PHARMACEUTICAL MANUFACTURING INSTALLATION AND METHOD OF MANUFACTURING OF A PHARMACEUTICAL PRODUCT

Abstract

A pharmaceutical manufacturing installation, including a processing equipment arranged to provide a pharmaceutical substance in a solid state and a solid fraction sensor is disclosed. The solid fraction sensor having a first conductor element, a second conductor element, an operation space, an energy source arranged to generate an electric field in the operation space by means of the first conductor element and the second conductor element, and a controller adapted to determine a capacitance between the first and second conductor element of the pharmaceutical substance in the solid state located in the operation space. The solid fraction sensor is arranged to receive the pharmaceutical substance in its solid state into the operation space by the processing equipment.

Claims

1-39. (canceled)

40. A pharmaceutical manufacturing installation comprising: a processing equipment arranged to provide a pharmaceutical substance in a solid state; and a solid fraction sensor, wherein the sensor has a first conductor element, a second conductor element, an operation space, an energy source arranged to generate an electric field in the operation space by means of the first conductor element and the second conductor element, and a controller adapted to determine a capacitance between the first and second conductor elements with the pharmaceutical substance in the solid state located in the operation space, and wherein the solid fraction sensor is arranged to receive the pharmaceutical substance in its solid state into the operation space by the processing equipment.

41. The pharmaceutical manufacturing installation of claim 40, wherein the processing equipment comprises a punch arrangement adapted to generate a tablet of the pharmaceutical substance.

42. The pharmaceutical manufacturing installation of claim 40, wherein one of the first conductor element and the second conductor element is a part of the punch arrangement of the processing equipment or of a tablet chute of the processing equipment.

43. The pharmaceutical manufacturing installation of claim 40, wherein the processing equipment comprises two rotatable rolls and a compacting space in between the rolls, the compacting space has a powder inlet zone and a ribbon outlet zone, and the solid fraction sensor is arranged adjacent to the ribbon outlet zone of the compacting space such that a ribbon generated by the two rolls exiting the compacting space is forwarded into the operation space of the solid fraction sensor.

44. The pharmaceutical manufacturing installation of claim 43, wherein the second conductor element is formed as a ribbon support adapted to guide a ribbon exiting the compacting space, or one of the two rolls is the second conductor element, and the first conductor element preferably is bent to correspond to the outer surface of the one of the two rolls.

45. The pharmaceutical manufacturing installation of claim 40, wherein the operation space of the solid fraction sensor is a gap separating the first conductor element and the second conductor element.

46. The pharmaceutical manufacturing installation of claim 40, wherein the controller of the solid fraction sensor comprises calibration data of a reference pharmaceutical substance having the essentially same dielectric properties as the pharmaceutical substance in its solid state, the calibration data of the controller of the solid fraction sensor comprises composition data about the composition of the reference pharmaceutical substance and thickness data about the thickness of the reference pharmaceutical substance, the controller of the solid fraction sensor is adapted to convert the calibration data and the determined capacitance into solid fraction data of the pharmaceutical substance in its solid state, and the controller is adapted to generate a solid fraction signal representing the solid fraction data.

47. The pharmaceutical manufacturing installation of claim 40, wherein the energy source of the solid fraction sensor is connected to at least one of the first conductor element and the second conductor element.

48. The pharmaceutical manufacturing installation of claim 40, wherein the controller of the solid fraction sensor is adapted to adjust a strength of the electric field in the operation space.

49. The pharmaceutical manufacturing installation of claim 46, wherein the controller of the solid fraction sensor has a data storage in which the calibration data is stored, and/or the calibration data comprises permittivity of the reference pharmaceutical substance and a solid fraction ratio of the reference pharmaceutical substance, wherein the calibration data preferably comprises pairs of permittivity and corresponding solid fraction ratio.

50. The pharmaceutical manufacturing installation of claim 40, wherein the first conductor element of the solid fraction sensor and the second conductor element of the solid fraction sensor are metallic and plate-like shaped.

51. The pharmaceutical manufacturing installation of claim 40, wherein the controller of the solid fraction sensor is adapted to determine the capacitance by a capacitance-to-digital conversion, wherein the controller of the solid fraction sensor preferably is adapted to apply sigma-delta modulation to determine the capacitance.

52. The pharmaceutical manufacturing installation of claim 40, wherein the controller of the solid fraction sensor is adapted to measure a discharge time and to determine the capacitance by using the measured discharge time, and/or a charge-balancing circuit is used to measure the capacitance.

53. The pharmaceutical manufacturing installation of claim 40, further comprising: a displacement structure, wherein at least one of the first conductor element of the solid fraction sensor and the second conductor element of the solid fraction sensor is mounted to the displacement structure such that the first conductor element of the solid fraction sensor and the second conductor element of the solid fraction sensor are movable relative to each other; and/or a thickness measuring unit adapted to measure a thickness of the pharmaceutical substance in its solid state, preferably, when positioned in the operation space of the solid fraction sensor, wherein the thickness measuring sensor preferably comprises a distance capacitance sensor.

54. The pharmaceutical manufacturing installation of claim 40, wherein at least one of the first conductor element of the solid fraction sensor and the second conductor element of the solid fraction sensor is equipped with an insulating layer towards the operation space.

55. A method of manufacturing a pharmaceutical product, comprising: providing a pharmaceutical substance in a solid state; positioning the pharmaceutical substance in its solid state in an operation space in which an electric field is generated by means of a first conductor element and a second conductor element; determining a capacitance of the pharmaceutical substance in its solid state located in the operation space; and converting the determined capacitance together with information about a composition of a reference pharmaceutical substance having the essentially same dielectric properties as the pharmaceutical substance in its solid state and about a thickness of the reference pharmaceutical substance into a solid fraction of the pharmaceutical substance in its solid state.

56. The method of claim 55, wherein the pharmaceutical substance in its solid state is bounded, or the pharmaceutical substance in its solid state is unbounded.

57. The method of claim 55, further comprising: adjusting a strength of the electric field in the operation space; and/or measuring a thickness of the target pharmaceutical sample positioned in the operation space.

58. The method of claim 55, wherein the information about the composition of the reference pharmaceutical substance comprises permittivity of the reference pharmaceutical substance and a solid fraction ratio of the reference pharmaceutical substance, the information about the composition of the reference pharmaceutical substance and about the thickness of the reference pharmaceutical substance preferably comprises pairs of permittivity and corresponding solid fraction ratio, and the information about the composition of the reference pharmaceutical substance and about the thickness of the reference pharmaceutical substance preferably is a calibration curve.

59. The method of claim 55, wherein the capacitance is determined by a capacitance-to-digital conversion, wherein preferably a sigma-delta modulation is applied to determine the capacitance, and/or a discharge time is measured and the capacitance is determined by using the measured discharge time, and/or a charge-balancing circuit is used to measure the capacitance.

60. The method of claim 55, wherein the at least one of the first conductor element and the second conductor element is displaced to adjust the operation space.

61. The method of claim 55, further comprising: positioning the pharmaceutical substance in its solid state in a further operation space of the solid fraction sensor or a further solid fraction sensor, having a further first conductor element, a further second conductor element, the further operation space and a further energy source arranged to generate an electric field in the further operation space by means of the further first conductor element and the further second conductor element; determining a further capacitance of the pharmaceutical substance in its solid state located in the further operation space; converting the determined further capacitance together with the information about the composition of the reference pharmaceutical substance and about the thickness of the reference pharmaceutical substance into a further solid fraction of the pharmaceutical substance in its solid state; and determining a solid fraction distribution of the solid fraction of the pharmaceutical substance in its solid state and the further solid fraction of the pharmaceutical substance in its solid state.

62. The method of claim 55, further comprising adjusting a distance between the first conductor element and the second conductor element such that the first conductor element and the second conductor element contact the pharmaceutical substance in its solid state when positioned in the operation space.

63. The method of claim 55, further comprising: positioning the pharmaceutical substance in its solid state in a reference operation space of a reference solid fraction sensor having a reference first conductor element, a reference second conductor element, the reference operation space and a reference energy source arranged to generate an electric field in the reference operation space by means of the reference first conductor element and the reference second conductor element; determining a reference capacitance of the pharmaceutical substance in its solid state located in the reference operation space; converting the determined reference capacitance together with the information about the composition of the reference pharmaceutical substance and about the thickness of the reference pharmaceutical substance into a reference solid fraction of the pharmaceutical substance in its solid state; and comparing the solid fraction of the pharmaceutical substance in its solid state to the reference solid fraction of the pharmaceutical substance in its solid state.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0053] The pharmaceutical manufacturing installation and the method of manufacturing a pharmaceutical product according to the invention are described in more detail herein below by way of exemplary embodiments and with reference to the attached drawings, in which:

[0054] FIG. 1a,b,c shows an arrangement of a capacitor completely filled with a dielectric, a capacitor partially filled with a dielectric and an equivalent circuit diagram for a theoretical evaluation;

[0055] FIG. 2 shows an embodiment of the pharmaceutical manufacturing installation according to the invention for the use with a pharmaceutical substance in form of a tablet;

[0056] FIG. 3a,b,c shows three further embodiments of the pharmaceutical manufacturing installation for the use with a pharmaceutical substance in form of a ribbon compressed out of a powder;

[0057] FIG. 4 shows an example of a calibration curve.

DESCRIPTION OF EMBODIMENTS

[0058] To avoid repetition in the figures and the descriptions of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. Omission of an aspect from a description or figure does not imply that the aspect is missing from embodiments that incorporate that aspect. Instead, the aspect may have been omitted for clarity and to avoid prolix description. In this context, the following applies to the rest of this description: If, in order to clarify the drawings, a figure contains reference signs which are not explained in the directly associated part of the description, then it is referred to previous or following description sections. Further, for reason of lucidity, if in a drawing not all features of a part are provided with reference signs it is referred to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0059] By reference to FIG. 1a,b,c a theoretical evaluation of capacitive sensing is illustrated. Capacitive sensing is a non-contact sensing widely used in many industries, including automotive, oil and gas, medical diagnostics or consumer electronics, and pharmaceutical manufacturing. In general, capacitive sensing is applicable to both conductors and non-conductors. It finds typical use as proximity and displacement sensors. Capacitive sensors are rather inexpensive, especially in comparison to spectroscopy systems, and their simple electronic nature makes them adept for online/inline implementation in manufacturing processes.

[0060] Capacitive sensing is also suitable to characterize non-conductive material properties, i.e. dielectrics. Material passing through the gap of the capacitive sensor changes the capacitance of the sensor. When the gap in the capacitor is kept constant, the sensor output will be linked to the change in the thickness, density or composition of the material. If two of these properties are kept constant, the third can be deducted from the measurement. Thus, having a material of homogeneous composition and thickness, its density can be deducted from the sensor output. With a simple calibration, this can be converted into the porosity of the material.

[0061] FIG. 1a shows an arrangement of a capacitor completely filled with a dielectric 12 between a first conductor element 5in the following also called electrode 5and a second conductor element 7in the following also called electrode 7. Both electrodes 5, 7 have the same surface size A like the dielectric between them, which dielectric has a thickness of d.sub.0 and a permittivity of .sub.r. The capacitance C of simple parallel plates is governed by

[00001]$\begin{array}{cc}C=\frac{{\mathrm{.Math.}}_0.Math.{\mathrm{.Math.}}_r.Math.A}{d_0}& \left(\mathrm{Eq}..Math.1\right)\end{array}$

[0062] Here .sub.0 is the permittivity of vacuum (.sub.0=8.85149 pF/m), .sub.r is the relative permittivity of a material between electrodes (.sub.r=1 for air), A is the surface area of the electrodes and d.sub.0 is the distance between the electrodes 5, 7. In order to evaluate the relative permittivity of the material of interest, namely the dielectric, one would normally first obtain the capacitance C.sub.0 of empty sensor and capacitance C of sensor fully filled with the material of interest. From the difference between these two, C=CC.sub.0, one can express the relative permittivity of the material as:

[00002]$\begin{array}{cc}{\mathrm{.Math.}}_r=1+\frac{.Math..Math.{\mathrm{Cd}}_0}{{\mathrm{.Math.}}_0.Math.A}& \left(\mathrm{Eq}..Math.2\right)\end{array}$

[0063] If the dielectric sample fills the full thickness of the sensor but does not cover the full area A (not shown), the resulting sensor can be represented by two capacitors in series, one filled with vacuum (air) and another with the sample. The change in capacity is influenced only by the covered surface area S (corresponding to sample surface area), hence one can simply adapt Eq. 2 as

[00003]$\begin{array}{cc}{\mathrm{.Math.}}_r=1+\frac{.Math..Math.{\mathrm{Cd}}_0}{{\mathrm{.Math.}}_0.Math.S}& \left(\mathrm{Eq}..Math.3\right)\end{array}$

[0064] It is to note that, within the approximation of homogeneous electric field between the electrodes (i.e. far from the sensor edges), the position of the sample on the electrode does not matter.

[0065] A further generalization is necessary in case that the sample does not fill the full thickness of the sensor, as shown in FIG. 1b. The resulting air gap can be represented by two capacitors in series, one filled with air and another with the material of interest, see also FIG. 1c with the corresponding equivalent circuit diagram. It is beneficial to define thickness fraction, where d corresponds to the sample thickness. The relative permittivity of the material with thickness d<d.sub.0 can be then expressed as

[00004]$\begin{array}{cc}{\mathrm{.Math.}}_r=1+{\left(\frac{d}{d_0}.Math.\frac{{\mathrm{.Math.}}_0.Math.S}{.Math..Math.{\mathrm{Cd}}_0}+\frac{d}{d_0}-1\right)}^{-1}& \left(\mathrm{Eq}..Math.4\right)\end{array}$

[0066] With a view to FIG. 2 the following sensitivity estimation can be determined. A change in sample porosity will result in change in the sample relative permittivity. The non-trivial part is finding a suitable circuitry that allows sensitive enough detection of changes in the relative permittivity. For example, consider a sensor with 3 mm gap between the electrodes 5 and 7 being filled with a 10 mm diameter and 2 mm thick non-porous tablet made of microcrystalline cellulose, which has relative permittivity .sub.r=5.6 at 58% relative humidity and 22 C. Using Eq. 1, the increase in the sensor capacitance in the presence of tablet would be approximately 1.6 pF. If a drop in the solid fraction results in a drop of relative permittivity by e.g. 1%, the expected drop in the sensor capacitance would be approx. 20 fF. Hence, the sensing circuit has to be able to detect the capacitance with a few fF accuracy for any practical application as a porosity sensor for solid dosage forms.

[0067] FIG. 2 shows as a unit a pharmaceutical installation according to the invention comprising a processing equipment 21 providing a pharmaceutical substance 10 in a solid state and comprising a solid fraction sensor 17. Additionally, a punch arrangement 22 for generating tablets 10 out of the pharmaceutical substance is part of this unit.

[0068] In FIG. 2 the pharmaceutical substance is a tablet 10, which is located in the operation space 15 between a first conductor element 5 and a second conductor element 7 of the solid fraction sensor 17. An energy source 13 is connected to the first and second conductor element 5, 7 via a cable 6 respectively via a cable 8. A controller 11 is adapted to adjust a strength of the electric field in the operation space 15 and furthermore, the controller 11 has a data storage 14 in which calibration data is stored. The data storage 14 can be any suitable permanent or volatile data storage such as, e.g., a flash memory, a hard disk, a memory chip, an external storage or cloud storage, or the like.

[0069] According to the invention the controller 11 can be adapted to determine the capacitance by a capacitance-to-digital conversion based on the charge-balancing method in combination with the known sigma-delta modulation.

[0070] Alternatively, the solid fraction sensor 17 adapted to measure a discharge time and to determine the capacitance by using the measured discharge time, wherein the solid fraction sensor 17 can be implemented as or comprise a PICO-CAP converter.

[0071] Furthermore, the solid fraction sensor comprises a displacement structure 18, wherein at least one of the first conductor element 5 and the second conductor element 7 is mounted to the displacement structure 18 such that the first conductor element 5 and the second conductor element 7 are movable relative to each other. By moving the first conductor element 5 and the second conductor 7 relative to each other, the size of the operation space 15 can be adjusted. For example, it can be achieved that the conductor elements preferably slightly contact an object arranged in the operation space 15. Thereby, the occurrence of free space, namely the air gap between the conductor elements 5, 7 and the tablet 10 can be reduced or minimized such that the accuracy of the solid fraction determination can be increased or optimized.

[0072] A thickness measuring unit (not shown in the Fig.) is adapted to measure a thickness of the tablet 10 positioned in the operation space 15, wherein the thickness measuring sensor comprises a distance capacitance sensor.

[0073] The first conductor element 5 and the second conductor element 7 is equipped with an insulating layer 19 towards the operation space 15 for minimizing effects of parasitic resistivity of the tablet 10 on the measurement. It may further help to increase the lifetime of the respective conductor element 5, 7. Also, it may help to prevent contamination of the tablet 10. Still further, it may prevent or reduce dust build up on the solid fraction sensor 17. Finally, it may also allow for easier cleaning of the solid fraction sensor 17 and particularly its conductor elements 5, 7.

[0074] In FIG. 3a,b,c another intended application of the solid fraction sensor 17 in embodiments of pharmaceutical manufacturing installations is shown in the measurement of ribbons 4 prepared by roller compaction before they are milled. A typical roller compaction contains two rolls 1 and 2 which press powder 3 into a ribbon 4. The ribbon 4 is then milled into granules. The solid fraction of the ribbon 4 influences both hardness and size of the granules. It is therefore highly relevant to the bioavailability of the final pharmaceutical products via dissolution and disintegration characteristics. As revealed in all FIG. 3a,b,c, an overall pharmaceutical manufacturing installation 23 comprises a processing equipment 21 arranged to provide a pharmaceutical substance 4 in a solid state and a solid fraction sensor 17. Part of this processing equipment 21 is additionally a first conductor element 5, a second conductor element 7, an operation space 15, an energy source 13 arranged to generate an electric field in the operation space 15 by means of the first conductor element 5 and the second conductor element 7, and a controller 11 adapted to determine a capacitance between the first and second conductor element 5, 7 with the pharmaceutical substance 4 in the solid state located in the operation space 15, wherein the solid fraction sensor 17 is arranged to receive the pharmaceutical substance 4 in its solid state into the operation space 15 by the processing equipment 21. Through a powder inlet zone 24 powder 3 is fed to the processing equipment 21.

[0075] In FIG. 3a,b,c a possible implementation of the solid fraction sensor 17 within the roller compactor 20 is outlined. In an ideal case, a representative sample of ribbon 4 is produced without being stuck or keyed to any of the rolls 1, 2. In such circumstances, a similar solid fraction sensor 17 to one shown in FIG. 2 can be used and the ribbon 4 can be fed between the electrodes 5, 7 as shown in FIG. 3a.

[0076] In practice, the ribbons 4 may not always be strong enough and break. In such cases, the ground electrode 7 can be extended and serve as a support 26, as shown in FIG. 3b. Alternatively, a mechanical support to collect and guide the ribbon 4 can be added to the design, with the electrode 7 implemented within such support. The sensing area will be defined by the solid fraction sensor electrode 5.

[0077] When a collar is applied to the fixed roll 1, the ribbons 4 have a strong tendency to remain keyed to the fixed roll 1 and have to be scrapped off by a scraper 9 as shown in FIG. 3c. In such cases, the fixed roll 1 can be used as electrode 7 and the solid fraction sensor requires only one custom-made electrode 5. The sensing area will be again defined by the sensor electrode 5. In this case, the sensor electrode 5 may be curved to limit the inhomogeneity in the generated electric field.

[0078] In all cases, the solid fraction sensor 17 can be connected as a floating sensor (with ground electrode floating) or as a grounded sensor (with ground electrode grounded). When the ground electrode is connected as a floating electrode, one of the electrodes can be used for the excitation and another for the read-out. When ground electrode is grounded, the setup requires a switch (not shown) to allow for use of the sensor electrode for both excitation and read-out. The latter is practically useful for the cases described in FIGS. 3b and 3c. Here either the support or the roll should be grounded to minimize the parasitic capacitive and resistive signals from the machinery and other external disturbances.

[0079] FIG. 4 shows an example of a calibration curve in which pairs of permittivity and corresponding solid fraction ratio of a reference pharmaceutical substance are displayed. In particular, in the example calibration curve, a calibration obtained at uniform operating conditions on tablets with different thickness after thickness correction is shown.

[0080] This description and the accompanying drawings that illustrate aspects and embodiments of the present invention should not be taken as limitingthe claims defining the protected invention. In other words, while the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this description and the claims. In some instances, well-known circuits, structures and techniques have not been shown in detail in order not to obscure the invention. Thus, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims.

[0081] Furthermore, in the claims the word comprising does not exclude other elements or steps, and the indefinite article a or an does not exclude a plurality. A single unit or step may fulfil the functions of several features recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. The terms essentially, about, approximately and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. The term about in the context of a given numerate value or range refers to a value or range that is, e.g., within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as coupled or connected may be electrically or mechanically directly coupled, or they may be indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.