WO2010055337A1 - Unité de traitement de comprimés - Google Patents

Unité de traitement de comprimés Download PDF

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Publication number
WO2010055337A1
WO2010055337A1 PCT/GB2009/051517 GB2009051517W WO2010055337A1 WO 2010055337 A1 WO2010055337 A1 WO 2010055337A1 GB 2009051517 W GB2009051517 W GB 2009051517W WO 2010055337 A1 WO2010055337 A1 WO 2010055337A1
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WO
WIPO (PCT)
Prior art keywords
tablet
receptacle
sonication
disintegrating
processing unit
Prior art date
Application number
PCT/GB2009/051517
Other languages
English (en)
Inventor
Michiel Postema
Andrew John Smith
Original Assignee
Univeristy Of Hull
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Univeristy Of Hull filed Critical Univeristy Of Hull
Publication of WO2010055337A1 publication Critical patent/WO2010055337A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
    • B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
    • B02C19/00—Other disintegrating devices or methods
    • B02C19/18—Use of auxiliary physical effects, e.g. ultrasonics, irradiation, for disintegrating
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N2013/006—Dissolution of tablets or the like

Definitions

  • This invention relates to a device and method for disintegrating tablets to force dissolution of the tablet in a solvent and a tablet processing unit comprising such a device, in particular, but not exclusively, for use in analysing the quality of pharmaceutical tablets.
  • each tablet batch must be tested to ensure there are no flaws in the tablet content. This is normally done by disintegrating the tablet, dissolving the disintegrated tablet into a solvent and subsequently analysing the tablet solution. If analysis of the tablet solution shows that the tablet is not according to the required tablet specification, the whole batch must be destroyed and timely measures taken in the production line to prevent further flaws in tablet properties. As the tablet is tested off the line of manufacture whilst production of the tablet batch is continuing, the time for the analysis process must be kept to a minimum. This is necessary to prevent a large batch of the tablets being destroyed if a flaw is found, which would be a very costly exercise.
  • the process of analysing the quality of tablets described above can be automated by providing a mechanical system to force dissolution of the tablet in a solvent.
  • This automated system first determines the mass of the tablet using a balance. The tablet is then transferred to a chamber of the mechanical system in which it is simultaneously broken down and dissolved in a solvent. The resulting solution may then be analysed.
  • a common system for breaking down pharmaceutical tablets is a mechanical homogeniser which utilises robotics to affect movement of the test tablet between chambers and grinding of the test tablet to a fine powder or emulsion.
  • a problem associated with such machinery is that carry-over from the tablet previously tested occurs in parts of the system that have been in contact with the dissolved solution, such as the dissolution chamber and devices used to break the tablet down. Therefore, lengthy and laborious cleaning techniques must be employed to ensure that all of the carry-over from the previously tested tablet is removed so as not to create a false result in analysis of the subsequent test tablet. This presents further disadvantages as the system is out of use for lengthy periods between successive tablet analyses.
  • An alternative method of disintegrating a tablet has been proposed which involves the use of a titanium sonotrode immersed in a solvent containing the tablet.
  • the sonotrode subjects the tablet to ultrasound which affects dissolution of the tablet within the solvent. Dissolution is sped up due to ultrasound causing the solvent around the tablet to stream, a phenomenon which is known as "acoustic streaming". Accordingly, a tablet solution is prepared suitable for analysing the quality of the tablet.
  • a further disadvantage of this method is that the sonotrode tends to lose power due to its acid-resistant housing. Therefore, the sonotrode will become less reliable at disintegrating the tablets.
  • a further known method of analysing the quality of tablets involves the use of sonication.
  • Sonication is the act of applying ultrasound energy to agitate particles in a sample. Sonication is employed in the final stages of tablet processing to effect complete dissolution of a pre-ground tablet in a solvent contained within a flow cell. The sonication is achieved by a sonotrode located externally of the flow cell.
  • the tablet Prior to introduction of the tablet into the flow cell for sonication, the tablet is pre-ground using a mechanical means, in order to reduce the particle size to allow the tablet to fit into the flow cell and speed up dissolution of the tablet.
  • a solvent is then mixed with the pre-ground tablet to partially dissolve the particles of the tablet therein, creating a crude emulsion.
  • the crude emulsion then flows through a glass tube (the flow cell).
  • the sonotrode sonicates the crude emulsion passing through the glass tube, subjecting the emulsion to continuous sound waves in order to affect complete dissolution of the tablet in the solvent. In this way, sonication affects the behaviour of the flowing solvent to aid the dissolution process but is not involved in the disintegration of the tablet.
  • the solution exiting the glass tube is a fine emulsion or solution, suitable for analysis of the quality of the tablet.
  • the sonotrode In addition to the intended use of the sonotrode being to influence the behaviour of the solvent in this method, the sonotrode is not capable of effecting disintegration of the tablet. Therefore, a mechanical grinding step involving the use of robotics is required. Accordingly, this method still suffers the disadvantages associated with fully mechanical devices. In particular, as there is a high possibility of carry-over from the previous tablet processed by the device in the grinding step, a lengthy and laborious cleaning process is required. Furthermore, such a device would be expensive to the manufacturer as it employs both mechanical means and ultrasound technology. Example of prior art methods of effecting disintegration of a solid in a liquid are given in WO 02/13754, US 4720374, GB 1562491 and US 3582283.
  • WO 02/13754 discloses apparatus in which an ultrasonic probe is used to effect vibration of a container in which a tablet is located, thereby effecting disintegration of the tablet and mixing with a palatable fluid. This disintegration is therefore produced as a consequence of mechanical vibration of the container and so ultrasound is used to only indirectly effect the disintegration of the tablet.
  • US 4720374 discloses apparatus in which dissolution of a tablet is effected by an ultrasonic transducer which is immersed in a container holding the tablet. Accordingly, this apparatus relies on acoustic streaming of the liquid in which the tablet is to be dissolved and so suffers the problems discussed above with regard to the titanium sonotrode. In particular, cavitation of the ultrasonic transducer can change the chemical properties of the tablet solution, thereby making the apparatus unsuitable for use in the analysis of pharmaceutical tablets in which a high degree of purity is required.
  • US 3582283 discloses a reaction compartment configured to receive a tablet, in which the bottom surface thereof is coupled to ultrasonic energy from an adjacent ultrasonic generating means.
  • the ultrasonic energy is used to create cavitation near the surface of the tablet. Cavitation is potentially detrimental to tablet analysis as it can change the tablet and liquid chemically, leading to inaccurate results.
  • GB 1562491 discloses apparatus for dissolving and/or dispersing solid materials.
  • An ultrasonic generator is connected to a vibration-generating tool, which is inserted into a container holding the solid material and a liquid to cause cavitation at the interface between the solid material and the liquid. Accordingly, such cavitation will potentially change the solid material and liquid chemically and further such apparatus will be prone to cavitation of the vibration-generating tool, as discussed above.
  • the present invention seeks to provide a tablet processing unit which does not suffer the aforementioned problems associated with prior art devices.
  • a device for disintegrating a tablet comprising a receptacle configured to receive a tablet and a sonication means for generating ultrasonic waves, wherein said sonication means is adapted to sonicate said tablet at a frequency suitable to effect resonance of said tablet to effect disintegration of said tablet.
  • the sonication means may be adapted to sonicate the tablet at a frequency suitable to effect resonance of the tablet itself.
  • the sonication means is preferably adapted to sonicate the tablet at a frequency suitable to effect resonance of air pockets within said tablet to effect disintegration of the tablet.
  • the sonication means is adapted to sonicate the tablet at a frequency substantially equal to the resonance frequency of air pockets within the tablet.
  • air pockets within a tablet are not generally uniform and so the air pocket size will tend to exhibit normal distribution about a mean value. Accordingly, the frequency at which mean air pockets resonate at the greatest amplitude is taken to be the resonance frequency.
  • the use of sonication in the disintegration of a tablet is advantageous over the use of a mechanical grinding means as it is a more efficient method which provides non-intrusive disintegration of the tablet.
  • the device of the present invention is advantageous as it provided a means to disintegrate a whole tablet without the need for physical contact between the tablet and the means of disintegration.
  • sonication being performed at a frequency suitable to effect resonance of the tablet in some way, and preferably to effect resonance of air pockets within the tablet, preferably at a frequency substantially equal to the resonance frequency of air pockets within the tablet, which effects speedy and thorough disintegration of the tablet.
  • Sonication of a tablet close to the resonance frequency causes air pockets in the tablet to oscillate vigorously, expanding and contracting, to effect break up of the tablet.
  • sonication close to the resonance of the tablet itself increases friction within the tablet and further, increases the severity of the vibration of the tablet, which is expressed as the amplitude ratio or the 'magnification factor' of the tablet, thereby enhancing disintegration.
  • the severity of the vibrations achieved with ultrasonic waves is much greater than that of mechanical vibrations, when the tablet is shaken vigorously.
  • the resonance frequency of an air pocket within a tablet depends upon the material properties of the tablet and is inversely proportional to the diameter of the air pocket. As will be appreciated, the diameter of air pockets will not be uniform throughout the tablet, but will tend to exhibit normal distribution about a mean value. Accordingly, subjecting a tablet to a frequency inversely proportional to the mean diameter of its air pockets will affect resonance of the bulk of the air pockets in the tablet, achieving successful disintegration of the tablet.
  • the person skilled in the art would readily be able to derive the desired frequency for disintegration of a specific tablet by subjecting the tablet to a range of ultrasonic wave frequencies in order to ascertain which ultrasonic wave frequency effects successful disintegration, as discussed in the specific example below.
  • the resonance frequency of the tablet itself is also dependent upon the material properties of the tablet and the length of the tablet, and so the desired frequency for disintegration may also be derived in much the same way as for that of the air pockets.
  • the resonance frequency of the air pockets of the tablet may be estimated by establishing the elastic properties of the solid tablet material, such as Young's modulus, the Poisson ratio, etc.
  • Young's modulus such as Young's modulus, the Poisson ratio, etc.
  • Such properties may be established either by consulting a material properties handbook, such as the CRC Handbook of Physics and Chemistry, for basic materials, or for more complex materials, these properties may be established by use of the methods described in 'Photoacoustic Evalution of Elasticity and Integrity of Pharmaceutical Tablets' by J. Ketolainen et al.
  • the distribution of the diameters of the air pockets is then measured using methods such as morphological sieving, MicroCT scanning or mercury porosimetry.
  • this allows a comparison to be made between the expected resonance frequency of the air pockets of the tablet and that previously measured for other tablets. For example, if the air pocket diameter of the tablet is larger than that of the known tablets, the resonance frequency is expected to be lower than that of the known tablets. Alternatively, if the material of the tablet is stiffer than that of known tablets, the resonance frequency will be higher.
  • the device of the present invention enables a dissolution liquid to be added to the receptacle during sonication of the tablet as the solvent will not interfere with the disintegration process.
  • the device has the further advantage of speeding up dissolution of the tablet in the solvent as the tablet and the solvent can be mixed at an earlier stage and sonication can also agitate the liquid, enhancing dissolution.
  • the amount of solvent added to the receptacle can be accurately controlled with a metering pump.
  • tablette any pharmaceutical or veterinary product comprising a powder which is pressed or compacted into a solid and is intend to be broken down and dissolved within the human and/or animal body.
  • tablette disintegrated by the device of the present invention for subsequent analysis may be any non-pharmaceutical powder which is pressed or compacted into a solid and is intended to be broken down and dissolved in a liquid.
  • the sonication means is adapted to sonicate the tablet at a frequency of from 2OkHz to 100MHz.
  • the sonication means is adapted to sonicate the tablet at a frequency of from 2OkHz to 25OkHz, alternatively from 20OkHz to 10MHz or 5MHz and above depending upon the tablet composition.
  • a frequency of 20OkHz has been shown to effect very efficient disintegration of a tablet.
  • the sonication means surrounds a portion of said receptacle.
  • the sonication means ensures the maximum amount of ultrasonic energy will be transferred to the interior of the receptacle where the tablet is located.
  • the receptacle is cylindrical, box-shaped, pyramid-shaped, spherical or polyhedron-shaped and the sonication means extends about the circumference/perimeter of the receptacle.
  • the receptacle is cylindrical and the sonication means is substantially ring-shaped (i.e. annular). This embodiment is preferred as it provides a smooth walled receptacle which will eliminate, or at least significantly reduce, the occurrence of sedimentation as a dissolution liquid is pumped through the receptacle.
  • the sonication means comprises a portion of the walls of said receptacle so that the ultrasonic waves generated are not required to propagate through an additional layer of the wall material of the receptacle. If the ultrasonic waves were required to propagate through the wall material, they would lose energy and hence be less efficient in effecting disintegration of the whole tablet. In this way, an interface is provided between the sonication means and the liquid, upon introduction into the receptacle, enhancing dissolution of the tablet. Furthermore, as the sonication means may comprise a portion of the walls of the receptacle, the device may be cleaned by simply flushing it with a cleaning solution.
  • the sonication means may conveniently be coated with a corrosion-resistant coating.
  • Suitable corrosion-resistant coatings are inert to the cleaning solution employed to clean the device whilst allowing the ultrasonic waves to propagate through the coating and into the receptacle, without losing a substantial amount of energy.
  • the corrosion- resistant coating employed is a fluoropolymer selected from the following: • polytetrafluoroethylene (PTFE);
  • coatings are preferred as they have an acoustic impedance similar to that of typical dissolution liquids and so there will be no unwanted reflections at the sonication means-liquid interface, preventing a loss of energy.
  • any material which has the desired characteristics may be used as the corrosion-resistant coating.
  • the sonication means is coupled to the receptacle of the device.
  • the sonication means and at least a portion of the receptacle are spaced apart within a coupling housing, which is filled with a coupling medium.
  • the coupling medium has an acoustic impedance similar to that of the dissolution liquid employed in the tablet processing device as it allows the ultrasonic waves generated by the sonication means to propagate through the coupling housing without any loss of energy or efficiency.
  • the portion of the receptacle coupled to the sonication means preferably comprises a coupling layer, for example a thin seal made of PTFE or a derivative thereof, of glass or of a fluoropolymer.
  • This alternative arrangement of the sonication means and the receptacle containing a tablet is preferred as it is relatively inexpensive to manufacture. Furthermore, as the sonication means is not in direct contact with the contents of the receptacle, this reduces the need to replace the sonication means at frequent intervals. In such an embodiment, the sonication means is distanced from the tablet within the receptacle such that the tablet is held within the focal point of the ultrasonic waves.
  • the sonication means generates pulsed ultrasonic waves.
  • the use of pulsed ultrasonic waves is preferred as it reduces heat generation in the sonication means, and this may help prevent overheating which can lead to malfunction.
  • the sonication means is undamped, i.e. it has no backing material, so that the sonication means will generate the maximum energy ultrasonic waves to be transferred to the tablet in the relevant frequency band.
  • the internal volume of said receptacle is greater than the size of the tablet. This enables the receptacle to accommodate a whole tablet, therefore removing the need for any mechanical pre-ghnding of the tablet so that it may fit into the receptacle. This enables disintegration of the whole tablet by sonication to take place within the receptacle.
  • the receptacle comprises a locating means for locating said tablet at a desired location within said receptacle.
  • the sonication means has a focal point within the receptacle of the device, in which case the locating means preferably locates said tablet at the focal point of said ultrasound waves generated by said sonication means. This allows the ultrasound energy to be focused on the tablet during sonication, thereby enhancing disintegration.
  • the locating means is further configured to retain the tablet within the receptacle during disintegration. In this way, the locating means prevents the tablet from exiting the receptacle until it is sufficiently disintegrated and dissolved with the dissolution liquid, thereby enabling efficient and successful disintegration.
  • the locating means comprises a mesh so that when a liquid such as a dissolution liquid or a cleaning solution is introduced into the receptacle it has relatively unrestricted flow throughout the receptacle.
  • said mesh is formed of a material which is resistance to the dissolution liquid and cleaning solution, and in particular of a material which does not affect the purity of the tablet solution obtained for analysis.
  • suitable materials include 316 stainless steel and equivalents thereof.
  • the sonication means comprises one or more ultrasound transducers to generate the ultrasonic waves.
  • the one or more ultrasound transducers may suitably be connected to a waveform generator which provides continuous or pulsed sine waves to be converted to continuous or pulsed ultrasonic waves by the one or more transducers.
  • the one or more transducers generate pulsed ultrasonic waves.
  • the receptacle may be formed of any material which is resistant to breakage when under the influence of ultrasonic waves generated by the sonication means. More preferably, the receptacle is formed of hard plastic material, glass or metal, such as stainless steel. It is advantageous for the receptacle to be formed of a hard plastic material when pulsed ultrasonic waves are employed, for example, polymethyl methacrylate (PMMA). Other suitable materials will be apparent to the person skilled in the art. However, where the sonication means is coupled to the receptacle, as discussed above, the portions of the receptacle not coupled to the sonication means may be formed of the above materials. The portion of the receptacle coupled to the sonication means comprises a material which is resistant to breakage under the influence of ultrasonic waves, but is also thin enough to allow the ultrasonic waves to propagate through the material without significant loss of energy or efficiency.
  • the device forms part of a tablet processing unit.
  • the tablet processing unit provides a means to assess the quality of a tablet.
  • the device disintegrates the tablet so that it may be dissolved in a solvent and then the tablet solution is transferred to analysis equipment in order to assess the quality of the tablet.
  • the tablet processing unit further comprises a weighing cell located adjacent to said device in which said tablet is weighed prior to entry into the device.
  • a weighing cell located adjacent to said device in which said tablet is weighed prior to entry into the device.
  • the weighing cell comprises a means to effect transfer of said tablet to said device, and advantageously the transfer means comprises a source of compressed air to blow the tablet from the weighing cell into the device.
  • the present invention does not require any robotics to transfer the tablet between the weighing cell and the device, thereby eliminating the cost associated with such elements.
  • the transfer means does not contact the tablet, no laborious cleaning techniques are required.
  • the tablet processing unit may further conveniently comprise a control cell and a liquid-handling loop, through which a dissolution liquid may be introduced and circulated to the device where it may interact with the disintegrated tablet.
  • the device is an inline flow cell forming a circuit with said liquid-handling loop and said control cell. This arrangement enables the disintegrated tablet and the solvent to be continually re-circulated until a homogenous mixture is obtained. The continuous recirculation speeds up the dissolution of the tablet.
  • the receptacle comprises a locating means configured to retain the tablet therein. This ensures that the tablet is suitably disintegrated and dissolved within the dissolution liquid before it is able to enter the liquid-handling loop.
  • the tablet processing unit is connected to an analyser cell so that the tablet solution produced may be analysed in order to assess the quality of the tablet.
  • the tablet processing unit is connected to the analyser cell via the control cell.
  • the tablet solution may be analysed by one of the following methods: • Spectroscopy (including NMR, Infrared and Raman);
  • HPLC high performance liquid chromatography
  • the tablet processing unit is suitable for processing a pharmaceutical tablet.
  • the pharmaceutical tablet is taken from a tablet production line to be processed and analysed in said tablet processing unit comprising said device.
  • a method for disintegrating a tablet comprising the steps of:
  • the tablet is sonicated at a frequency suitable to effect resonance of air pockets within said tablet to effect disintegration thereof.
  • the tablet is weighed prior to insertion of said tablet into said receptacle.
  • the tablet may conveniently be inserted into said receptacle using compressed air.
  • a dissolution liquid is introduced into said receptacle to effect dissolution of the disintegrated tablet to form a tablet solution.
  • the dissolution liquid is introduced prior to sonicating the tablet.
  • At least a portion of said tablet solution is analysed.
  • the preferred methods of analysis are as follows:
  • HPLC high performance liquid chromatography
  • the remaining tablet solution is removed from the receptacle.
  • a cleaning solution may be introduced into said receptacle to flush said receptacle.
  • Preferred cleaning solutions include methanol or acetonitrile.
  • pressured air is preferably pumped into said receptacle to dry the receptacle.
  • Figure 1 is a schematic representation of a tablet processing unit in accordance with one embodiment of the present invention.
  • Figure 2 is a schematic representation of a tablet processing unit in accordance with a second embodiment of the present invention.
  • Figure 3 is an exploded view of a means for generating ultrasound waves in accordance with a further embodiment of the present invention.
  • Figure 4 is a schematic representation of a transformer suitable for use with the means for generating ultrasound waves of figure 2;
  • Figure 5 is a perspective view of an experimental setup of a device for disintegrating a tablet
  • Figure 6A, 6B, 6C and 6D is a schematic view showing the four stadia of tablet disruption; and Figure 7 is a graphical representation of the results of a comparative study on the time taken to reach the first three stadia of tablet disruption.
  • the transducer of the sonication means of the present invention is pre-programmed with a frequency substantially equal to the resonance frequency of either the air pockets of the tablets to be tested, or the tablet itself, prior to use.
  • the person skilled in the art would readily be able to derive the desired frequency for disintegration of a specific tablet by known methods.
  • An example of such known methods involves apparatus in which a broadband ultrasound transducer is placed in a water tank and positioned such that the elevation of its longitudinal axis is 0°, i.e. it is horizontal.
  • a sensitive hydrophone is also placed in the water tank and positioned such that the elevation of its longitudinal axis is 0° and its axial azimuth is 90° relative to the longitudinal axis of the transducer. In this way, the longitudinal axis of the hydrophone crosses the acoustic focus of the transducer.
  • control measurements are taken without a tablet being present at the acoustic focus of the transducer.
  • the transducer is set to produce short ultrasonic pulses at set frequencies.
  • the acoustic amplitude is kept constant, by adjusting the voltage according to the transducer calibration specification and measurements are taken at each frequency, the frequency being increased after each measurement.
  • a tablet is then positioned in the acoustic focus of the transducer and the measurements are repeated as described above.
  • the air pockets of a tablet are not uniform in size and so will effectively have a range of resonance frequencies, they do exhibit a normal distribution about a mean value. Therefore, when the frequency of the ultrasonic pulse is close to the resonance frequency of the air pockets with the mean value, a sudden increase in the acoustic response is measured, when compared to the control measurements. This is followed by a slight decrease, which indicates that the frequency of the ultrasonic pulses is just above the resonance frequency of the air pockets with the mean value, and then a steady increase in the response to the increase in frequency.
  • the frequency of the ultrasonic pulses can then be fine-tuned by repeating the measurements around the frequency at which the sudden increase in acoustic response was observed in the previous measurements, with smaller increments.
  • the ultrasound transducer can be tuned for use in a tablet processing unit of the present invention capable of disintegrating the given tablet.
  • Such method can also be employed to establish the resonance frequency of the tablet itself.
  • the resonance frequency of the tablet itself will be lower than the resonance frequency of air pockets within the tablet, as it is proportional to the length of the tablet, which will be significantly greater than the mean diameter of the air pockets. Therefore, in order to derive the frequency necessary to effect resonance of the tablet itself using the above method, the transducer will be set to produce ultrasonic pulses at a lower range of frequencies.
  • a wide range of frequencies is employed in the method, at least two significant sudden increases in the acoustic output will be observed, the lower sudden increase relating to resonance frequency of the tablet itself and the higher sudden increase relating to resonance frequency of the bulk of air pockets within the tablet.
  • FIG 1 there is shown a schematic overview of a tablet processing unit 101 which forces dissolution of a tablet in a solvent so that the quality of the tablet may be assessed.
  • Tablet processing unit 101 comprises a device for disintegrating a tablet 103, a weighing cell 105, a control cell 107, a liquid-handling loop 109, a first valve 111 , a rotary valve 113 and a second valve 115.
  • the device for disintegrating a tablet 103 comprises a receptacle 117, a sonication means 119 and a locating means 121.
  • the receptacle 117 defines a chamber for receiving a tablet within the device 103 and the locating means 121 is located within the receptacle 117.
  • the sonication means 119 comprises a sonication ring which generates ultrasonic waves and is formed integrally with a portion of the walls of the receptacle 117.
  • the locating means 121 is positioned within the receptacle 117 such that the ultrasound waves generated by the sonication means 119 are focused upon the locating means 121.
  • the locating means 121 is in the form of a grid.
  • the sonication means 119 further comprises one or more ultrasound transducers which are connected to a waveform generator (not shown) or a pulser-receiver (not shown) to generate the required ultrasonic waves.
  • the receptacle 117 of the device for disintegrating a tablet 103 is sized such that it has sufficient volume to accommodate an entire tablet.
  • the receptacle 117 has an inlet 123 which is located adjacent to the weighing cell 105 so that a tablet may pass from the weighing cell 105 into the receptacle 117 via the inlet 123.
  • the liquid-handling loop 109 connects the device for disintegrating a tablet 103 to the control cell 107 which is located at a position remote from the device 103. In this way, the device 103 and the control cell 107 are in fluid communication with one another and the liquid-handling loop 109.
  • a pump 125 is located within the liquid-handling loop 109 between the device 103 and the control cell 107.
  • a valve 127 is also located within the liquid-handling loop 109, which allows pressurised air or a dissolution liquid to enter the circuit formed by the device 103, the control cell 107 and the liquid handling loop 109. The dissolution liquid is metered into the cell to ensure the volume of dissolution liquid is accurately controlled, ensuring the correct dilution is obtained.
  • the control cell 107 comprises a series of five openings, two of which are connected to the liquid-handling loop 109 to provide a circuit through which fluid may flow from the control cell 107 to the device 103 via liquid- handling loop 109.
  • the further three openings provide inlets and/or outlets to the circuit.
  • the control cell 107 is connected to the first valve 111 via one such inlet/outlet, which leads to the analysis system.
  • the other two inlets and/or outlets provide a first waste outlet 129 to remove waste fluid from the circuit and a breather 131 to allow air to enter or exit the tablet processing unit 101.
  • the first valve 111 is a two-way valve which connects the control cell 107, and hence the circuit formed by the device, 103, the control cell 107 and the liquid-handling loop 109, to the rotary valve 113. In this way, fluid is allowed to pass from the control cell into the rotary valve 113 or from the rotary valve 113 to the control cell 107.
  • Rotary valve 113 regulates the flow of fluid exiting or entering the circuit formed by the device 103, the control cell 107 and the liquid-handling loop 109 via first valve 111 and is movable between two main positions. In the first position, the first valve 111 is in fluid communication with an outlet 133 which is connected to the appropriate analyser, such as a high performance liquid chromatography (HPLC) system. In the second position, the first valve 111 is in fluid communication with the second valve 115 (as shown in figure 1 ). Rotary valve 113 further comprises an inlet 135 through which a cleaning solution may enter the appropriate analyser.
  • HPLC high performance liquid chromatography
  • Second valve 115 is a three-way valve comprising a first inlet 137 through which cleaning solution may be pumped into the tablet processing unit 101 and a second inlet 139 through which pressurised air may enter the tablet processing unit 101.
  • a tablet such as a pharmaceutical tablet
  • a tablet is taken off the line of production and placed in the weighing cell 105 in order to determine the mass of the tablet.
  • the tablet is transferred to the receptacle 117 of the device for disintegrating a tablet 103 via inlet 123.
  • the tablet is transferred to the receptacle 117 of the device 103, via the inlet 123 by the introduction of compressed air into the weighing cell 105, thereby blowing the tablet through the inlet 123 and into the receptacle 117.
  • the inlet 123 is closed.
  • the tablet is positioned upon the locating means 121 within the receptacle 117 such that the tablet is located at the focal point of the ultrasonic waves generated by the sonication means 119.
  • the first valve 111 , the waste outlet 129 and the breather 131 are "closed" with respect to receiving fluid from the control cell 107, such that the device for disintegrating a tablet 103, the liquid-handling loop 109 and the control cell 107 form a closed circuit.
  • the ultrasound transducers of the means for generating ultrasonic waves 119 are subjected to continuous or pulsed sine waves from the waveform generator or pulser-receiver (not shown).
  • the ultrasound transducers convert these sine waves into pulsed ultrasonic waves which propagate throughout the receptacle 117 of the device 103 to effect disintegration of the tablet contained therein.
  • the ultrasonic waves produced have a frequency substantially equal to the resonance frequency of air pockets within the tablet which enables the device 103 to disintegrate the bulk tablet.
  • the relevant resonance frequency of the air pockets within the test tablet will have been previously determined by subjecting the test tablets to a range of frequencies.
  • the resonance frequency will be the frequency at which the mean air pockets resonate at the greatest amplitude, thereby effecting most efficient tablet disintegration.
  • a controlled amount of dissolution liquid is added to the tablet processing unit 101 via valve 127 in the liquid-handling loop 109.
  • the dissolution liquid is circulated around the liquid-handling loop 109 using pump 125, into the device 103 where it interacts with the tablet as it disintegrates to affect dissolution.
  • the liquid containing the dissolved tablet is continually re- circulated by the pump 125 to the control cell 107, around the liquid- handling loop 109 and back to the device 103 until a homogenous mixture is obtained.
  • the ultrasound waves generated by the sonication means 119 in the device 103 which is coupled to the dissolution liquid due to the sonication means 119 being integral with a portion of the walls of the receptacle 117, speeds up natural dissolution of the tablet.
  • first valve 111 is opened to allow a sample of the homogenous mixture to be diverted to the rotary valve 113.
  • the rotary valve 113 is positioned such that the first valve 111 is in fluid communication with the outlet 133, allowing the sample to pass through outlet 133 and into a high performance liquid chromatography (HPLC) system.
  • HPLC high performance liquid chromatography
  • the remainder of the homogenous mixture is removed from the tablet processing unit 101 via waste outlet 129 of the control cell 107.
  • the unit 101 and the appropriate analyser must be cleaned thoroughly to prevent contamination of the subsequent tablet by any remaining particles from the previous tablet processed.
  • the unit 101 may simply be flushed with a cleaning solution.
  • a cleaning solution such as methanol or acetonitrile, is pumped into the tablet processing unit 101 via first inlet 137 of the second valve 115.
  • the cleaning solution passes to the control cell 107 via rotary valve 113, which is positioned such that the second valve 115 is in fluid communication with the first valve 111 , and first valve 111 , which is in an open position.
  • the cleaning solution is then circulated throughout the control cell 107, the liquid-handling loop 109 and the device for disintegrating a tablet 103, to remove any residual particles from the previous test.
  • the appropriate analyser which is connected to the rotary valve 113 via outlet 133, is cleaned by a cleaning solution entering inlet 135, when the rotary valve 113 is positioned as shown in figure 1.
  • the cleaning solution Once the cleaning solution has been re-circulated throughout the tablet processing unit 101 , it is pumped out of the unit 101 via the waste valve 129 of the control cell 107. Pressurised air is then pumped into the tablet processing unit 101 via the second inlet 139 of the second valve 115 and via valve 127 located within the liquid-handling loop 109. This pressurised air is circulated throughout the tablet processing unit 101 to dry the apparatus, thereby preventing the cleaning solution from contaminating the solution of the subsequent test tablet. The pressurised air then leaves the tablet processing unit 101 via breather 131 of the control cell 107.
  • the cleaning solution used in the cleaning step may damage the sonication means 119 where it is exposed to the contents of the receptacle 117
  • the sonication means 119 is coated with a corrosion- resistant material.
  • the corrosion-resistant coating is Teflon® PFA.
  • the receptacle 117 of the device for disintegrating a tablet 103 is formed from Perspex® as this material is resistant to breakage under the influence of the ultrasonic waves employed in the present invention.
  • Figure 2 show an alternative tablet processing unit 201 comprising a device for disintegrating a tablet 203, a weighing cell 205, a control cell 207, a liquid-handling loop 209, a first valve 211 , a rotary valve 213 and a second valve 215.
  • the weighing cell 205 control cell 207, liquid-handling loop 209, and valve system (comprising the first valve 211 , rotary valve
  • the device for disintegrating a tablet 203 comprises a receptacle 217, a sonication means 219 and coupling housing 245 having a coupling medium 241 received therein.
  • Receptacle 217 defines a chamber sized to receive a whole tablet within the device 203 and is in fluid communication with liquid-handling loop 209.
  • Receptacle 217 comprises a locating means 221 , positioned within the chamber, an inlet 223, located adjacent to weighing cell 205, and a coupling layer 243 forming one of the faces of the receptacle 217.
  • sonication means 219 comprises one or more ultrasound transducers which are connected to a waveform generator (not shown) or a pulser-receiver (not-shown) to generate ultrasonic waves at the required frequency.
  • Sonication means 219 is positioned at one side of coupling housing 245, with a portion thereof located within the coupling medium 241.
  • Receptacle 217 is located at the opposite side of the coupling housing 245 such that coupling layer 243 is exposed to coupling medium 241.
  • Sonication means 219 and receptacle 217 are spaced apart such that when a tablet is received within receptacle 217, it is held at the focal point of the ultrasonic waves generated by the sonication means 219.
  • Locating means 221 comprises two sections of supporting mesh which extend fully across the width of the receptacle 217, either side of inlet 223 and so retain the tablet within the focal point of the ultrasonic waves while disintegration is taking place.
  • the supporting mesh further acts to prevent the disintegrated particles of the tablet from passing into the liquid- handling loop 209 until it have been sufficiently disintegrated and dissolved in a dissolution liquid.
  • the supporting mesh of locating means 221 may be made from any material which is inert to the contents of the receptacle 217, so that it will not affect the purity of the solution obtained for analysis.
  • the mesh is made of 316 stainless steel.
  • Receptacle 217 is a substantially rectangular cuboid in which five of the six walls are formed from stainless steel 316.
  • the sixth wall, which defines the coupling layer 243, is formed from a relatively thin material which is resistant to breakage under the influence of ultrasonic waves but allows the ultrasonic waves to propagate therethrough without losing efficency.
  • the material used to form the thin coupling layer 243 of the sixth wall is glass, PTFE or a derivative thereof.
  • Coupling housing 245 may also be formed of Perspex® as this material is resistant to breakage when it is subjected to ultrasonic waves as in the present invention.
  • Coupling medium 241 may be any liquid which does not impede propagation of the ultrasonic waves generated by the sonication means 219. In this embodiment, the coupling medium 241 is water.
  • a tablet is transferred from the weighing cell 205 to the receptacle 217 of the device 203 via inlet 223 by the introduction of compressed air into the weighing cell 205. Once the tablet is in place between the supporting mesh of the locating means 221 , the inlet 223 is closed.
  • the first valve 211 , waste outlet 229 and breather 231 are "closed" with respect to receiving fluid from the control cell 207, such that the device for disintegrating a tablet 203, the liquid-handling loop 209 and the control cell 207 form a closed circuit.
  • the ultrasound transducers of the sonication means 219 are then subjected to pulsed or continuous sine waves from a waveform generator or pulser-receiver (not shown).
  • the ultrasound transducers covert the sine waves into pulsed ultrasonic waves at a predetermined frequency to effect resonance of air pockets within the tablet.
  • the pulsed ultrasonic waves then propagate through the coupling medium 241 of the coupling housing 245, through the coupling layer 243 of the receptacle 217 to the tablet positioned within the focal point of the ultrasonic waves.
  • a controlled amount of dissolution liquid is introduced into the tablet processing unit 201 via valve 227 in the liquid-handling loop 209.
  • the dissolution liquid is then circulated around the "closed circuit" of the liquid-handling 209, device for disintegrating a tablet 203 and the control cell 207 by pump 225.
  • the dissolution liquid passes through the receptacle 217 of device 203, it interacts with the tablet as it disintegrates to effect dissolution.
  • the liquid containing the dissolved tablet is then continually circulated through the "closed circuit" until the tablet has been fully dissolved in the liquid and a homogenous mixture is obtained.
  • the sonication means 219 is not integral with the receptacle 217 in this embodiment, efficient coupling of the sonication means 219 to the receptacle 217 as in this embodiment, with reduced loss of energy, enables the ultrasound waves generated by the sonication means 219 to speed up natural dissolution of the tablet in the dissolution liquid.
  • FIG 3 there is shown an exploded view of one embodiment of the ultrasound transducer 301 for a means for generating ultrasonic waves for use in a tablet processing unit of the present invention.
  • Ultrasound transducer 301 comprises a housing 303, a piezo element 305, a matching layer 307, an end piece 309, a first cable 311 and a second cable 313.
  • Housing 303 is box-shaped having a first open end 315 and a second open end 317.
  • Piezo element 305 is located at the first end 315 of the housing 303.
  • the lower surface of the piezo element 305 is attached to the housing using RTV 630 2-component adhesive.
  • Matching layer 307 is located at the upper surface 319 of the piezo element 305 and is attached thereto using the RTV 630 2-component adhesive.
  • End piece 309 is located at the second end 317 of housing 303 and is attached thereto using the same adhesive.
  • the first and second cables 311 and 313 connect the piezo element 305 to a transformer (as exemplified in figure 4) to transfer power from the transformer to the ultrasound transducer 301.
  • first ends of the first cable 311 and the second cable 313 are soldered to the positive and negative points of a high-impedance part of the transformer respectively.
  • the first cable 311 and the second cable 313 are then led through inlet holes located near to the second end 317 of the housing 303 and run upwards towards piezo element 305.
  • the second end of the first cable 311 is soldered to the lower surface 319 of the piezo element 305, providing the positive side of the piezo element 305.
  • the second end of the second cable 313 is soldered to the upper surface 321 of the piezo element 305 providing the negative side of the piezo element 305.
  • the ultrasound transducer 301 of figure 3 produces a frequency of 20OkHz.
  • Housing 303 is formed of Perspex®, as are the matching layer 307 and the end piece 309.
  • the piezo element 305 consists of a 20OkHz 50 x 30 x 5mm 3 single PIC155 piezo element (supplied by Pl Ceramics, Lederhose, Germany).
  • the first cable 311 is a 2mm cable and is treated with waterproof silicon at the point at which it is soldered to the lower surface 319 of the piezo element 305.
  • the second cable 313 consists of a 1 mm cable connected to a 2mm cable prior to entry into housing 303.
  • Figure 4 herein shows a transformer scheme 401 which is suitable for use with the ultrasound transducer 301 of figure 3.
  • Transformer scheme 401 comprises an 'in' portion 403 and an 'out' portion 405.
  • the 'in' portion 403 is soldered to a BNC connector (not shown) which provides electrical energy to the transformer scheme 401.
  • a capacitor 407 is located in the 'in' portion 403.
  • the 'out' portion 405 is soldered to the relevant cables of the ultrasound transducer (first and second cables 311 and 313 in figure 3).
  • the transformer scheme 401 is a type 749196511 WE044 transformer (supplied by W ⁇ rth Elektronik eiSos GmbH und Co. KG, Waldenburg, Germany) with a transmission ratio of 1 :5.
  • the 'in' portion 403 forms the low-impedance part of the transformer scheme 401 and the 'out' portion 405 forms the high-impedance part of the transformer scheme 401.
  • the capacitor 407 of the 'in' portion 403 has a capacitance of 3.3nF.
  • the experimental setup 501 comprises the ultrasound transducer 301 of figure 3 which is positioned over a tank 503 and held in place by clamp 505.
  • Tank 503 is an 80 x 80 x 85mm 3 Perspex® box open at its upper side.
  • the ultrasound transducer 301 is connected to a V1.0 pulser-receiver (supplied by Sonemat Limited, Coventry) (not shown), which is internally triggered to provide continuous or pulsed sine waves.
  • tank 503 is filled with air-saturated water at a temperature of 2O 0 C to a height of 65 mm.
  • Two test tablets are placed in the air-saturated water.
  • Ultrasound transducer 301 is partially submerged in the air- saturated water over the tank 503 such that the piezo element 305 of the ultrasound transducer 301 is submerged within the air-saturated water.
  • the pulser-receiver (not shown) is switched on to generate 16-Vpp square pulses with a 17-kHz pulse repetition rate, which are transmitted to the ultrasound transducer 301.
  • Ultrasound transducer 301 produces pulsed ultrasound waves to effect grinding and therefore dissolution of the test tablets in the air- saturated water.
  • the test tablet employed in the experimental setup 501 of figure 5 has a sugar coating forming an outer shell of the tablet.
  • Figure 6A shows the outer shell of the tablet cracking, where visual lines appear over the sugar coating of the tablet.
  • Figure 6B shows outer shell detachment where the sugar coating of the tablet breaks loose from the tablet.
  • Figure 6C shows particle flow as fragments of the tablet float away from the mass of the tablet. The smaller fragments of the tablet enter solution with the air- saturated water as they float away from the mass of the tablet.
  • the final stage of the tablet disruption and dissolution is shown in figure 6D in which the tablet is pulverised. Once the tablet is pulverised, dissolution of the tablet in the air-saturated water occurs quickly.
  • the vertical axis represents the time taken for each stage to be reached in increments of five minutes.
  • the black bars represent an average of the results for the tablets tested without the application of ultrasonic waves, i.e. the control experiments.
  • the white bars represent the results for the tablets tested which were subjected to ultrasonic waves in accordance with the present invention.
  • the first set of results represent the time taken to reach stage A - outer shell cracking; the second set represent the time taken to reach stage B - outer shell detachment; and the third set represent the time taken to reach stage C - particle flow.
  • Successful ultrasonic tablet grinding in the tablet processing unit of the present invention may depend on the geometry of the flow cell, ultrasonic frequency, ultrasonic amplitude, and tablet composition.

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  • Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Sampling And Sample Adjustment (AREA)

Abstract

L'invention concerne un dispositif de désintégration d’un comprimé comprenant un réceptacle recevant le comprimé et un moyen de sonification produisant des ultrasons. Ledit moyen de sonification soumet le comprimé à des ultrasons à une fréquence qui y crée une résonance provoquant la désintégration du comprimé. L'invention concerne également une méthode de désintégration d’un comprimé.
PCT/GB2009/051517 2008-11-11 2009-11-11 Unité de traitement de comprimés WO2010055337A1 (fr)

Applications Claiming Priority (2)

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GB0820586.6 2008-11-11
GB0820586A GB0820586D0 (en) 2008-11-11 2008-11-11 Tablet processing unit

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WO2010055337A1 true WO2010055337A1 (fr) 2010-05-20

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Cited By (1)

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CN107249751A (zh) * 2015-02-24 2017-10-13 李奎塔布系统有限公司 改进的固体分解设备及方法

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EP0209873A2 (fr) * 1985-07-22 1987-01-28 E.I. Du Pont De Nemours And Company Hydratation récipient
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US4779806A (en) * 1984-07-23 1988-10-25 Massachusetts Institute Of Technology Ultrasonically modulated polymeric devices for delivering compositions
EP0209873A2 (fr) * 1985-07-22 1987-01-28 E.I. Du Pont De Nemours And Company Hydratation récipient
DE3545351A1 (de) * 1985-12-20 1987-06-25 Siemens Ag Verfahren zur kontrolle der lage des fokus eines ultraschallfeldes und vorrichtung zur durchfuehrung des verfahrens
DE19839398A1 (de) * 1998-08-29 2000-03-16 Hoechst Marion Roussel De Gmbh Mini-Basket zur Untersuchung der Wirkstoffreisetzung aus einer Arzneiform
EP1167946A2 (fr) * 2000-07-01 2002-01-02 Malvern Instruments Limited Système de manipulation d'échantillons
WO2002013754A1 (fr) * 2000-08-18 2002-02-21 Liquitab Pty. Limited Distributeur de produits medicamenteux et procede correspondant

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Publication number Priority date Publication date Assignee Title
CN107249751A (zh) * 2015-02-24 2017-10-13 李奎塔布系统有限公司 改进的固体分解设备及方法
US20180029041A1 (en) * 2015-02-24 2018-02-01 Liquitab Systems Limited Improved Apparatus for Disintegration of a Solid and Method

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