivity with hardness for a plurality of reference tablets of varying thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablets, and the controller is configured to determine the hardness of the pharmaceutical tablets using the determined relative permittivity and determined thickness of the pharmaceutical tablets by comparison with the reference data.

[0022] In one embodiment of the apparatus, in the first pair of conductive elements, the conductive elements have flat surfaces of the same dimensions, and / or in the second pair of conductive elements, the conductive elements have flat surfaces of the same dimensions.

[0023] In a further embodiment, the apparatus comprises a conduit for a pharmaceutical tablet in which one or more sensing sections are arranged, the conduit enabling the pharmaceutical tablet to pass through the apparatus and one or more sensing sections such that a first capacitance measurement and a second capacitance measurement are obtained.

[0024] The apparatus may comprise a shielding for shielding the plurality of capacitance sensors from variations in external conditions, and optionally, the shielding is electromagnetic shielding.

[0025] The apparatus may also comprise one or more positioning elements for positioning the pharmaceutical tablet within the gap between the flat surfaces of the first pair of conductive elements and / or within the gap between the flat surfaces of the second pair of conductive elements.

[0026] In a further aspect, the present invention provides a tableting unit for manufacturing a plurality of pharmaceutical tablets, the tableting unit including a tableting module (e.g., including a tableting press) and at least one such apparatus arranged in-line downstream of the tableting module, such that a plurality of pharmaceutical tablets can pass through the apparatus to obtain a first capacitance measurement and a second capacitance measurement. The tableting unit may comprise a plurality of apparatuses arranged in-line downstream of the tableting module, the plurality of apparatuses being arranged in series or in parallel to increase the throughput and / or the number of pharmaceutical tablets for which capacitance measurements can be obtained.

[0027] A further aspect of the present invention is a method for determining the relative permittivity and thickness of a pharmaceutical tablet using one or more capacitance sensors, each of the one or more capacitance sensors comprising a pair of conductive elements, each conductive element of the pair having a flat surface, the flat surfaces of the pair of conductive elements being arranged in parallel such that capacitance measurements can be obtained from the gap therebetween, the method comprising: (a) obtaining a first differential capacitance measurement by measuring the capacitance between the flat surfaces of the pair of conductive elements with one of the one or more capacitance sensors, with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, wherein when the capacitance is measured using the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a first orientation in which the thickness of the pharmaceutical tablet is parallel to the flat surfaces of the pair of conductive elements; (b) obtaining a second differential capacitance measurement by measuring the capacitance between the flat surfaces of the pair of conductive elements with one of the one or more capacitance sensors, with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, wherein when the capacitance is measured using the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a second orientation in which the thickness of the pharmaceutical tablet is perpendicular to the flat surfaces of the pair of conductive elements; (c) determining the relative permittivity and thickness of the pharmaceutical tablet using the first and second differential capacitance measurements; and (a) and (b) are performed in either order.

[0028] 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 the steps of: determining the relative permittivity and thickness of the pharmaceutical tablet according to (a)-(c) of the above aspect; using the determined relative permittivity and determined thickness of the pharmaceutical tablet to determine the solid fraction of the pharmaceutical tablet by comparison with reference data, wherein the reference data correlates the relative permittivity with the solid fraction for a plurality of reference tablets having the same chemical composition and other dimensions as the pharmaceutical tablet but different thicknesses; and / or using the determined relative permittivity and determined thickness of the pharmaceutical tablet to determine the hardness of the pharmaceutical tablet, wherein the reference data correlates the relative permittivity with the hardness for a plurality of reference tablets having the same chemical composition and other dimensions as the pharmaceutical tablet but different thicknesses.

[0029] In particular, in the above method, one or more of (c)-(e) can be executed on a computer.

[0030] In one embodiment of the above method, one capacitance sensor is used to obtain a first differential capacitance measurement and a second differential capacitance measurement, and the method includes the step of reorienting the pharmaceutical tablet between the first orientation and the second orientation, or vice versa, between the measurements.

[0031] In an alternative embodiment of the above method, the one or more capacitance sensors are a first capacitance sensor for obtaining a first differential capacitance measurement and a second capacitance sensor for obtaining a second differential capacitance measurement, the first capacitance sensor comprising a first pair of conductive elements and the second capacitance sensor comprising a second pair of conductive elements.

[0032] In particular, the first capacitance sensor and the second capacitance sensor can be arranged within the device in one or more sensing sections.

[0033] For example, the first capacitance sensor and the second capacitance sensor may be disposed within the device in one sensing section where the flat surfaces of the first pair of conductive elements are disposed perpendicular to the flat surfaces of the second pair of conductive elements, and the method includes positioning the pharmaceutical tablet in a first orientation with respect to the flat surface of the first pair of conductive elements, which is also a second orientation with respect to the flat surface of the second pair of conductive elements.

[0034] In another example, the first capacitance sensor is disposed in a first sensing section, the second capacitance sensor is disposed in a second sensing section, and the method includes reorienting the pharmaceutical tablet between a first orientation and a second orientation, or between the second orientation and the first orientation, as the pharmaceutical tablet is moved between the first sensing section and the second sensing section, and vice versa.

[0035] In a further example, the first capacitance sensor is disposed in a first sensing section, the second capacitance sensor is disposed in a second sensing section, the flat surfaces of the first pair of conductive elements are disposed perpendicular to the flat surfaces of the second pair of conductive elements, and the method includes moving the pharmaceutical tablet between the first sensing section and the second sensing section, or between the second sensing section and the first sensing section.

[0036] In one embodiment of the method, the pair of conductive elements is a pair of parallel plates.

[0037] In a further embodiment of the method, the pair of conductive elements has flat surfaces of the same dimensions.

[0038] The method can include obtaining capacitance measurements while the pharmaceutical tablet is stationary, optionally while the pharmaceutical tablet is stationary within one or more sensing sections.

[0039] Alternatively, the method may include obtaining capacitance measurements while the pharmaceutical tablet is moving, and optionally, the pharmaceutical tablet is moving through one or more sensing sections.

[0040] The method may include the step of using a phase offset technique to eliminate interference with capacitance measurement.

[0041] The method may be implemented inline in a tabletting unit.

[0042] In yet another aspect, the present invention provides a pharmaceutical tabletting method including the step of manufacturing a pharmaceutical tablet using a tablet manufacturing module, and the step of determining the relative dielectric constant and thickness of the pharmaceutical tablet according to the above method. In particular, the tablet manufacturing module may comprise a tablet press.

[0043] In a further aspect, the present invention provides the use of the above-described apparatus for determining the relative dielectric constant and thickness of a pharmaceutical tablet. In particular, the use may be such that the relative dielectric constant and thickness are determined according to the above method.

[0044] In particular, in one aspect, the present invention discloses an inline, high-speed and non-destructive quantitative measurement method and apparatus based on electrical tomography for determining the solid fraction and thickness of tablets in a pharmaceutical tabletting process. Tablet hardness can also be inferred by a non-destructive method. The apparatus can comprise (or consist of) a plurality of sensors in one or more sensing sections that can be used to obtain high-speed, non-invasive and non-destructive inline measurements that can be used to determine the thickness and solid fraction of the tablet.

[0045] The present invention uses only electrical tomography to determine these quantities and does not require additional apparatus and techniques.

[0046] Regarding its use, when installed at the outlet of a tablet press, the device of the present invention guarantees the quality of the pharmaceutical tableting process throughout the batch, increases sample representativeness, while reducing the need for destructive offline experiments, and can facilitate the implementation of real-time release due to the information it can generate. Also, this device has the potential to be an important and extensive tool in the definition of control strategies for some applications (e.g., continuous manufacturing). Destructive and sporadic tablet analysis can be replaced by non-destructive and high-frequency measurements.

[0047] For increased throughput and scale-up, multiple devices can be installed either in series or in parallel to increase the representativeness of batch samples (i.e., sample analysis across the entire batch).

Brief Description of the Drawings

[0048] To assist in the understanding of the present disclosure and to show how embodiments can be implemented, reference is made by way of example to the accompanying drawings.

[0049]

Figure 1

Figure 2

Figure 3

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Figure 8

Mode for Carrying Out the Invention

[0050] The description of the present invention provided herein uses the terms "first" and "second" which refer to, for example, "first capacitance sensor", "second capacitance sensor", "first capacitance measurement", and "second capacitance measurement". The use of the terms "first" and "second" herein is for identification purposes only and does not refer to the order of use or the order in which the described method steps should be performed. In particular, the "first capacitance sensor" and "second capacitance sensor" in the device described herein may be for use in any order to obtain capacitance measurement values, may be arranged in series in the device in any order, and in the method described herein, the "first capacitance measurement value" and "second capacitance measurement value" may be obtained in any order.

[0051] The present invention can implement a non-destructive in-line quantification method for determining the relative permittivity and thickness of pharmaceutical tablets, which can infer the solid content fraction and hardness of the tablets, for example, in the tablet forming process of pharmaceuticals, and discloses a high-resolution electrical tomography-based device.

[0052] In a first aspect, the present invention provides an apparatus for obtaining capacitance measurement values for use in determining the relative permittivity and thickness of pharmaceutical tablets, the apparatus comprising a plurality of capacitance sensors within one or more sensing sections, the plurality of capacitance sensors being (i) A first capacitance sensor for obtaining a first capacitance measurement value, the first capacitance sensor comprising a first pair of conductive elements each having a flat surface, the flat surfaces of the first pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the first capacitance measurement value being obtained when a pharmaceutical tablet is positioned in the gap between the flat surfaces of the first pair of conductive elements in a first orientation with respect to the flat surfaces of the first pair of conductive elements, the first capacitance sensor; (ii) A second capacitance sensor for obtaining a second capacitance measurement value, the second capacitance sensor comprising a second pair of conductive elements each having a flat surface, the flat surfaces of the second pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the second capacitance measurement value being obtained when the pharmaceutical tablet is positioned within the gap between the flat surfaces of the second pair of conductive elements in a second orientation with respect to the flat surfaces of the second pair of conductive elements, the second capacitance sensor; and The apparatus is configured to enable the first orientation to be 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, 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.

[0053] As described above, the capacitance sensors used in the apparatus each comprise a pair of conductive elements each having a flat surface, the flat surfaces being arranged in parallel with a gap (or operating space) therebetween from which a capacitance measurement value can be obtained. The conductive elements may be any 3D structure having a flat surface, but preferably, the pair of conductive elements is two parallel plates.

[0054] The flat surfaces may be of any shape, such as rectangular, square, circular, or ring-shaped.

[0055] The flat surfaces of the conductive elements have an area (A) and are arranged parallel to each other, separated by a distance (d) that defines a gap between the flat surfaces. Preferably, the flat surfaces of the conductive elements have the same dimensions as the flat surfaces of the other conductive elements of the same pair.

[0056] Preferably, the area (A) and the distance (d) of the first pair of conductive elements are the same as the area (A) and the distance (d) of the second pair of conductive elements.

[0057] The accuracy of the measurement values obtained by the capacitance sensor can be improved or optimized by minimizing the free space around the pharmaceutical tablet when the pharmaceutical tablet is placed within the gap in the first orientation and / or the second orientation.

[0058] To obtain capacitance measurements, the conductive elements are connected to a power source to generate an electric field within the gap between the flat surfaces of the conductive elements and to obtain capacitance measurement values from the gap.

[0059] The first and second capacitance measurement values are obtained using the device when the pharmaceutical tablet is in a first orientation with respect to the parallel flat surfaces of the first pair of conductive elements and when the pharmaceutical tablet is in a second orientation with respect to the parallel flat surfaces of the second pair of conductive elements. In particular, the device is configured to enable the first orientation to be perpendicular to the second orientation, such that as a result, 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 capacitance sensor from which the measurement values are obtained, 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 capacitance sensor from which the measurement values are obtained. 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 tablet.

[0060] As used herein, the term "perpendicular" refers to 90° ± 5°, preferably 90° ± 2°, more preferably 90° ± 1°, and most preferably 90° ± 0.5° in order to obtain the determination of the relative permittivity and thickness of the pharmaceutical tablet as accurately as possible.

[0061] In particular, some variability around the 90° angle is acceptable and may be required due to limitations in sensor / device manufacturing. However, the most accurate determination is considered to be obtained at an angle as close as possible to 90°.

[0062] Similarly, the term "parallel" as used herein includes variations of ± 5° from parallel, preferably ± 2° from parallel, more preferably ± 1°, and most preferably ± 0.5°. Again, it is considered that the accuracy is improved by keeping this variation as low as possible.

[0063] Examples of suitable configurations of the first and second capacitance sensors within the device to enable these capacitance measurements are shown in FIGS. 1 to 3.

[0064] In the method of the present invention, as will be described below, two capacitance measurements can be obtained by one capacitance sensor, and the orientation of the pharmaceutical tablet with respect to the flat surface of the conductive element of the capacitance sensor changes between a first orientation and a second orientation, or vice versa, between different capacitance measurements. This can be done by hand or using a machine.

[0065] However, the device described herein comprises two capacitance sensors, namely a first capacitance sensor for obtaining a first capacitance measurement and a second capacitance sensor for obtaining a second capacitance measurement.

[0066] The two capacitance sensors may be arranged in parallel in one sensing section, for example, as shown in FIGS. 1 and 2. In this configuration, the device may be box-shaped. In particular, FIG. 1 shows an example of a device having one sensing section in which the parallel flat surfaces of the first pair of conductive elements (1a and 1b) are arranged perpendicular to the parallel flat surfaces of the second pair of conductive elements (2a and 2b). In this example, in the first orientation (where measurement 1 in FIG. 2 is performed), the thickness (t) of the pharmaceutical tablet (3) is perpendicular to the parallel flat surfaces of the first pair of conductive elements, and in the second orientation (where measurement 2 in FIG. 2 is performed), the thickness (t) of the pharmaceutical tablet (3) is parallel to the parallel flat surfaces of the second pair of conductive elements.

[0067] Alternatively, the two capacitance sensors may be arranged in series in two detection parts. The sensing sections may be directly adjacent, or may be two separate sensing sections or regions. A schematic diagram of a possible configuration using two separate sensing regions is shown in FIG. 3. In particular, FIG. 3 shows an example of a device having two sensing sections in which the parallel flat surfaces of the first pair of conductive elements (1a and 1b) are arranged perpendicular to the parallel flat surfaces of the second pair of conductive elements (2a and 2b). In this example, in the first orientation of the pharmaceutical tablet (as indicated by the tablet shown between conductive elements 1a and 1b), the thickness (d t ) of the pharmaceutical tablet (3) is perpendicular to the parallel flat surfaces of the first pair of conductive elements, and the capacitance streamlines are parallel to the thickness (d t ). In the second orientation of the pharmaceutical tablet (as indicated by the tablet shown between conductive elements 2a and 2b), the thickness (d t ) of the pharmaceutical tablet (3) is parallel to the parallel flat surfaces of the first pair of conductive elements, and the capacitance streamlines are perpendicular to the thickness (d t ).

[0068] The device may be configured to enable the first and second capacitance measurements to be perpendicular to each other as described above through the arrangement of the parallel flat surfaces of the second conductive element with respect to the parallel flat surfaces of the first conductive element. For example, as in the embodiments shown in FIGS. 1 and 3, the parallel flat surfaces of the first pair of conductive elements may be arranged perpendicular to the parallel flat surfaces of the second pair of conductive elements. For example, one capacitance sensor may have its conductive elements on each side of an opening or conduit, and the other may have its conductive elements at the top and bottom of the opening or conduit.

[0069] Alternatively, when the device comprises two sensing parts arranged in series, the first and the second sensing parts, the device may be configured to enable the first and second capacitance measurements to be perpendicular to each other by comprising a reorientation element that reorients the pharmaceutical tablet between the first and the second sensing parts, or vice versa, depending on the sensing part into which the pharmaceutical tablet first enters. (As described above, this may be in any order.) The reorientation element may comprise a funnel or other mechanical means.

[0070] The device may be configured to perform capacitance measurements while the pharmaceutical tablet is stationary within one or more sensing parts, or while the pharmaceutical tablet is moving within one or more sensing parts. In particular, the device may comprise a conduit (e.g., a tube) that enables the pharmaceutical tablet to pass through one or more sensing parts. The conduit may be horizontal or may be angled with respect to the ground. For example, the conduit (e.g., a tube) may be horizontal to ensure that the pharmaceutical tablet is stationary within one or more sensing parts, or may be angled with respect to the ground to enable the pharmaceutical tablet to move through one or more sensing parts under the influence of gravity. Preferably, the conduit is at an angle such that the pharmaceutical tablet moves rapidly through one or more sensing sections to ensure high throughput. As an alternative means, for example when the conduit is horizontal, the pharmaceutical tablet can also be moved through one or more sensing sections. Such means include, for example, a conveyor or a pneumatic system.

[0071] As the pharmaceutical tablet moves through the device, multiple capacitance measurements can be obtained as the pharmaceutical tablet passes through the gap between the flat surfaces of the conductive elements (in a first or second direction), as further explained below.

[0072] The order of the first and second capacitance measurements is not relevant, especially since both are used together to solve the system of equations described below.

[0073] The device may comprise a connection for connection to a controller. Further, the device can comprise a controller configured to determine the relative permittivity and thickness of the pharmaceutical tablet using the first and second capacitance measurements obtained using the device. For example, the device may comprise an integrated chip.

[0074] In particular, the controller can include reference data correlating the relative permittivity with the solid fraction for a plurality of reference tablets having various thicknesses and the same chemical composition and other dimensions as the pharmaceutical tablet. For example, when the pharmaceutical tablet is manufactured by a tablet press, the area of the upper surface of the pharmaceutical tablet is known as it is determined by the punch installed in the press, and for example, for a circular tablet, the circular surface area of the tablet is known. The reference data can include a set 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 permittivities and tablet thicknesses that correlate with the solid fraction and / or hardness. Such a reference data set can be established using existing offline methods. (For example, the thickness of the reference tablet can be determined using a multi-tester device such as those currently used in commercial pharmaceutical tablet manufacturing processes, and the hardness can be determined using conventional fracture tests.)

[0075] The controller may also be configured to determine the solid fraction and / or hardness of the pharmaceutical tablet using the determined relative permittivity and the determined thickness of the pharmaceutical tablet by comparison with the reference data.

[0076] The device can be configured to eliminate interference such as the proximity of a person who is near or in contact with the device, using a plurality of channels that enable the use of out-of-phase (OoP) techniques. Using this technology, the measurements can be asynchronous. The device may include one or more environmental reference sensors to help compensate for environmental changes. The device may also include a shield, optionally an electromagnetic shield, to protect the capacitance sensor from variations in external conditions. The shielding may be active or passive. An example of a passive shield is a layer made of a metal such as tin.

[0077] The device can also include positioning elements for positioning a pharmaceutical tablet within the gap between the flat surfaces of the first pair of conductive elements and / or within the gap between the flat surfaces of the second pair of conductive elements. The positioning elements may be used to ensure that the tablet (if not circular) is properly aligned with the conductive elements of the sensor. In particular, the positioning elements may be a funnel or a chute, and may ensure that the pharmaceutical tablet is positioned at a certain distance from the flat surface of the conductive element.

[0078] In an alternative, alignment of the tablet with the flat surface of the conductive element can use a force, such as a centripetal force or gravity.

[0079] The device may include a positioning sensor for detecting the position of the pharmaceutical tablet. In particular, if alignment is not guaranteed, more tomographic measurements can be used to detect the position of the pharmaceutical tablet.

[0080] The positioning element may be a reorientation element as described above. For example, the apparatus may include a first positioning element that ensures that a pharmaceutical tablet (otherwise in a first orientation) is (directly) aligned with a parallel flat surface of a conductive element of a first capacitance sensor within a first sensing unit, and a second positioning element that reorients the pharmaceutical tablet from the first orientation to a second orientation in front of a second sensing unit and ensures that the pharmaceutical tablet in the second orientation is aligned with a parallel flat surface of a conductive element of a second capacitance sensor.

[0081] As is known in the art, it is preferred that the apparatus be arranged such that the position of the pharmaceutical tablet is away from the edge of the conductive element due to the fringe effect of capacitance.

[0082] As described above, the apparatus of the present invention is particularly useful in-line in the pharmaceutical tablet manufacturing process. Thus, in a further aspect, the present invention provides a tableting unit for manufacturing a plurality of pharmaceutical tablets, the tableting unit comprising a tablet manufacturing module and at least one apparatus as described herein arranged in-line downstream of the tablet manufacturing module, such that a plurality of pharmaceutical tablets can pass through the apparatus to obtain a first capacitance measurement and a second capacitance measurement. The tableting unit may include a plurality of apparatuses as described herein arranged in series or in parallel. In particular, this increases the throughput and / or the number of pharmaceutical tablets evaluated by the apparatus. Preferably, the tablet manufacturing module is a tablet press.

[0083] The tableting unit may further include sorting means for sorting the pharmaceutical tablets based on a determined thickness, solids fraction, and / or hardness.

[0084] The tableting unit may further comprise a feedback system for adjusting the manufacturing parameters of the tablet manufacturing module based on a determined thickness, solids fraction, and / or hardness.

[0085] The pharmaceutical tablet can have any composition or shape. For example, the pharmaceutical tablet can be circular, rectangular, elliptical or torpedo-shaped. In a preferred embodiment, the pharmaceutical tablet is circular.

[0086] The pharmaceutical tablet is preferably manufactured from a tablet press. In particular, as described above, the pharmaceutical tablet from the tablet press has a known surface area (determined by the shape of the punch installed in the press), and the method is particularly useful in determining the thickness of such tablets.

[0087] The above-described apparatus can be used to (statically or dynamically) independently perform high-resolution capacitance measurements of a pharmaceutical tablet (i.e., the object of interest) located between the conductive elements of the first and second capacitance sensors. Thus, two types of signals are obtained, which can then be correlated with different properties of the tablet. Since the relative permittivity of the sample is the same, it is possible to determine both the thickness and the solid fraction (and the hardness can also be inferred). This design allows a single technique (electrical tomography) to be used to extract all the necessary information about the tablet without relying on other techniques or additional equipment, resulting in a simpler and more compact device, which is an important part of the present invention.

[0088] In a further aspect, the present invention provides a method for determining the relative permittivity and thickness of a pharmaceutical tablet using one or more capacitance sensors, each of the one or more capacitance sensors comprising a pair of conductive elements, each conductive element of the pair having a flat surface, the flat surfaces of the pair of conductive elements being arranged in parallel such that the capacitance measurements can be obtained from the gap between them, the method comprising (a) Using one of the one or more capacitance sensors, measuring the capacitance between the flat surfaces of the pair of conductive elements with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, thereby obtaining a first differential capacitance measurement value, wherein when the capacitance is measured using the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a first orientation in which the thickness of the pharmaceutical tablet is parallel to the flat surfaces of the pair of conductive elements; (b) Using one of the one or more capacitance sensors, measuring the capacitance between the flat surfaces of the pair of conductive elements with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, thereby obtaining a second differential capacitance measurement value, wherein when the capacitance is measured using the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a second orientation in which the thickness of the pharmaceutical tablet is perpendicular to the flat surfaces of the pair of conductive elements; (c) Using the first and second differential capacitance measurement values to determine the relative permittivity and thickness of the pharmaceutical tablet; (a) and (b) are performed in either order.

[0089] A further aspect is a method for determining the solids fraction and / or hardness of a pharmaceutical tablet, the method comprising determining the relative permittivity and thickness of the pharmaceutical tablet according to the method of the above paragraph; and (d) determining the solids fraction of the pharmaceutical tablet using the determined relative permittivity and determined thickness of the pharmaceutical tablet by comparison with reference data, the reference data correlating the relative permittivity with the solids fraction for a plurality of reference tablets having the same chemical composition and other dimensions as the pharmaceutical tablet but different thicknesses; and / or (e) determining the hardness of the pharmaceutical tablet using the determined relative permittivity and determined thickness of the pharmaceutical tablet, the reference data correlating the relative permittivity with the solids fraction for a plurality of reference tablets having the same chemical composition and other dimensions as the pharmaceutical tablet but different thicknesses.

[0090] In a preferred embodiment, one or more of the above steps (c) to (e) are executed on a computer or a controller.

[0091] The description of the features of the present invention provided above in relation to the apparatus also applies to the same features recited in the method of the present invention. However, as described above, in one embodiment of the method of the present invention, one capacitance sensor is used to obtain both a first differential capacitance measurement and a second differential capacitance measurement, and between measurements, the pharmaceutical tablet is moved between a first orientation and a second orientation (or vice versa).

[0092] The method may include one or more steps of placing a pharmaceutical tablet in a gap between flat surfaces of a pair of conductive elements. In particular, the positioning step can be used to align the pharmaceutical tablet with the flat surface of the conductive element of the capacitor so that it is straight. If the pharmaceutical tablet is circular, such positioning for aligning the tablet is not required.

[0093] In one example of the present invention, the above-described apparatus is used to execute the method.

[0094] The method may include the step of using a heterophase technique as described above to eliminate any interference in the capacitance measurement from the external environment of the capacitance sensor. Appropriate techniques are known in the art from the use of capacitance sensing to determine the height of a liquid in a tank or container.

[0095] In this method, the step of obtaining the capacitance measurement can be performed while the pharmaceutical tablet is stationary within one or more sensing sections or while the pharmaceutical tablet is moving through one or more sensing sections. Preferably, this method is implemented using tablets moving through one or more sensing sections as it provides a higher throughput. High throughput is required if this method is used inline in the pharmaceutical tablet manufacturing process.

[0096] In particular, in one embodiment, the method is carried out inline in the tabletting unit.

[0097] Accordingly, in a further aspect, the present invention provides a pharmaceutical tabletting process comprising the step of manufacturing a pharmaceutical tablet using a tabletting module and the step of determining the relative permittivity and thickness of the pharmaceutical tablet according to the method described herein. Preferably, the tabletting module comprises a tableting press.

[0098] In the method described herein, once the solids fraction and / or hardness have been determined, this information can be further used to sort the tablets and / or to adjust the manufacturing parameters of the tabletting module, such as a tableting press, via a feedback loop. Accordingly, the method described herein may include the step of sorting the pharmaceutical tablets according to the determined thickness, solids fraction and / or hardness, and / or the step of adjusting the manufacturing parameters of the tabletting module that manufactured the pharmaceutical tablets to change the thickness, solids fraction and / or hardness of the subsequently manufactured tablets.

[0099] The method enables the determination of the thickness using a tomography sensor because of specific measurement conditions, namely the orientation of the pharmaceutical tablet with respect to the flat surface of the conductive element during the first and second capacitance measurements, which cannot be derived in an obvious way from the prior art.

[0100] The determination of the relative permittivity and thickness is further explained as follows.

[0101] Determination of relative permittivity

[0102] Capacitance measurements are useful in this application because the sensors respond to the mass, density, and volume of the material present between the plates. Thus, by the difference, it is possible to obtain the capacitance of the material located between the parallel plates.

[0103] The capacitance of parallel plates having the same dimensions is described by the following equation.

Number

[0104] Since the sample only occupies a part of the gap between the sensor plates, in order to obtain a representative equation of the system, it is necessary to apply the equations of series and parallel capacitors. By using differential measurement between the sensor with the sample and the sensor without the sample, the following equation can be obtained.

Number

[0105] By rearranging (Equation 2), it is possible to derive the relative permittivity directly related to the solid content and hardness of the tablet using a simple calibration.

Number

[0106] Determination of Thickness

[0107] The design and characteristics of the sensor plates are well known and are part of the construction of the device-gap distance (d) and the permittivity of vacuum (ε0). The area of the tablet (A t ) is also known and depends only on the punch attached to the press and used to manufacture the tablet.

[0108] To estimate the solid fraction, the thickness of the pharmaceutical tablet is required. This value is not constant for all tablets produced (e.g., from a tablet press) as there are non - negligible variations between tablets. Therefore, determination of the thickness is an important part of the present invention.

[0109] The present invention proposes using another (second or further) capacitance measurement to be able to estimate the thickness. This enables the use of a single technique to extract all the necessary information from the tablets without relying on other techniques, resulting in a simpler and more compact device.

[0110] An equation for determining the general tablet thickness can be estimated. Therefore, · Assuming thickness t, width b (a second measurement perpendicular to the width of the tablet) and length a,

Equation

[0111] Similar equations can be obtained for all tablet shapes and sizes.

[0112] Determination of solid fraction and hardness

[0113] Next, using the relative permittivity and thickness determined for the pharmaceutical tablets, the solid fraction and / or hardness of the pharmaceutical tablets is / are determined.

[0114] For each type of pharmaceutical tablet (having a specific composition as well as specific dimensions and shape), a reference dataset related to a plurality of reference tablets can be created. This dataset correlates the relative permittivity to values of the solid fraction and / or hardness for a plurality of reference tablets having various thicknesses (each reference tablet having a different thickness). Thus, using the relative permittivity and thickness determined for the pharmaceutical tablets, the values of the solid fraction and / or hardness can be determined through correlation with the reference dataset.

[0115] The following is intended as an example only and does not limit the present disclosure.

[0116] Example 1

[0117] The prototype of the present invention was used, which has two capacitance sensors arranged in one sensing section (similar to FIG. 1), and the parallel plates of the first capacitance sensor are arranged perpendicular to the parallel plates of the second capacitance sensor. The prototype was tested using placebo pharmaceutical tablets. The tablets tested were circular, with a mass range of 121 g to 132 g and a thickness range of 3.4 mm to 4.1 mm.

[0118] As described above, using the first and second capacitance sensors, two independent capacitance measurements were made for each tablet, and the aforementioned equations were applied to calculate their thickness and relative permittivity.

[0119] The presented data (FIGS. 5, 6, and 7) shows a good relationship between the predicted and measured characteristics, which would not be achieved with a single capacitance measurement. This demonstrates the functionality of the present invention since both the solid fraction and hardness of the tablets correlate well with the relative permittivity.

[0120] Example 2

[0121] In another example, a device having two capacitance sensors disposed within two sensing regions in a tube (similar to FIG. 3) is used, and the parallel plates of the second capacitance sensor in the second sensing region are arranged perpendicular to the parallel plates of the first capacitance sensor in the first sensing region. The device was installed at an angle of approximately 45° to allow the tablet to pass through the device under the influence of gravity (along the tube). The same tablets as in Example 1 were used. Capacitance measurements from the two capacitance sensors were obtained. FIG. 8 shows an example of the capacitance measurements obtained for one tablet. 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, allows for approximately 30 stable measurement points per capacitance sensor as the tablet moves through the tube. In addition, signal separation of both sensors was also observed, which confirms the feasibility of using the apparatus and method described herein inline in the pharmaceutical tablet manufacturing process to achieve a fast and high-resolution determination of the thickness and solid fraction of pharmaceutical tablets produced by a tablet press.

[0122] References Beck, M, and RA Williams. 1995. Process Tomography: Principles, Techniques and Applications. Edited by Butterworth-Heinemann. Beck, M, and R Williams. 1996. “Process Tomography: A European Innovation and Its Applications.” Measurement Science and Technology 7: 215. Crowe, CT. 2005. Multiphase Flow Handbook. Edited by CT Crowe, E Michaelides, and JD Schwarzkopf. Boca Raton: CRC Press - Taylor & Francis Group. 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. Dyakowski, T, and AJ Jaworski. 2003. “Non-Invasive Process Imaging-Principles and Applications of Industrial Process Tomography.” Chemical Engineering & Technology 26 (6): 697-706 Muller, 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 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 Rimpilainen V., 2012, “Electrical tomography imaging in pharmaceutical processes”, Publications of the University of Eastern Finland, Dissertations in Forestry and Natural Sciences, No 68 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 Ehrhardt N., Montagne M., Berthiaux H., Dalloz-Dubrujeaud B., Gatumel C., 2005, Chemical Engineering and Processing: Process Intensification Volume 44, Issue 2, February 2005, Pages 303-313

Claims

1. An apparatus for obtaining capacitance measurement values for use in determining the relative permittivity and thickness of a pharmaceutical tablet, the apparatus comprising a plurality of capacitance sensors within one or more sensing sections, the plurality of capacitance sensors comprising: (i) a first capacitance sensor for obtaining a first capacitance measurement value, the first capacitance sensor comprising a first pair of conductive elements each having a flat surface, the flat surfaces of the first pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the first capacitance measurement value being obtained when the pharmaceutical tablet is positioned within the gap between the flat surfaces of the first pair of conductive elements in a first orientation with respect to the flat surfaces of the first pair of conductive elements; a first capacitance sensor; (ii) a second capacitance sensor for obtaining a second capacitance measurement value, the second capacitance sensor comprising a second pair of conductive elements each having a flat surface, the flat surfaces of the second pair of conductive elements being arranged in parallel such that a capacitance measurement value can be obtained from the gap therebetween, the second capacitance measurement value being obtained when the pharmaceutical tablet is positioned within the gap between the flat surfaces of the second pair of conductive elements in a second orientation with respect to the flat surfaces of the second pair of conductive elements; a second capacitance sensor; The apparatus is configured such that the thickness of the pharmaceutical tablet is parallel to the parallel flat surfaces of a pair of conductive elements in one of the first orientation and the second orientation, and the thickness of the pharmaceutical tablet is perpendicular to the parallel flat surfaces of the pair of conductive elements in the other of the first orientation and the second orientation, such that the first orientation is perpendicular to the second orientation. An apparatus.

2. The arrangement of the parallel flat surfaces of the first pair of conductive elements with respect to the parallel flat surfaces of the second pair of conductive elements enables the first orientation to be perpendicular to the second orientation. The apparatus according to claim 1.

3. The apparatus according to claim 2, comprising one sensing section in which the flat surfaces of the first pair of conductive elements are arranged perpendicular to the flat surfaces of the second pair of conductive elements.

4. The device comprises two sensing sections arranged in series, the first pair of conductive elements being arranged in the first sensing section, the second pair of conductive elements being arranged in the second sensing section, and the second pair of conductive elements being arranged perpendicular to the first pair of conductive elements. The device according to claim 2.

5. The device comprises two sensing sections arranged in series, the first pair of conductive elements being arranged in the first sensing section, the second pair of conductive elements being arranged in the second sensing section, and the device comprising a reorientation element for reorienting the pharmaceutical tablet between the first orientation in the first sensing section and the second orientation in the second sensing section when the pharmaceutical tablet is within the device. The device according to claim 1.

6. The reorientation element includes a funnel. The device according to claim 5.

7. The first pair of conductive elements are a first pair of parallel plates, and the second pair of conductive elements are a second pair of parallel plates. The device according to any one of claims 1 to 6.

8. The device comprises a connection for connection to a controller or comprises a controller, the controller being configured to use the first and second capacitance measurements to determine the relative permittivity and thickness of the pharmaceutical tablet. The device according to any one of claims 1 to 7.

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

10. The controller includes reference data correlating relative permittivity with hardness for a plurality of reference tablets of various thicknesses and having the same chemical composition and other dimensions as the pharmaceutical tablet, and the controller is configured to use the determined relative permittivity and determined thickness of the pharmaceutical tablet to determine the hardness of the pharmaceutical tablet by comparison with the reference data. The device according to claim 8 or 9.

11. The device according to any one of claims 1 to 10, wherein in the first pair of conductive elements, the conductive elements have flat surfaces of the same dimensions, and / or in the second pair of conductive elements, the conductive elements have flat surfaces of the same dimensions.

12. The device according to any one of claims 1 to 11, comprising a conduit for the pharmaceutical tablet in which the one or more sensing sections are arranged, the conduit enabling the pharmaceutical tablet to pass through the device and the one or more sensing sections, and the first capacitance measurement value and the second capacitance measurement value to be obtained.

13. The device according to any one of claims 1 to 12, comprising shielding for shielding the plurality of capacitance sensors from fluctuations in external conditions, and optionally, the shielding being electromagnetic shielding.

14. The device according to any one of claims 1 to 13, wherein the device comprises one or more positioning elements for positioning the pharmaceutical tablet within the gap between the flat surfaces of the first pair of conductive elements and / or within the gap between the flat surfaces of the second pair of conductive elements.

15. A tableting unit for manufacturing a plurality of pharmaceutical tablets, the tableting unit comprising a tablet manufacturing module and at least one device according to any one of claims 1 to 14 arranged in-line downstream of the tablet manufacturing module, the plurality of pharmaceutical tablets being able to pass through the device to obtain the first capacitance measurement value and the second capacitance measurement value.

16. The tableting unit according to claim 15, comprising a plurality of devices according to any one of claims 1 to 14 arranged in-line downstream of the tablet manufacturing module, the plurality of devices being arranged in series or in parallel to increase the throughput and / or the number of pharmaceutical tablets for which the capacitance measurement values can be obtained.

17. The tableting unit according to claim 15 or 16, wherein the tablet manufacturing module includes a tablet press.

18. A method for determining the relative permittivity and thickness of a pharmaceutical tablet using one or more capacitance sensors, each of the one or more capacitance sensors comprising a pair of conductive elements, each conductive element of the pair of conductive elements having a flat surface, the flat surfaces of the pair of conductive elements being arranged in parallel such that capacitance measurements can be obtained from the gap therebetween, the method comprising: (a) obtaining a first differential capacitance measurement by measuring the capacitance between the flat surfaces of the pair of conductive elements with one of the one or more capacitance sensors with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a first orientation in which the thickness of the pharmaceutical tablet is parallel to the flat surfaces of the pair of conductive elements; (b) obtaining a second differential capacitance measurement by measuring the capacitance between the flat surfaces of the pair of conductive elements with one of the one or more capacitance sensors with the pharmaceutical tablet positioned within the gap and without the pharmaceutical tablet positioned within the gap, wherein when the capacitance is measured with the pharmaceutical tablet positioned within the gap, the pharmaceutical tablet is in a second orientation in which the thickness of the pharmaceutical tablet is perpendicular to the flat surfaces of the pair of conductive elements; (c) determining the relative permittivity and thickness of the pharmaceutical tablet using the first and second differential capacitance measurements; and (a) and (b) are performed in either order. **Claim 19** A method for determining the solids content and / or hardness of a pharmaceutical tablet, the method comprising: the steps (a) to (c) of the method for determining the relative permittivity and thickness of a pharmaceutical tablet according to claim 18; (d) determining the solids content of the pharmaceutical tablet using the determined relative permittivity and determined thickness of the pharmaceutical tablet by comparison with reference data, the reference data being determined by correlating the relative permittivity with the solids content for a plurality of reference tablets having various thicknesses and the same chemical composition and other dimensions as the pharmaceutical tablet; and / or (e) a step of determining the hardness of the pharmaceutical tablet by using the determined relative permittivity and the determined thickness of the pharmaceutical tablet by comparison with reference data, wherein the reference data includes a step of correlating and determining the relative permittivity with hardness for a plurality of reference tablets having various thicknesses and the same chemical composition and other dimensions as the pharmaceutical tablet.

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

21. One capacitance sensor is used to obtain the first differential capacitance measurement value and the second differential capacitance measurement value, and the method includes a step of reorienting the pharmaceutical tablet between the first orientation and the second orientation, or vice versa, between the measurement values. The method according to any one of claims 18 to 20.

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

23. The method according to claim 22, wherein the first capacitance sensor and the second capacitance sensor are disposed within the device in one or more sensing sections.

24. The first capacitance sensor and the second capacitance sensor are disposed within the device in one sensing section where the flat surface of the first pair of conductive elements is disposed perpendicular to the flat surface of the second pair of conductive elements, and the method includes positioning the pharmaceutical tablet in the first orientation of the flat surface of the first pair of conductive elements, which is also the second orientation with respect to the flat surface of the second pair of conductive elements. The method according to claim 23.

25. The first capacitance sensor is disposed in a first sensing section, the second capacitance sensor is disposed in a second sensing section, and 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 is moved between the first sensing section and the second sensing section, and vice versa, the method according to claim 23.

26. The first capacitance sensor is disposed in a first sensing section, the second capacitance sensor is disposed in a second sensing section, the flat surfaces of the first pair of conductive elements are disposed perpendicular to the flat surfaces of the second pair of conductive elements, and the method includes moving the pharmaceutical tablet between the first sensing section and the second sensing section, or between the second sensing section and the first sensing section, the method according to claim 23.

27. The pair of conductive elements are a pair of parallel plates, the method according to any one of claims 18 to 26.

28. The pair of conductive elements have flat surfaces of the same dimensions, the method according to any one of claims 18 to 27.

29. The method includes obtaining the capacitance measurement while the pharmaceutical tablet is stationary, the method according to any one of claims 18 to 28.

30. The method includes obtaining the capacitance measurement while the pharmaceutical tablet is moving, the method according to any one of claims 18 to 28.

31. The method includes using a phase-out technique to eliminate interference with the capacitance measurement, the method according to any one of claims 18 to 30.

32. The method is implemented inline in a tableting unit, the method according to any one of claims 18 to 31.

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

34. The tablet manufacturing module includes a tablet press, the pharmaceutical tableting process according to claim 33.

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

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

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