BETTEY WILLIAM JOHN (GB)
BRINKLEY DANNY JOHN (GB)
WO2011020862A1 | 2011-02-24 | |||
WO2008003942A2 | 2008-01-10 | |||
WO2011020862A1 | 2011-02-24 |
US20090056826A1 | 2009-03-05 | |||
US20040050860A1 | 2004-03-18 | |||
US20040153262A1 | 2004-08-05 | |||
US20070104864A1 | 2007-05-10 | |||
SU595629A1 | 1978-02-28 | |||
US20070193646A1 | 2007-08-23 | |||
EP0282958A1 | 1988-09-21 |
LU X ET AL: "Ultrasound-assisted microfeeding of fine powders", PARTICUOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 6, no. 1, 1 February 2008 (2008-02-01), pages 2 - 8, XP022938299, ISSN: 1674-2001, [retrieved on 20080122], DOI: 10.1016/J.CPART.2007.10.007
XUESONG LU ET AL: "Microfeeding with different ultrasonic nozzle designs", ULTRASONICS, vol. 49, no. 6-7, 16 January 2009 (2009-01-16), pages 514 - 521, XP055111857, ISSN: 0041-624X, DOI: 10.1016/j.ultras.2009.01.003
S. YANG; J. R. G. EVANS: "A dry powder jet printer for dispensing and combinatorial research", POWDER TECHNOLOGY, vol. 142, no. 2-3, 2004, pages 219 - 222
X. LU; S. YANG; J. R. G. EVANS: "Studies on ultrasonic microfeeding of fine powders", JOURNAL OF PHYSICS D: APPLIED PHYSICS, vol. 39, no. 11, 2006, pages 2444 - 2453, XP020094513, DOI: doi:10.1088/0022-3727/39/11/020
X. LU; S. YANG; L. CHEN; J. R.G. EVANS: "Dry powder microfeeding system for solid freeform fabrication", THE SEVENTEENTH SOLID FREEFORM FABRICATION SYMPOSIUM, 14 August 2006 (2006-08-14)
X. LU; S. YANG; J. R. G. EVANS: "Dose uniformity of fine powders in ultrasonic microfeeding", POWDER TECHNOLOGY, vol. 175, no. 2, 2007, pages 63 - 72, XP022085724, DOI: doi:10.1016/j.powtec.2007.01.029
S. YANG; J. R. G. EVANS: "Metering and dispensing of powder; the quest for new solid freeforming techniques", POWDER TECHNOLOGY., vol. 178, no. 1, 2007, pages 56 - 72, XP002547432, DOI: doi:10.1016/j.powtec.2007.04.004
X. LU; S. YANG; J. R. G. EVANS: "Ultrasound-assisted microfeeding of fine powders", PARTICUOLOGY, vol. 6, no. 1, 2008, pages 2 - 8, XP022938299, DOI: doi:10.1016/j.cpart.2007.10.007
X. LU; S. YANG; J. R. G. EVANS: "Microfeeding with different ultrasonic nozzle designs", ULTRASONICS, Retrieved from the Internet
MATSUSAKA ET AL.: "Microfeeding of a fine powder using a vibrating capillary tube", ADV. POWDER TECHNOL, vol. 7, 1996, pages 141 - 151
Y. YANG; X. LI: "Experimental and analytical study of ultrasonic micro powder feeding", J. PHYS., D, APPL. PHYS., vol. 36, 2003, pages 1349 - 1354, XP055053305, DOI: doi:10.1088/0022-3727/36/11/316
SAITO ET AL.: "A quantitative powder supply method using ultrasonic vibration", J. JPN ACOUST. SOC., vol. 45, 1989, pages 38 - 43
YAHCHUCK ET AL.: "Production of dry powder clots using a piezoelectric drop generation", REV.SCI. INSTRUM., vol. 73, 2002, pages 2331 2335
Claims: 1. Apparatus for dispensing a powder comprising:- a dispensing nozzle having an upper portion for containing a quantity of the powder, a dispensing orifice for dispensing the powder, the dispensing orifice being disposed below the upper portion, wherein the dispensing orifice has a maximum internal horizontal dimension of from 6 mm to 9 mm, an internal passage leading from the said upper portion to the dispensing orifice, wherein the internal passage has an upper end communicating with the said upper portion, and a lower end, communicating with the said orifice, and wherein the said internal passage tapers in a linear manner from its said upper end to its said lower end at a taper angle of from 2° to 60°, and an ultrasonic transducer rigidly coupled to the dispensing nozzle for applying vibrational pulses thereto, and thereby dispensing a dose of powder from the orifice of the dispensing nozzle. 2. Apparatus as claimed in claim 1, wherein the ultrasonic transducer is rigidly fixed to the nozzle by means of a thermosetting adhesive or a UV curable adhesive. 3. Apparatus for dispensing a powder comprising:- a dispensing nozzle having an upper portion for containing a quantity of the powder, a dispensing orifice for dispensing the powder, the dispensing orifice being disposed below the upper portion, wherein the dispensing orifice has a maximum internal horizontal dimension of from 6 mm to 9 mm, an internal passage leading from the said upper portion to the dispensing orifice, wherein the internal passage has an upper end communicating with the said upper portion, and a lower end, communicating with the said orifice, and wherein the said internal passage tapers in a linear manner from its said upper end to its said lower end at a taper angle of from 2° to 60°, an ultrasonic transducer coupled to the dispensing nozzle for applying ultrasonic energy to the nozzle to cause the powder to be dispensed, and a signal generator for supplying a pulsed ultrasonic waveform to the ultrasonic transducer, whereby each said pulse causes the nozzle to dispense a single dose of powder from the orifice, wherein the signal generator includes means for adjusting the frequency, amplitude and duration of said vibrational pulses. 4. Apparatus as claimed in any of the preceding claims wherein the said taper angle is from 25° to 60°, preferably from 25° to 35°. 5. Apparatus as claimed in any one of the preceding claims, including a hopper rigidly fixed to the upper portion of the dispensing nozzle 6. Apparatus as claimed in any one of the preceding claims, including a tank surrounding the dispensing nozzle for containing a fluid, whereby in use, vibrational pulses are transmitted through the fluid to an upper portion of the dispensing nozzle. 7. Apparatus as claimed in claim 6, wherein the dispensing nozzle is formed of a glass and is fused to a glass base portion of the tank. 8. Apparatus as claimed in claims 6, wherein the dispensing nozzle is formed of stainless steel, titanium, an epoxy resin, or polytetrafluoroethylene. 9. Apparatus as claimed in claims 6, wherein the dispensing nozzle is formed of a material having an electrical conductivity that is sufficient to disperse electrostatic charge in the powder. 10. Apparatus as claimed in claim 6, wherein the dispensing nozzle is formed of a metal or metal alloy, and is welded to a metallic base portion of the tank. 11. Apparatus as claimed in any one of the preceding claims, wherein the transducer is a piezoelectric annulus. 12. Apparatus as claimed in any one of the preceding claims, wherein the upper portion of the dispensing nozzle has a maximum internal horizontal dimension of from 10 mm to 12.5 mm. Apparatus as claimed in any one of the preceding claims, wherein the dispensing has a maximum internal horizontal dimension of from 7.5 mm to 8.5 mm. 14. Apparatus as claimed in any one of the preceding claims, including at least one further transducer, positioned so as to direct ultrasonic pulses to the upper portion of the dispensing nozzle. 15. A method of dispensing a powder comprising providing a supply of the powder to a nozzle as claimed in any one of the preceding claims, and supplying a pulsed ultrasonic waveform to the ultrasonic transducer to provide a vibrational pulse train, and thereby dispensing a single dose of powder from the orifice for each pulse of the pulsed waveform. 16. A method as claimed in claim 15, wherein the powder has an angle of repose of from 45°-49°, a particle size distribution such that it has a D50 value of up to 70 μπι, and a Carr' s compressibility index of greater than 25. 17. A method as claimed in claim 16, wherein the powder has a D50 value of from 0.2 μπι to 10 μπι 18. A method as claimed in claim 16, wherein the powder is acetaminophen, a maltodextrin, or lactose. 19. A method as claimed in any one of claims 15 to 18, wherein the nozzle is a nozzle according to claim 6, and wherein a fluid is provided within the tank, for transmitting vibrational pulses to an upper portion of the dispensing nozzle, and wherein the level of the fluid or gel in the tank is maintained at from 50-70% of the tank volume. 20. A method as claimed in any one of claims 15 to 19, wherein a conditioning waveform is applied to the ultrasonic transducer, for a period of at least 12 hours prior to use. |
The present invention relates to the dispensing of powders, and in particular the rapid and accurate dispensing of powders in quantities of greater than 100 mg. There are many situations in which powders must be weighed out or dispensed, rapidly and with high degrees of accuracy and reproducibility. For example, in many industrial research settings, a chemist may be required to prepare dozens of samples daily either from a single stock powder or from various powder samples. Another commercially important situation in which a need exists for the rapid and accurate dispensing of powders is for the industrial production of pharmaceutical products, which are subject to strict quality tests. For example, it is often necessary to dispense precise dosages of a number of powder ingredients into capsules, blister packs and containers. Traditional metering and dispensing methods can be time consuming and labour intensive, and can represent a significant bottleneck in the drug development process.
Laboratory dispensing stations exist in which powders are vacuum aspirated into small vials which are then carried by robot to the destination. The vial is weighed by a built-in balance and this step is repeated until the expected mass is transferred. The devices have high capital cost, and the aspiration method is time consuming, and tends to lose fine powders through the filter and to leave coarse powders in the source bottle.
Many of the most common types of device used for powder dispensing operate pneumatically. Pneumatic devices are able to produce on/off switch control. Metering and dispensing devices based on the pneumatic method are generally simple and therefore easily available for mass production. However, all of the above types of device are lacking in accuracy and reproducibility, especially for poorly flowing powders, of the type frequently used for formulating pharmaceuticals, such as starch and the like. In recent years, vibratory devices have offered the promise of improved accuracy for certain types of powder dispensing operations. US-A-2004/0050860 and US-A- 2004/0153262 disclose devices for dispensing dry powders, in which the powder is contained in a conical hopper, and dispensed by means of a mechanical valve. Vibrational energy, generated by means of a piezoelectric layer on the surface of the hopper is used to assist movement of the powder in the hopper.
This method requires a mechanical valve to close and open the hopper outlet, and is prone to blockage. It is also not well adapted to dispensing powders that are poorly flowing, such as starch-based materials that are frequently used in the preparation of pharmaceuticals.
A number of publications also describe methods for dispensing powders by the use of vibrational pulses, without the need for a mechanical closure valve. Examples of such publications are the following:-
S. Yang and J. R. G. Evans. A dry powder jet printer for dispensing and combinatorial research, Powder Technology 142 (2004), 2-3, 219-222.
X. Lu, S. Yang, J. R. G. Evans. Studies on ultrasonic microfeeding of fine powders, Journal of physics D: Applied physics, 39 (1 1): 2444-2453 2006 DOI: 10.1088/0022- 3727/39/1 1/020
X. Lu, S. Yang, L. Chen and J. R.G. Evans, Dry powder microfeeding system for solid freeform fabrication. The Seventeenth Solid Freeform Fabrication Symposium, Austin, Texas, USA. August 14-16, 2006.
X. Lu, S. Yang, J. R. G. Evans. Dose uniformity of fine powders in ultrasonic microfeeding, Powder Technology, 175 (2) 2007, 63-72.
doi: 10.1016/j.powtec.2007.01.029
S. Yang and J. R. G. Evans. Metering and dispensing of powder; the quest for new solid freeforming techniques. Powder Technology. 178 (1) 2007, 56-72. doi:
10.1016/j .powtec.2007.04.004.
X. Lu, S. Yang, J. R. G. Evans. Ultrasound-assisted microfeeding of fine powders, Particuology 6 (1) 2-8, 2008, DOI: 10.1016/j .cpart.2007.10.007.
X. Lu, S. Yang, J. R. G. Evans. Microfeeding with different ultrasonic nozzle designs, Ultrasonics. http://dx.doi.Org/10.1016/j.ultras.2009.01.003 2009
Matsusaka et al. Microfeeding of a fine powder using a vibrating capillary tube, Adv.
Powder Technol. 7 (1996) 141-151
Y. Yang, X. Li, Experimental and analytical study of ultrasonic micro powder feeding, J. Phys., D, Appl. Phys. 36 (2003) 1349-1354. Saito et al. A quantitative powder supply method using ultrasonic vibration. J. Jpn Acoust. Soc. 45 (1989) 38-43
Yahchuck et al. Production of dry powder clots using a piezoelectric drop generation. Rev. Sci. Instrum. 73 (2002) 2331 2335.
Although these methods have shown considerable promise for dispensing small quantities of powders, we have found that dispensing is frequently inconsistent, because of a tendency for the powder column in the dispensing hopper to break, and/or the formation of "domes" within the dispensing capillary. Such difficulties are particularly acute in the dispensing of certain powder types, especially powders with one or more of the following properties :-
(i) a low bulk density (for example, less than 2,000 kg/m 3 , particularly less than 1,000 kg/m 3 , more particularly less than 500 kg/m 3 ),
(ii) a high angle of repose (for example at least 30°, more particularly at least 40°), (iii) a Carr's compressibility index of greater than 25.
The angle of repose of a granular material can be determined by pouring the material onto a horizontal surface to form a conical pile, and measuring the angle formed between the surface of the conical pile of material, and the horizontal.
There are a number of methods for measuring particle size, which give generally comparable results. For the avoidance of doubt, however, in case of ambiguity, the term "particle size" as used herein is intended to refer to measurements made according to ASTM B822-02.
Many powders used in the formulation of pharmaceuticals are generally found to have poor flowability. Although some of the vibrational dispensing methods discussed above are successful with powders with high flowability (for example metal powders, which have a density of more than 2,000 kg/m 3 ), they are far less successful with poorly flowing powders. US-A-2007/0104864 discloses a method for vaporising particulate material and depositing it on a surface to form a layer. A supply hopper is used to supply the powder material. SU-A-595629 describes a powder dispenser in which a vibrated hopper dispenses powder onto a rotating disc. The powder is sucked through the nozzle by a pump.
US-A-2007/193646 describes a powder-fluidising apparatus for feeding ultrafine and nano-sized powders. The powder is brushed through holes in a removable sieve plate, which breaks up agglomerated particles in the powder and controls the powder feed rate. The funnel surface is continuously vibrated to avoid powder build up on the surface. EP-A-0282958 describes a device for feeding powders by applying mechanical vibrations directly or indirectly to the powder and thereby driving it through a nozzle. The frequency of the vibrations is preferably made equal to the natural resonance of the particles. WO-A-2008/003942 describes a powder dispensing system utilising a complex nozzle structure for delivering a powdered metal to a laser beam for spot wielding.
None of the methods described above are capable of accurately dispensing doses of a powder, in rapid succession, and with high dose accuracy.
WO 2011/020862 discloses a powder dispenser which uses vibrational pulses to accurately dispense small and precise quantities of powders, without the need for a mechanical closure valve. This apparatus is particularly effective for dispensing powder quantities of up to 100 mg. However, the dispenser described is unsuitable for dispensing larger aliquots of poorly flowing powders, for example aliquots in the range of 100 - l,500mg, and in particular for dispensing powders with a Carr's
compressibility index of greater than 25.
Summary of the Invention
We have now developed an improved dispenser which uses vibrational pulses to accurately dispense larger quantities (greater than 100 mg) of poorly flowing powders, in rapid succession, and with high dose accuracy. The novel dispenser does not require a mechanical closure valve, and shows a significantly reduced tendency to stoppages due to dome formation and breakage of the powder column, particularly for dispensing sample aliquots of relatively poorly flowing powders, in particular powders with a Carr's compressibility index of greater than 25 and/or in aliquots of 100 - 1,500 mg.
The apparatus described in WO 201 1/020862 describes the coupling of the dispensing nozzle to a piezoelectric transducer by means of an intermediate "O-ring" seal.
Surprisingly, we have discovered that significantly improved consistency of dispensing can be achieved, as well as higher dosage levels, by fixing the transducer rigidly to the nozzle. The rigid fixing can be achieved for example by means of welding, or by the use of a thermosetting or UV curable adhesive.
According to the first aspect of the present invention, there is provided apparatus for dispensing a powder comprising:- a dispensing nozzle having an upper portion for containing a quantity of the powder, a dispensing orifice for dispensing the powder, the dispensing orifice being disposed below the upper portion, wherein the dispensing orifice has a maximum internal horizontal dimension of from 6 mm to 9 mm, an internal passage leading from the said upper portion to the dispensing orifice, wherein the internal passage has an upper end communicating with the said upper portion, and a lower end, communicating with the said orifice, and wherein the said internal passage tapers in a linear manner from its said upper end to its said lower end at a taper angle (i.e., the angle subtended by the internal walls of the nozzle) of from 2° to 60°, for example 8° to 15° or 25° to 60°,
and an ultrasonic transducer rigidly coupled to the dispensing nozzle for applying vibrational pulses thereto, and thereby dispensing a dose of powder from the orifice of the dispensing nozzle.
The dispensing device in accordance with the invention is capable of providing controlled release, "drop-on-demand" dispensing. The powder flow is controlled by a train of ultrasonic pulses, so that the device behaves like a valve and yet has no mechanical closure. When a wave pulse is sent, the behaviour is like a valve opening, and the powder flows. When the wave is switched off, the valve effectively closes, and powder flow stops. By the choice of an appropriate ultrasonic pulse waveform, accurate dispensing of known doses of a wide range of desired magnitude can be achieved.
A number of factors influence the powder dispense rate and the precision of repeat dispensing, for example, nozzle diameter, waveform, and the amplitude, frequency, and duration of the vibrational pulses in the pulse train. The preferred method of controlling dose size is by control of the amplitude and of the duration of the pulses in the ultrasound pulse train.
Accordingly, a preferred embodiment of the device in accordance with the invention includes means for controlling various parameters associated with the vibrational pulses, for example a signal generator connected to the piezoelectric transducer. The signal generator is configured so as to produce a train of electrical pulses such that the amplitude, frequency, and duration of the pulses, as well as the frequency of the underlying waveform can be controlled so as to match the characteristics of the piezoelectric transducer and the desired dispensing pattern (e.g., the quantity of the powder to be dispensed, and the frequency of the doses dispensed).
Accordingly, a further aspect of the invention provides apparatus for dispensing a powder comprising :- a dispensing nozzle having an upper portion for containing a quantity of the powder, a dispensing orifice for dispensing the powder, the dispensing orifice being disposed below the upper portion, wherein the dispensing orifice has a maximum internal horizontal dimension of from 6 mm to 9 mm, an internal passage leading from the said upper portion to the dispensing orifice, wherein the internal passage has an upper end communicating with the said upper portion, and a lower end, communicating with the said orifice, and wherein the said internal passage tapers in a linear manner from its said upper end to its said lower end at a taper angle of from 2° to 60°, for example 8° to 15° or 25° to 60°,
an ultrasonic transducer coupled to the dispensing nozzle for applying ultrasonic energy to the nozzle to cause the powder to be dispensed , and a signal generator for supplying a pulsed ultrasonic waveform to the ultrasonic transducer, whereby each said pulse causes the nozzle to dispense a single dose of powder from the orifice, wherein the signal generator includes means for adjusting the frequency, amplitude and duration of said vibrational pulses. In a preferred embodiment applicable to all aspects of the invention, the taper angle (i.e., the angle subtended by the internal walls of the nozzle) is in the range from about 25° to about 60°, for example 25° to 35°, such as approximately 30°. In an alternative preferred embodiment the taper angle is in the range from about 8° to about 15°, more preferably from about 9° to about 14°, most preferably about 10° to about 13°.
In a preferred embodiment, the apparatus of the present invention includes a tank surrounding the dispensing nozzle for containing a fluid, for example a liquid or a gel, of the kind described in WO 201 1/020862. The fluid serves as an effective transmitter of ultrasonic pulses generated by a signal generator, from the piezoelectric transducer to an upper portion of the dispensing nozzle. In a further preferred embodiment the tank is filled with a fluid, for example water, to a level of 50-70% of the tank volume.
WO 201 1/020862 describes a dispensing apparatus in which the nozzle is held in position in the tank by means of a rubber "O-ring" to create a water tight seal. We have discovered that a significantly enhanced dispense rate, and an improved consistency of dispensing can be achieved if the nozzle and tank are rigidly coupled to one another. The rigid coupling may be provided, in one embodiment, by forming the dispensing nozzle of glass, and fusing it rigidly to a glass base portion of the tank. In an alternative embodiment, the dispensing nozzle is formed of a metal or a metal alloy, and is welded to a metal base portion of the tank. In a further alternative embodiment, the dispensing nozzle may be formed of stainless steel, titanium, an epoxy resin, or
polytetrafluoroethylene, and may be secured in position in the tank by means of a rigid adhesive (e.g., a thermosetting adhesive such as an epoxy resin).
As described in WO 201 1/020862, the apparatus of the present invention may also include a piezoelectric transducer which is annular in shape which encases the dispensing nozzle.
According to our investigations, the use of a dispensing orifice with a maximum internal dimension of from 6.0 mm to 8.5 mm, in combination with the use of a continuously tapering internal passage from the upper portion of the body of the dispensing apparatus to the dispensing orifice enables powders, and in particular powders otherwise difficult to dispense (i.e. powders with poor flowability), to be delivered from the nozzle by the use of vibrational pulses alone, without the need for a control valve to open or close the orifice, and with a reduced tendency to flow stoppage, as compared with the prior art methods as previously discussed. The taper angle of the walls of the internal passage can play an important role in ensuring the free flowing of the powder through the apparatus without blocking. It is particularly preferred that the walls of the internal passage taper at an angle of from 25° to 60°, more preferably from 25° to 35°, for example approximately 30°. In an alternative preferred embodiment applicable to all aspects of the invention, the taper angle (i.e., the angle subtended by the internal walls of the nozzle) is in the range from about 8° to about 15°, more preferably from about 9° to about 14°, most preferably about 10° to about 13°. The term "the maximum internal horizontal dimension" is used herein since there is no strict requirement that the dispensing orifice should be circular, and other configurations (for example elliptical) are theoretically possible. In most cases, however, the orifice will be circular in cross section, in which case, the term "maximum internal horizontal dimension" refers to the internal diameter of the orifice.
The upper portion of the dispensing nozzle essentially forms a container for the bulk of the powder to be dispensed. Like the dispensing orifice, the upper portion will generally be circular in cross section. Although there is no maximum size for the upper portion, its maximum internal horizontal dimension is usually from 10 mm to 12.5 mm.
According to a second aspect of the present invention, the power dispensed has the following properties:-
(i) low bulk density (for example, less than 2,000 kg/m 3 , particularly less than
1,000 kg/m 3 , more particularly less than 500 kg/m 3 ),
(ii) a high angle of repose (for example, at least 30°, more particularly at least 40°),
(iii) a Carr's compressibility index of greater than 25. Detailed Description
Extensive research has been carried out into understanding the process critical parameters which may influence the dispense rate and the consistency of dispensing for powders of various particle size and flowability, for example, the amplitude, frequency and duration of the signal used to drive the transducer, waveform, ageing of the piezo and the coupling of the various components of the apparatus.
In particular, it was found that the apparatus disclosed in WO 201 1/020862 could not rapidly and accurately dispense poorly flowing powders with a Carr' s compressibility index of greater than 25 such as the maltodextrin powder Pearlitol®160 C.
At least in its preferred embodiments the apparatus of the present invention is able to dispense 100 mg to 1,500 mg of the powder Pearlitol®160 C (and similar large particle size, poorly flowing powders) in less than 1 second with a relative standard deviation (RSD) of less than 5% over prolonged periods of time (i.e. over a period of 7 days). A number of preferred embodiments of the invention will now be illustrated with reference to the accompanying drawings, in which: -
Figure 1 is schematic view of the cross-section of a preferred embodiment of the dispensing device.
Figure 2 shows a detailed view of the cross-section of a preferred embodiment of the dispensing device.
Figure 3 shows a a three-dimensional representation of the embodiment shown in figure 2.
Figure 4 shows the variation of mass dispensed with the distance the nozzle protrudes from the base of the tank, for Pearlitol® 160 C.
Figure 5 shows the relationship between the nozzle diameter, the volume of water in the tank, and the dispense rate for Pearlitol® 160 C.
Figure 6 shows the variation of mass dispensed, with the peak amplitude of the signal used to drive the transducer for Pearlitol® 160 C.
Figure 7 shows the relationship between the peak amplitude of the signal used to drive the transducer, and the precision of repeat dispensing (RSD), for Pearlitol® 160 C. Figure 8 shows the variation of mass dispensed with acoustic drive frequency, for Pearlitol® 160 C. Figure 9 shows the variation of mass dispensed with pulse duration, for Pearlitol® 160 C.
Figure 10 shows the effect of pulse duration on the precision of repeat dispensing (RSD) for Pearlitol® 160 C.
Figure 11 shows the variation of mass dispensed, with the nozzle taper angle, and with the size of the dispensing orifice for a range of powders.
Figure 12 shows the variation of mass dispensed, with the nozzle taper angle, and with the size of the dispensing orifice for a range of powders.
Figures 13-22 show the effect of the nozzle taper angle, and of the size of the dispensing orifice, on the precision of repeat dispensing (RSD) for a range of powders.
Figure 23 shows the relationship between the angle of repose of the powder and the dispense rate, for dispensing nozzles of various dimensions.
Figure 24 shows the relationship between the bulk density of the powder and the dispense rate, for dispensing nozzles of various dimensions.
Figure 25 shows the variation of mass dispensed with pulse duration, using an apparatus with a dispensing orifice of 3 mm, for Acetaminophen APAP
Figures 26 to 27 show the dispensing consistency for various pulse durations, using an apparatus with a dispensing orifice of 6 mm, for Acetaminophen APAP.
Figure 28 shows the variation of mass dispensed with pulse duration, using an apparatus with a dispensing orifice of 6 mm, for Acetaminophen APAP.
Figures 29 to 34 show the dispensing consistency for various pulse durations, using an apparatus with a dispensing orifice of 6 mm, for Acetaminophen APAP.
Figure 35 shows the variation of mass dispensed with pulse duration, using an apparatus with a dispensing orifice of 6.6 mm, for Acetaminophen APAP.
Figures 36 to 40 show the dispensing consistency for various pulse durations, using an apparatus with a dispensing orifice of 6.6 mm, for Acetaminophen APAP.
Figure 41 shows the relationship between the peak amplitude of the signal used to drive the transducer, and the precision of repeat dispensing (RSD), for Inhalac® 70.
Figure 42 shows the variation of mass dispensed and of the precision of repeat dispensing (RSD), with pulse duration, for Inhalac® 70.
Figure 43 shows the variation of mass dispensed with the size of the dispensing orifice, for Inhalac® 230. Figures 44 to 46 show the dispensing consistency, using various sized dispensing orifices for Inhalac® 230.
A preferred embodiment of the invention will now be described with reference to Figure 1. The device of Figure 1 includes an outer glass tank (3), and a glass dispensing nozzle (2), which is fused to a glass hopper (1) and to the base of the tank (3). The tank (3) is filled with water (4) to a level of approximately 65%. A piezoelectric transducer (6) is affixed to the base of the tank (5) by means of a layer of epoxy resin adhesive approximately 0.5 mm thick. The water (4) in the tank (3) assists the transmission of ultrasonic vibration from piezoelectric transducer (6) to nozzle (2).
The lower end of nozzle (2) terminates in a dispensing orifice (7) and protrudes through an opening in the base of the tank (5), which is sealed to prevent egress of water. In an alternative embodiment, the dispensing nozzle is formed of a metal or metal alloy, and is welded to a metal base of the tank. In a further preferred embodiment, the dispensing nozzle is formed of a material with an electrical conductivity such that it is able to disperse electrostatic charge in the powder.
As an alternative to the nozzle being fused or welded to the base of the tank, it may be fixed by an adhesive, preferably a rigid adhesive.
The adhesive is a thermosetting adhesive or a UV cured adhesive which absorbs only relatively small amounts of ultrasonic energy. Preferred thermosetting adhesives are epoxy resins such as UHU 300. Preferably, the thickness of the adhesive layer between the coupled components is between 0.1 mm and 0.5 mm.
In a preferred embodiment, the dispensing nozzle protrudes from the base of the tank such that there is good contact between the piezoelectric transducer and the dispensing nozzle, and thus efficient transfer of vibrational energy between the two components. The distance between the base of the tank and the tip of the dispensing nozzle is preferably greater than 1 mm, more preferably greater than 4 mm, even more preferably greater than 8 mm, and most preferably up to 11 mm. Any small gaps between the piezoelectric transducer and the dispensing nozzle may be filled with a thermosetting adhesive.
Figure 2 shows a detailed schematic of a preferred embodiment, applicable to all aspects of the invention. The features of figure 1 as described above may equally be applied to the embodiment illustrated in figure 2.
The device of Figure 2 includes an outer tank (H) and a dispensing nozzle which may be fused to a hopper and/or may be fixed, fused or welded to the base of the tank.
The hopper walls are of approximate thickness (R) of 1.4 mm and it has a horizontal diameter at the upper end (S) of approximately 40 mm. The hopper walls subtend an angle (T) of approximately 37.3°. The hopper has a vertical dimension (M) of approximately 40 mm.
The nozzle walls are of approximate thickness (N) 1.1 mm. The nozzle has an internal diameter (P) of approximately 10.8 mm and external diameter (C, Q) of approximately 13 mm. The nozzle has a vertical dimension (K+F) of approximately 160 mm from the dispensing orifice to the base of the hopper.
The lower end of the nozzle terminates in a dispensing orifice and protrudes through an opening in the base of the tank, which is sealed to prevent egress of water.
The total vertical dimension (L, where L = F + K + M) from the dispensing orifice to the top of the hopper is approximately 200 mm.
The upper portion of the nozzle has a vertical dimension (K) of approximately 149 mm. The internal passage of the nozzle has a vertical dimension (F), from the end of the upper portion to the dispensing orifice, of approximately 11 mm. Said internal passage tapers in a linear manner from its upper end to the dispensing orifice at a taper angle
(i.e., the angle subtended by the internal walls of the nozzle) of from approximately 10° to approximately 13°. The internal diameter (E) of the dispensing orifice is
approximately 8.2 mm and external diameter (D) is approximately 10 mm. The walls of the tank have a thickness (G) of approximately 1.6 mm. The tank is approximately 40 mm in external diameter (B) and 122 mm in height (J). The tank may be filled with water to a level of approximately 65%. A piezoelectric transducer may be affixed to the base of the tank as described for figure 1 above, by means of a layer of epoxy resin adhesive approximately 0.5 mm thick. The water in the tank assists the transmission of ultrasonic vibration from piezoelectric transducer to the nozzle.
Figure 3 shows a three-dimensional representation of a preferred embodiment such as that shown in figure 2 and described in detail above.
Figure 4 shows the effect of the distance the dispensing nozzle protrudes from the base of the tank on the dispense rate. The figure clearly shows that the dispense rate is approximately doubled when the vertical distance between the base of the tank and the dispensing orifice is 1 1 mm, compared to when the dispensing orifice is level with the base of the piezo (0 mm protrusion).
The upper portion of the dispensing nozzle essentially forms a container for the bulk of powder to be dispensed. The larger the dispensing nozzle, the more powder can be stored to be dispensed, but also the larger degree of powder compaction and particle segregation.
The upper portion of the dispensing nozzle will generally be circular in shape, however, other configurations (for example elliptical) are theoretically possible. The maximum internal horizontal dimension of the upper portion of the dispensing nozzle is at least 10 mm, preferably at least 10.5 mm, and more preferably at least 1 1 mm. Although there is no maximum value for the size of the upper portion, its maximum internal horizontal dimension is typically less than 20 mm, preferably less than 15 mm and more preferably less than or equal to 12.5 mm. The volume of fluid in the surrounding vessel has a significant effect on dispensing performance. Furthermore, the maximum horizontal dimension of the dispensing nozzle can significantly affect the volume of the fluid required in the tank in order to achieve the optimum dispensing performance.
In a preferred embodiment, the maximum internal horizontal dimension of the upper portion of dispensing nozzle is about 1 1 mm, and the volume of fluid in the tank surrounding the dispensing nozzle is greater than 50 percent, preferably greater than 55 percent, more preferably greater than 60 percent, and most preferably greater than 65 percent based on the total volume of the tank. The volume of fluid in the tank surrounding the dispensing nozzle is preferably less than 100 percent, more preferably less than 90 percent, even more preferably less than 80 percent, and most preferably less than 70 percent based on the total volume of the tank. The volume of fluid in the tank is such that there is sufficient fluid to sonicate a sufficient portion of the dispensing nozzle to permit a controlled flow of powder from the dispensing orifice. When the fluid level in the tank is too high, the transmission of ultrasonic energy provided by the
piezoelectric transducer is reduced such that powder bridges begin to form in the dispensing nozzle.
In another embodiment, the tank for containing fluid is omitted, and the maximum internal horizontal dimension of the upper portion of the dispensing nozzle is at least 12.5 mm, such that the upper portion of the dispensing nozzle is large enough to allow the powder to flow freely through the dispensing nozzle without the need for ultrasonic energy
Figure 5 shows the effect of water volume on dispense rate for dispensing nozzles with an upper portion with a maximum internal horizontal dimension of 1 1 mm or 12.5 mm. As can be seen, when the maximum internal horizontal dimension is 1 1 mm, dispense rate increases with increasing water volume, whereas when the maximum internal horizontal dimension is 12.5 mm, the optimal dispense rate is observed when the tank is empty.
The maximum internal horizontal dimension of the upper portion of the dispensing nozzle, the taper angle of the walls of the internal passage and the maximum internal horizontal dimension of the dispensing orifice are to some extent interdependent. The taper angle of the walls of the internal passage can play an important part in ensuring the free flowing of the powder through the apparatus without blocking.
Preferably, the walls of the internal passage taper at an angle of from 2° to 60°, preferably 25° to 60°, more preferably from 25° to 35°, for example approximately 30°. In an alternative preferred embodiment applicable to all aspects of the invention, the taper angle (i.e., the angle subtended by the internal walls of the nozzle) is in the range from about 8° to about 15°, more preferably from about 9° to about 14°, most preferably about 10° to about 13°. The preferred taper angle for dispensing Pearlitol® 160 C is 60°. The preferred taper angle for dispensing some other powders is as shown in Figures 1 1 to 22.
There is a delicate balance between determining the optimal dispensing orifice size required in order to achieve a sufficient powder flow rate and a high degree of precision. Preferably, the maximum internal horizontal dimension of the dispensing orifice is from 3 mm to 9 mm, preferably from 6 mm to 9 mm.
The dispensing nozzle preferably extends above the tapered nozzle section by at least 50 mm, preferably at least 75 mm, and most preferably at least 100 mm. The wall thickness of the dispensing nozzle influences the propagation of the ultrasonic waves. Preferably the dispensing nozzle has a wall thickness of up to 1 mm.
The frequency of the signal used to drive the piezoelectric transducer has a direct relationship with the powder dispense mass. The signal generator preferably generates a signal in the frequency range of 20-60 kHz, and most preferably about 50 kHz, suitable for causing generation of an acoustic signal, preferably an ultrasonic signal, by the piezoelectric transducer. The frequency of the signal generated by the signal generator is in the region of the resonant frequency of the piezoelectric transducer, and may for example be in the range 49.5 kHz to 51.0 kHz
In one embodiment, the signal generator produces a waveform of fixed amplitude and of fixed frequency. In an alternative preferred embodiment, the device employs a "phase locked loop" driving mode in which the ultrasonic driver is able to match the frequency of the piezoelectric transducer. The signal generator may be configured so that the signal is modulated to form a pulse train, preferably with a pulse rate of from 10-0.5 Hz, and a mark: space ratio of approximately 1 : 1. There is a direct relationship between the dispense rate and the peak amplitude of the signal used to drive the piezoelectric transducer. There is also a direct relationship between the precision of repeat dispensing (i.e., relative standard deviation, or "RSD"), and the peak amplitude of the acoustic signal used to drive the piezoelectric transducer.
Figure 6 shows the relationship between pulse amplitude and the mean dispense mass at a predetermined pulse frequency and duration, using Pearlitol® 160 C. The figure demonstrates that the dispense mass increases with increasing the amplitude from 600 mV to 1500 mV, with a gradual plateau at about 1100 mv.
Figure 7 shows the relationship between precision of repeat dispensing (RSD) and the amplitude of the acoustic signal, over a range of 600 mV to 1500 mV, using Pearlitol® 160 C. The figure indicates that the optimal amplitude range is from about 900 mV to about 1100 mV.
Figure 8 shows the effect of acoustic drive frequency on the amount of powder dispensed per dose, using Pearlitol® 160 C. It can be seen that there is a clear relationship between the acoustic drive frequency and the amount of powder dispensed, and an optimum drive frequency of 50.1 kHz. According to our investigations, dispense mass increases linearly with the duration of the pulse used to drive the piezoelectric transducer, when a pulse of a predetermined amplitude and frequency is applied. In the specific embodiments shown in Figure 1 and Figure 2, the pulse duration required in order to achieve a specific powder dispense mass can be calculated according to the following equation: Dispense time = (Target mass - 44.471) / 0.8572
The pulse duration is preferably between 100 ms and 1000 ms, and most preferably greater than 300 ms.
Figure 9 shows the effect of pulse duration on the amount of powder dispensed per dose, using Pearlitol® 160 C, dispensed using a 8.0 mm nozzle size, at varying pulse durations (100 ms to 1000 ms), with a signal amplitude of 500 mV. It can be seen that the mass dispensed per dose is directly proportional to the pulse duration.
Figure 10 shows the effect of pulse duration on the precision of repeat dispensing (RSD), using Pearlitol® 160 C, dispensed using a nozzle with a 8.0 mm dispensing orifice, at varying pulse durations, (100 ms to 1000 ms), with a signal amplitude of 500 mV. It can be seen that the RSD ranged from 8.2% to 2.5%, and an RSD of less than 5% was achieved for all pulse durations of greater than 300 ms.
Table 1 - Specification for nozzle for dispensing Pearlitol® 160 in quantities of >100mg
The piezoelectric transducer is preferably formed of a so-called "hard" piezoceramic material. Preferred piezoelectric transducers include those of types PZT4 and PZT8.
The piezoelectric transducer is preferably annular in shape. It may be orientated so as to provide either latitudinal or longitudinal vibrations. In an alternative preferred embodiment, the piezoelectric transducer may be in the form of a sheet which is wrapped around the dispensing nozzle. In a further alternative embodiment, the entire nozzle, or an inner coating of the nozzle, may be formed of a piezoelectric oscillator material.
The ultrasonic transducer is preferably "conditioned" before use, in order to improve dispensing consistency. In a preferred embodiment, this may be done by applying a conditioning waveform to the ultrasonic transducer, for a period of at least 12 hours prior to use.
Typically, the powder is fed into the dispensing nozzle by means of a non-compacting feeding mechanism.
Conditioning of the powder may be necessary in some cases to ensure optimal dispensing. This may be achieved via the feeding mechanism, and may consist of aeration, tapping, or sonication.
Environmental conditions such as humidity can be important to dispensing consistency. In a preferred embodiment of the present invention, the humidity is less than 50 percent, preferably less than 45 percent, and most preferably less than 30 percent.
The dispensing nozzles may be interchangeable thus enabling various dosages of a range of powders to be dispensed.
The following Examples demonstrate the effect of the taper angle and the size of the dispensing orifice on the mean dispense mass and precision of repeat dispensing (i.e. RSD) for a range of powders, at a fixed signal amplitude of 2000 mV, a pulse duration of 1000 ms, and using a dispensing nozzle with an upper portion internal diameter of 1 1 mm. In general, an apparatus with a dispensing orifice of 6 mm internal diameter, in combination with a 30° taper angle was found to give the optimal performance across the range of powders tested in terms of mean dispense mass. Table 2 - Powder properties
Dispensing of Acetaminophen APAP
The following Examples demonstrate the effect of the dispensing orifice diameter and pulse duration on the mean dispense mass and the precision of repeat dispensing (RSD) using Acetaminophen APAP powder mixture (coated with Eudragit LI 00 50%, Pearlitol® 160 C 44.75%, Nutriose FB 06 2.5%, Emcompress Premium 2.5%, Vivastar P 0.25%).
A dispensing apparatus with a dispensing orifice of 3 mm internal diameter dispensed aliquots of 50 mg to 100 mg with an RSD ranging from 4.8% to 5.9%, employing a pulse duration of 400 ms to 1000 ms. The results show a linear relationship between pulse duration and the mean dispense mass. Target Max Min
Dosage Pulse Mean Dose SD RSD Dose Dose Dose
(mg) Length (s) Mass (mg) (mg) (%) (mg) (mg) No.
100 1 105 5 4.8 119 95 76
50 0.4 49 3 5.9 58 44 68
A dispensing apparatus with a dispensing orifice of 6 mm internal diameter dispensed aliquots of about 300 mg to 1300 mg with an RSD ranging from 4.7% to 5.9%, employing a pulse duration of 120 ms to 1000 ms. The results show a linear relationship between pulse duration and the mean dispense mass.
Table 4
Target Max Min
Dosage Pulse Mean Dose SD RSD Dose Dose Dose (mg) Length (s) Mass (mg) (mg) (%) (mg) (mg) No.
1300 1 1272 47 4.7 1389 1141 40 1
1100 0.8 1105 58 5.2 1252 927 71
900 0.66 946 47 4.9 1090 864 93
700 0.46 704 37 5.3 812 627 113
500 0.3 501 24 4.8 577 449 120
300 0.12 319 19 5.9 370 277 128
The use of an apparatus with a dispensing orifice of 6.6 mm internal diameter dispensed aliquots of about 900 mg to 2400 mg with an RSD ranging from 3% to 4.9%, employing a pulse duration of 200 ms to 1000 ms. The results show a linear relationship between pulse duration and the mean dispense mass. Target Max Min
Dosage Pulse Mean Dose SD RSD Dose Dose Dose (mg) Length (s) Mass (mg) (mg) (%) (mg) (mg) No.
2400 1 2373 102 4.3 2560 2110 35
2000 0.8 1998 61 3 2107 1894 36
1700 0.6 1659 50 3 1773 1540 48
1300 0.4 1306 52 4 1447 1216 50
900 0.2 918 45 4.9 1058 826 64
Dispensing of Inhalac® 70
Figure 41 shows the influence of the pulse amplitude on the dispense mass and the precision of repeat dispensing (RSD) using Inhalac® 70. It can be seen that dispense mass increases with increasing pulse amplitude, with an optimal pulse amplitude in the range of about 1200 and 1500 mV. A general increase in precision of repeat dispensing is also observed with increasing pulse amplitude.
Figure 42 shows the effect of pulse duration on the amount of powder dispensed per dose and the precision of repeat dispensing (RSD) using Inhalac® 70. It can be seen that the mass dispensed per dose is linearly related to the pulse duration. The RSD ranged from about 5.0% to 2.5%.
Dispensing of Inhalac® 230
Figures 43 to 46 show the effect of the dispensing orifice diameter and pulse duration on the mean dispense mass for Inhalac® 230. As can be seen in the figures, the mean dispense mass increases with increasing size of the dispensing orifice. Embodiments of the present invention have been described with particular reference to the examples illustrated. However, it will be appreciated that variations and
modifications may be made to the examples described within the scope of the
appending claims.