Apparatus and method to collect respirable drug particles

Abstract

An apparatus (1) for collecting respirable drug particles (3) from a transporting fluid (5), the apparatus comprising at least one inertial particle separator and a collector (9). The inertial particle separator (7) is configured to receive the fluid (5) and separate a particle size fraction from the fluid. The collector (9) is operably in flow connection (11) with the inertial particle separator (7) to receive the fluid proceeding (13) from the inertial particle separator (7), the collector (9) comprising a chamber (15) for receiving the fluid at a proximate end (17) and having an outlet (19) at a distal end (21) at which the fluid exits the chamber (15), the chamber (15) configured to have a filter (23) disposed at a first distance (25) from the proximate end (17) and at a second distance (27) from the distal end (21) to allow for a substantially laminar fluid flow through the filter (23) and disperse the respirable drug particles (3) for collection over the filter (23).

Description

“Apparatus and method to collect respirable drug particles”Technical Field

[0001] The present disclosure relates to an apparatus, collector, and method to collect respirable drug particles. This has particular application in collecting drug particles as aerosols in a transporting fluid. The drug particles can include orally inhaled and nasal drug products.Background

[0002] One form of pharmaceutical drug delivery includes pharmaceuticals in the form of respirable drug particles. These drugs may be delivered by inhalation and typically require the drug in a powdered aerosol form. This can include dry powder inhaler (DPI) The drug particles are aerosols in a transporting fluid, which typically includes air.

[0003] Other known drug delivery methods include metered dose inhalers (MDI) that has a pressurised transporting fluid, such as a hydrofluorocarbon. Yet another drug delivery system includes soft mist inhalers (SMI). Yet another drug delivery method includes nebulisers.

[0004] To analyse the physiochemical properties of aerosols containing drug (and other) particles from an inhaler, instruments have been developed to capture such particles. One example is to use a cascade impactor. A cascade impactor can include multiple stages, where particles impact respective collection plates for collection. Generally the upstream stages collect larger particles, and subsequent downstream stages collect successively smaller particles. The particles deposited on the collection plates may be collected for further analysis.

[0005] An example of an impactor is a Next Generation Impactor (NGI) offered by MSP Corporation, a division of TSI International, and Copley Scientific. This is a multi-stage impactor with multiple stages, where each stage has successively smaller nozzles to increase fluid velocity and corresponding impaction cups. A schematic example is illustrated in Figs. 13 to 15.

[0006] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0007] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.Summary

[0008] There is provided an apparatus for collecting respirable drug particles from a transporting fluid, the apparatus comprising: an inertial particle separator configured to receive the fluid and separate a particle size fraction from the fluid; and a collector operably in flow connection with the inertial particle separator to receive the fluid proceeding from the inertial particle separator, the collector comprising a chamber for receiving the fluid at a proximate end and having an outlet at a distal end at which the fluid exits the chamber, the chamber configured to have a filter disposed at a first distance from the proximate end and at a second distance from the distal end to allow for a substantially laminar fluid flow through the filter and disperse the respirable drug particles for collection over the filter.

[0009] In some examples the apparatus comprises a sequence of inertial particle separator stages, each stage in the sequence being an inertial particle separator configured to separate a respective particle size fraction from the fluid, the collector operably in flow connection with any one stage in the sequence, wherein successive stages downstream in the sequence are configured to separate successively smaller particle size fractions from the fluid.

[0010] In further examples of the apparatus, the collector is operably in flow connection with any one stage in the sequence by means of a selectively removable coupling, wherein the collector is selectively coupled subsequent to a selected stage to divert the fluid proceeding from the selected stage from successive stages in the sequence for receipt at the collector.

[0011] In some examples of the apparatus, each stage in the sequence is a stage of an impactor used for aerodynamic particle size distribution testing, the collector selectively coupled subsequent to the selected stage by means of the selectively removable coupling securing the collector at an aperture provided at an interstage passage between the selected stage and a successive stage.

[0012] In some examples of the apparatus, the impactor used for aerodynamic particle size distribution testing is a Next Generation Impactor (NGI).

[0013] In some examples of the apparatus, the collector is configured to deposit the respirable drug particles for collection substantially uniformly over the filter.

[0014] In some examples of the apparatus, a fluid flow rate in the chamber is in a range of 30 L / min to 100 L / min and the first distance at which the filter is disposed from the proximate end is greater than, or equal to, 50 mm.

[0015] In further examples of the apparatus, the first distance at which the filter is disposed from the proximate end is greater than, or equal to, 100 mm.

[0016] In further examples of the apparatus, the first distance at which the filter is disposed from the proximate end is greater than, or equal to, 200 mm.

[0017] In further examples of the apparatus, the fluid flow rate in the chamber is approximately 60 L / min and the first distance is approximately 100 mm.

[0018] In further examples of the apparatus, the chamber comprises a first part defining the first distance between the proximate end and the filter, the first part having a substantially conical shape tapering towards the proximate end.

[0019] In further examples of the apparatus, the chamber comprises a second part defining the second distance between the filter and the distal end, the second part having a substantially cylindrical shape.

[0020] In further examples of the apparatus, the second distance is greater than or equal to 7 mm.

[0021] In further examples of the apparatus, the second distance is greater than 10mm.

[0022] In some examples of the apparatus, the outlet comprises a vacuum connector for coupling a suction source to enable fluid flow from an inlet of the chamber to the outlet.

[0023] There is also provided a process for collecting respirable drug particles from a transporting fluid for solid state analysis, the process comprising: receiving the fluid in an inertial particle separator to separate a particle size fraction from the fluid; and receiving the fluid proceeding from the inertial particle separator into a collector. The collector comprising: a chamber for receiving the fluid at a proximate end and having an outlet at a distal end; the chamber configured to have a filter disposed at a first distance from the proximate end and at a second distance from the distal end to allow for a substantially laminar fluid flow through the filter and disperse the respirable drug particles. The method further comprising: collecting the respirable drug particles over the filter; and flowing the fluid to exit the chamber at the outlet.

[0024] There is also provided a method of modifying an impactor used for aerodynamic particle size distribution testing of respirable drug particles, the impactor comprising a sequence of stages, each stage comprising an inertial particle separator configured to separate a particle size fraction from a fluid. The method comprising: defining an aperture at an interstage passage between a selected stage and a consecutive stage of the sequence of stages; affixing an attachment at the aperture, the attachment configured to selectively couple a collector at the aperture; and securing the collector at the aperture to operably bring the collector in flow connection with selected first stage and divert the fluid proceeding from the selected stage for receipt at a proximate end of the collector, the collector configured to have a filter at a first distance from the proximate end and at a second distance from a distal end having an outlet at which the fluid exits the chamber to allow for a substantially laminar fluid flow through the filter to collect respirable drug particles over the filter.

[0025] There is also provided a collector for an impactor used for aerodynamic particle size distribution testing of respirable drug particles in a transporting fluid and comprising a sequence of stages in flow connection by respective interstage passages, each stage comprising an inertial particle separator configured to separate a respective particle size fraction from the fluid. The collector comprising: a chamber having a proximate end and adistal end, the proximate end configured to be selectively coupled at an aperture defined in an interstage passage of the interstage passages to operably bring the collector in flow connection with a stage of the impactor and divert fluid proceeding from the stage from a successive stage in the sequence for receipt at the proximate end of the collector; the chamber configured to have a filter disposed at a first distance from the proximate end and at a second distance from the distal end to allow for a substantially laminar fluid flow through the filter; an outlet disposed at the distal end and at which the fluid exits the chamber, wherein the chamber is configured to deposit the respirable drug particles for collection over the filter.Brief Description of Drawings

[0026] Fig. 1 illustrates a sectioned side view of an apparatus for collecting respirable drug particles from a transporting fluid;

[0027] Fig. 2 illustrates a view of the apparatus of Fig. 1 in a closed configuration;

[0028] Fig. 3 illustrates a view of the apparatus of Figs. 1 and 2 with a lid opened and showing stage nozzle units of a sequence of stages of inertial particle separators;

[0029] Fig. 4 illustrates the top of the apparatus of Fig. 1 and illustrating a selectively removable coupling at the lid for attaching a collector;

[0030] Fig. 5 is a flow diagram of a process for collecting respirable drug particles from a transporting fluid;

[0031] Fig. 6 is a flow diagram of a method of modifying an impactor used for aerodynamic particle size distribution testing of respirable drug particles;

[0032] Fig. 7 illustrates a sectioned side view of an apparatus for collecting respirable drug particles where a collector is configured to receive transporting fluid from a first stage of the apparatus;

[0033] Figs. 8(a) to 8(d) illustrates a computational fluid dynamics model (CFD) of flow velocity of a transporting fluid through a conical first part of a collector, and with various first distance lengths of the first part;

[0034] Figs. 9(a) and 9(b) illustrates a CFD model of flow velocity of a transporting fluid through a conical first part of a collector, where the flow rate is at 30L / min and at 90 L / min;

[0035] Fig. 10(a) illustrates a CFD model of flow velocity of a transporting fluid through a chamber of the collector, including the flow at a second part of the collector with various second distance lengths of the second part, where the flow rate is at 60L / min;

[0036] Fig. 10(b) illustrates a CFD model of flow velocity of a transporting fluid through a chamber of the collector through the second part where the flow rate is at 90L / min;

[0037] Fig. 11(a) illustrates an example filter used in a collector where the second distance of the second part in the collector is negligible and showing particle accumulating near a centre;

[0038] Fig. 11(b) illustrates an example filter used in a collector where the second distance of the second part in the collector is at 7mm and showing uniform distribution of particles;

[0039] Fig. 12(a) is an electron microscope image of a filter placed in a collection cup of a next generation impactor and showing particles compacting in the filter;

[0040] Fig. 12(b) is an electron microscope image of a filter used in a collector of the apparatus of Fig. 1 where the particles a dispersed in the filter;

[0041] Fig. 13 illustrates an example of a next generation impactor;

[0042] Fig. 14 illustrates the next generation impactor of Fig. 13 in an open configuration;

[0043] Fig. 15 illustrates a schematic sectioned side view of one stage of the next generation impactor of Figs. 13 to 14.

[0044] Fig. 16 are graphs illustrating the result of an experiment with a first distance of 50 mm; and

[0045] Fig. 17 are graphs illustrating the result of an experiment with a first distance of 100 mm.Description of Embodiments

[0046] Example of a next generation impactor

[0047] A next generation impactor 900 is illustrated in Figs. 13 to 15. This includes an induction port 901 to receive a stream of transporting fluid 5 containing respirable drug particles 3, such as from an inhaler. A pre- separator 904 may be provided to separate large particles before the transporting fluid is passed through a sequence 930 of inertial particle separator stages 931 at a body 932.

[0048] Referring to Fig. 14 where the next generation impactor 900 is in the open configuration, each stage 931 has an inertial particle separator 307 with a stage nozzle unit 934. The stage nozzle unit 934 that has one, or more nozzle apertures 936. A first stage 938, in this illustrated example, has a single nozzle aperture 940. Successive stages 931 have multiple nozzle apertures, with each successive stage having nozzle apertures with smaller diameters (and a large number of nozzle apertures 936).

[0049] Fig. 15 illustrates a cross-section of one example stage 931. As the transporting fluid 5 travels downstream from the induction port 901 (or from an interstage passage 945 from a previous upstream stage), the transporting fluid passes through the stage nozzle unit 934. The diameter (i.e. size) of the nozzle apertures 936 as well as the number of nozzle apertures 936 affect the velocity of the transporting fluid 5 travelling through the stage nozzle unit 934.Smaller diameters of the nozzle apertures 936 can increase the velocity of the flow of transporting fluid 5. The transporting fluid 5 subsequently impinges against a collection cup 944, where at least some of the drug particles 3 are collected.

[0050] The transporting fluid 5 then travels to a subsequent interstage passage 945’ and flows to the next downstream stage. The next stage, in this example, will be provided with a stage nozzle unit 934 with relatively smaller diameter nozzle apertures 936 so that the transporting fluid 5 will impact the next collection cup 944 with a higher velocity. After the final stage, the transporting fluid passes through an outlet 950. The outlet 950 may be in communication with a vacuum or suction source to assist removal of the transporting fluid.

[0051] During use as an impactor, the next generation impactor 900 is typically in a closed configuration as illustrated in Fig. 13. After the samples of particles are collected at the collection cups 944, a clamping mechanism 952 is released so that the impactor 900 can be opened to an open configuration in Fig. 14. The collection cups 944 can then be removed to recover the collect samples for further analysis.

[0052] It is to be appreciated that impactors can be in other forms, such as those listed in the United States Pharmacopeia. This can include the Andersen Cascade Impactor (ACI).

[0053] Overview

[0054] An example of an apparatus 1 for collecting respirable drug particles 3 from a transporting fluid 5 will now be described with reference to Figs. 1 to 4. The drug particles can include orally inhaled and nasal drug products. This can include very fine respirable drug particles, that in some examples have an average aerodynamic diameter of 10 microns or less. In some examples, this the particles have an average diameter of 20 microns or less.

[0055] At Fig. 1, the apparatus 1 includes an inertial particle separator 7 configured to receive the fluid and separate a particle size fraction from the fluid 5. The inertial particle separator 7 may be similar, or based on, the inertial particle separator 907 or stage 931 described above.

[0056] A collector 9 is operably in flow connection 11 with the inertial particle separator 7 to receive fluid proceeding 13 from the inertial particle separator 7. This includes, receiving fluid 5 that has impacted the collection cup 44 of the inertial particle separator 7.

[0057] The collector 9 comprises a chamber 15 for receiving fluid at a proximate end 17 and having an outlet 19 at a distal end 21 (where the fluid exits the chamber 15). The chamber 15 is configured to have a filter 23 disposed at a first distance 25 from the proximate end 17.The filter 23 is also disposed at a second distance 27 from the distal end 21 to allow for a substantially laminar fluid flow through the filter 23 and to disperse the respirable drug particles 3 for collection over the filter 23.

[0058] The filter 23 can then be removed from the collector 9 so that the respirable drug particles 3 collected at the filter 23 can be further analysed.

[0059] The apparatus 1 may be part of a multi-stage impactor. Referring to Fig. 2, the impactor may include multiple stages, each with an inertial particle separator. A collector 9 may be selectively located after one of the multiple stages so that the aerosols (i.e. drug particles 3) in the transporting fluid 5 after that stage can be collected and analysed.

[0060] There is also described a process 100 for collecting respirable drug particles 3 from a transporting fluid 5 to enable solid state analysis as illustrated in Fig. 5. In some examples, this includes first receiving 110 the fluid 5 in an inertial particle separator to separate a particle size fraction from the fluid 5. The process includes subsequently receiving 120 fluid 5 proceeding from the inertial particle separator 7 into a collector 9 (as described above). The process includes collecting 130 the respirable drug particles 3 over the filter and flowing 140 the fluid 5 to exit the chamber 15 of the collector 9 at an outlet 19.

[0061] There is also disclosed a method 200 of modifying an impactor 41 used for aerodynamic particle size distribution testing of respirable drug particles. The impactor 41, in some examples, includes the impactor 900 described above with reference to Figs. 13 to 15. The method 200 includes defining 210 an aperture 43 at an interstage passage 45, 945 between a selected stage 35 and a consecutive second stage 37 of the sequence of stages 30. The method includes affixing 220 an attachment 34 at the aperture 43, the attachment 34 configured to selectively couple a collector 9 at the aperture 43. The method includes securing 230 the collector 9 at the aperture 43 to operably bring the collector 9 in flow connection 11 with the selected stage 35 and divert the fluid 5 proceeding from the selected stage 35 for receipt at a proximate end 17 of the collector 9. The collector 9, as described above, is configured to have a filter 23 at a first distance 25 from the proximate end 17 and a second distance 27 from a distal end 21 that has the outlet 19 for the fluid 5 to exit the chamber 15. This configuration enable substantially laminar fluid flow through the filter 23 to collect respirable drug particles 3 over the filter 23.

[0062] Components of the apparatus 1, of a non-limiting example, will now be described in detail.

[0063] Impactor 41

[0064] Referring to Figs. 2 and 3, the apparatus 1, may be in the form of an impactor 41. The impactor 41 includes an impactor frame 10 that is hinged 14 to an impactor lid 12. During operation, the impactor 41 is normally closed (as shown in Fig. 2) to enable the transporting fluid to flow through at least one of the inertial particle separators (7). In the closed configuration, the lid 12 is secured to the frame 10 by clamping mechanism 52.

[0065] Transporting fluid 5 is received into the impactor 41 via an inlet.

[0066] The transporting fluid can be received from induction port to receive a stream of transporting fluid 5 containing respirable drug particles 3, such as from an inhaler. The induction port, in turn is fluidly connected to an inlet 16 of the impactor 41. A pre- separator (not shown) may be provided between the induction port and the inlet 16 to separate larger particles.

[0067] As illustrated in Fig. 3, this example impactor 41 includes a sequence 30 of inertial particle separator stages 31. Each stage in the sequence has a respective inertial particle separator 7 configured to separate a respective particle size fraction from the fluid. As will be discussed in further detail below, each stage has stage nozzle units 34 with respective one or more nozzle apertures 40. Starting with the first stage (see left-hand side of Fig. 3), the nozzle unit 34 has a single nozzle aperture 40 that is relatively larger than nozzle apertures 40 of other stages. The downstream stages have nozzle units 34 that have additional nozzle apertures 36 with successively smaller nozzle aperture diameters. The size of the nozzle apertures 40 (as well as number of nozzle apertures) at the stage nozzle unit 34 can affect the velocity of the transporting fluid 5 flowing out of the stage nozzle unit 34. Each inertial particle separator stage 31 are configured to collect different particle sizes.

[0068] In this examples, a stage is linked to a preceding and / or successive stage by respective interstage passage 45. That is the fluid 5 flowing out of an upstream stage flows as an input to the next downstream stage.

[0069] The multiple stages enable cascading, and targeted, collection of respirable drug particles 3 based (in part) on particle size. Generally, it can be expected that particles of alarger size are collected at the earlier stages. Successive stages (37) downstream in the sequence (30) are configured to separate successively smaller particle size fractions from the fluid (5). However, it is to be appreciated that smaller particles may also collect at earlier stages).

[0070] A difference between the impactor 41 illustrated in Figs. 1 to 4 compared with the impactor 900 of Figs. 13 to 15, is the inclusion of an aperture 43 at one or more interstage passage(s) 45 between a selected stage 35 and a successive stage 37 in the sequence of particle separator stages 31. The selected stage 35 is the stage just before fluid is diverted for receipt at the collector 9. This diversion to the collector 9 mean that the fluid does not reach the successive stage(s) 37 in the sequence.

[0071] The impactor 41 may be configured with an aperture 43 for each (or for the substantial majority) of the inertial particle separator stages 31 in the sequence 30. Referring to Fig. 2, there are seven apertures 41 provided through the lid 12, where each of the apertures are in fluid connection with a respective interstage passage 45 after an inertial particle separator stage 31. The first three apertures 43 are each covered with a blanking plate 48. Similarly, the last three apertures 43 are also each covered with a blanking plate 48. By using blanking plates 48 covering the apertures 43, the interstage passage 45 effectively functions to provide fluid connection as if the apertures 43 were not present.

[0072] Referring to Figs. 2 and 3 the middle aperture 43, that is in fluid connection with the interstage passage 45 connecting the fourth and fifth stages, is connected to a selectively removable coupling 33. The coupling 33 enables a flow connection 11 from the fluid 13 flowing out of the selected stage 35 (which in this example is the fourth stage) whereby the fluid is diverted from the interstage passage 45 to be received at the collector 9.

[0073] In the example with a plurality of apertures 43, this enables an operator to have a choice to select which one of the stages 31 in the sequence 30 for use with the collector 9. That is, the blanking plates 48 and the coupling 33 may be removed and arranged based on user selection. In some examples, only one collector 9 is used to be operably in flow connection 11 with any one stage in the sequence 30.

[0074] Referring to Fig. 3, there are eight overall stages. This includes a sequence 30 of seven inertial particle separator stages 31 with nozzle apertures 36. This is followed by an eighth stage that includes a micro-orifice collector stage, where the nozzle unit 34 includes very small nozzle apertures 36 (such as ~70 microns in diameter) to collect extremely fine particles at a respective collection cup 44.

[0075] In some examples, the impactor 41 is used for aerodynamic particle size distribution testing and is, or a modified, form of a Next Generation Impactor (NGI).

[0076] Individual stage

[0077] An example of a selected stage 35 of the inertial particle separator 7 is illustrated in Fig. 1. The fluid 5 is received from an interstage passage 45” from a preceding stage, whereby the fluid 5 passes through the nozzle apertures 40 of the stage nozzle unit 34. The transporting fluid 5 passes through the nozzle apertures 40 at a velocity and impacts the collection cup 44. Some of the drug particles 3, of the particle size fraction, collects at the collection cup 44. The collection cup 44 may be subsequently removed from the impactor 41 so that the collected drug particle fraction can be analysed.

[0078] The remaining transporting fluid 13 (with some remaining respirable drug particles 3) continue towards the next interstage passage 45. This can be directed towards a subsequent successive inertial particle separator stage 37. However, in the illustrated example of Figs. 1 and 3, the remaining transporting fluid 13 after the selected stage 35 is directed from the interstage passage 45 to the collector 9 via a flow connection 11 facilitated by the aperture 43 and removable coupling 33.

[0079] Selectively removable coupling 33 and aperture 43

[0080] Referring to Fig. 4, the aperture 43 is a circular aperture passing through the impactor lid 12 and to the interstage passage 45 (as shown in Fig. 3). A plurality of fasteners 62 attach the selectively removable coupling 33 to the impactor lid 12.

[0081] It is to be appreciated that the aperture 43 has a diameter sized to enable laminar flow. In some examples, to achieve laminar flow the minimum diameter of an aperture is 18mm (for 30 L / min), 36mm (for 60 L / min), and 54mm (for 90 L / min). However, due tospace constrictions between aperture 43 and the adjacent nozzle, the minimum diameter of the aperture 43, in some examples is 41 mm (for 90 L / min).

[0082] In some examples, the apertures 43 has a diameter of between 10mm to 55mm. In further examples the aperture 43 is between 18mm to 41mm (inclusive).

[0083] The selectively removable coupling 33 also includes a corresponding aperture to enable flow connection 11 of the fluid to the collector 9. As shown in Fig. 4, the coupling includes threaded apertures 64 configured to receive additional fasteners which, in some examples, could be used to secure the collector 9 to the coupling 33.

[0084] It is to be appreciated that the selective attachments to the coupling 33 may be achieved by other means. For example, the aperture 43 may include an internal thread and the coupling 33 having a corresponding external thread to enable the coupling 33 to be in threaded engagement with the aperture 43 in the lid 12.

[0085] Fig. 4 also illustrates examples of blanking plates 48 that can be used to close off other apertures 43 in the impactor lid 12 that are not being used with the collector 9. The blanking plates 48 may comprise a cover that are selectively secured over apertures 43, such as by fasteners 66.

[0086] Collector 9

[0087] An example of the collector 9 will now be described with reference to Figs. 1 and 2. The collector 9 includes a chamber 15 having a proximate end 17 and a distal end 21. The proximate end 17 is configured to be selectively coupled at the aperture 43 defined in the interstage passage 45. The fluid 13 diverted to the collector 9 enters the chamber 15 via the proximate end 17.

[0088] As noted above, this selective coupling may be achieved via the coupling 33. This arrangement brings the collector 9 into flow connection 11 with the selected stage 35 of the impactor 41 such that fluid proceeding from the selected stage 35 is diverted into the collector 9 rather than to the successive stage 37 in the sequence 30.

[0089] The collector 9 is further configured to receive a filter 23 disposed at a first distance 25 from the proximate end 17. This arrangement is configured to deposit respirable drug particles 3 in the fluid for collection over the filter 23.

[0090] The filter 21, when in place, is disposed at a second distance 27 from the distal end 21 of the chamber 15. The collector 9 is ideally configured to allow for a substantially laminar fluid flow through the filter 23.

[0091] An outlet 19 is disposed at the distal end 21 at which the fluid exits the chamber 15. This can include using a vacuum connector 61 that, in turn, is coupled to a suction source (not shown) to collect the remaining fluid 5, 13. The suction source can facilitate fluid flow from the inlet 18 of the chamber 15 to the outlet 19. The suction source may, in some examples, be important for safe disposal or venting of the fluid that may contain trace amounts of drugs and / or gasses of the transporting fluid that should be removed from a laboratory environment.

[0092] The filter 23 may be configured as a substantially planar circular disc with a surface that is surface normal to the flow of fluid through the chamber 15. In some examples, the filter may include glass fibres. In one example, the filter is an A / E glass microfiber offered by Cytiva / Pall Lab / Pall Lie Sciences). Other types of filters may include fibres of: nylon, polytetrafluoroethylene (PTFE), polyethersulfone, polyamide, quartz, cellulose acetate, and polycarbonate.

[0093] In some examples, the filter 23 is between 30mm and 100mm in diameter. In further examples, the filter 23 is between 30mm and 70mm in diameter. In yet further examples, the filter 23 is approximately 40mm to 60mm in diameter. In yet further examples, the filter 23 is approximately 50mm in diameter. In yet another example, the filter 23 is approximately 47mm in diameter.

[0094] In some examples, the filter 23 is a glass fibre filter with borosilicate glass without binder. This can include filters with thickness of approximately 30 micrometres. In some examples, the filter 23 may be 8 inches by 10 inches (20.3cm by 25.4cm) with a thickness of 330 micrometres and with a maximum operating temperatures of approximately 550 degrees Celsius.

[0095] The collector 9 is configured so that as the fluid 5, 13, passes through the filter 23, respirable drug particles are deposited substantially uniformly over the filter 23. This is aided by the laminar flow of the fluid through the chamber 15. This can be further aided by the selected shape, dimensions, and flow rates as will be described in non-limiting examples below.

[0096] In some examples, the fluid flow rate in the chamber 15 is in a range of 30L / min to lOOL / min. In some examples, the fluid flow rate through the chamber is approximately 30L / min. In other examples, the fluid flow rate through the chamber 15 is approximately 60L / min. In yet other examples, the fluid flow rate through the chamber 15 is approximately 90L / min.

[0097] In some examples, the first distance 25 at which the filter 23 is disposed from the proximate end 17 is greater than, or equal to 50mm. In further examples, the first distance 25 at which the filter 23 is disposed from the proximate end 17 is greater than, or equal to 100mm. In yet further examples, the first distance 25 at which the filter 23 is disposed from the proximate end 17 is greater than, or equal to 200mm. In some examples, the first distance 25 is between 50mm and 200mm. In some examples, the first distance 25 is approximately 150mm.

[0098] In some examples, the chamber 15 comprises a first part 51 that defines the first distance 25 between the proximate end 17 and the filter 23. The first part 51 having a substantially conical shape 53 (of the interior surface) that tapers towards the proximate end 17. This is illustrated at Fig. 1 where the first part 51 is wider near the filter 23 and narrows towards the proximate end 17. It is to be appreciated that the substantially conical shape 53 can include a frustoconical shape.

[0099] The substantially conical shape 53 staring with a relatively smaller diameter at the proximate end 17 and leading to a wider diameter near the filter 23 assists in slowing the velocity of the fluid 13 flowing into the filter 23. This can also assist in reducing turbulence and providing substantially laminar flow as the fluid 13 flows to the filter 23.

[0100] In some examples, the substantially conical shape 53 of the first part 51 near the proximate end has a diameter of between 10 to 55mm. In further examples, the diameter isbetween 18mm and 41mm (inclusive). In other examples, the diameter is between 15mm and 30mm.

[0101] In some examples, the conical shape 53 of the first part 51 near the filter 23 has a diameter of between 30 and 100mm. In further examples, the diameter is between 30mm and 60mm. In further examples, the diameter is approximately 50mm. In yet another example, the diameter is approximately 47mm.

[0102] The chamber 15 also comprises a second part 55 defining the second distance 27 between the filter 23 and the distal end 21. In some examples, the second part 55 has a substantially cylindrical shape (in the interior surface). The second distance 27 in some examples, is greater than or equal to 7mm. In other examples, the second distance 27 is greater than or equal to 10mm. In other examples, the second distance 27 is greater than or equal to 20mm. In some examples, the second distance 27 is approximately 14mm. In yet other examples, the second distance is approximately 15mm. In some examples, the second distance is between 7mm and 20mm.

[0103] Example computation fluid dynamics modelling of the chamber 15

[0104] Computational fluid dynamics (CFD) simulation was performed to determine the optimal first distance 25 and second distance 27. The optimal first distance 25 provided the least degree of air re-circulation (turbulence) inside the collector 9 to prevent any behaviour change e.g. in situ de- agglomeration and re-agglomeration that can affect aerosols to be collected. The second distance 27 corresponded to the height that allowed fluid flow to be fully developed so aerosols can be collected uniformly on the filter surface instead of concentrating at the centre part of the filter 23.

[0105] Optimal first distance 25 (modelled)

[0106] CFD simulation showed that at a fluid flow rate into the chamber of 60 E / min, when the first distance 25 is increased from 12.5 to 25 and further to 50 mm, the degree of air turbulence increased. We refer to Figs. 8(a) to 8(c) (with first distances of 12.5mm, 25mm, and 50mm respectively) that illustrate velocity of fluid flow 74, where circles 70 indicate regions of the flow inside the chamber where fluid re-circulation is occurring. That is, part ofthe fluid is flowing back towards the proximate end 17 rather than flowing through the filter to the distal end 21. However, when the first distance 25 was increased to 200mm, the air recirculation was eliminated in the modelling. This is illustrated at Fig. 8(d).

[0107] With the above models (with first distance 25 of 12.5mm to 50mm), when the air flow rate increased from 30 to 60 to 90 L / min, the degree of air re-circulation only increased slightly. Where the first distance 25 was at 200 mm, the air re-circulation was eliminated at both 30 and 90 L / min. This is illustrated in Figs. 9(a) and 9(b) that shows the modelled flow with a first distance of 200mm, where Fig. 9(a) is with a flow rate into the chamber of 30L / min and Fig. 9(b) is with a flow rate of 90L / min.

[0108] Optimal second distance 27 (modelled)

[0109] CFD showed that a second distance of 7 mm is the minimum height required for the fluid flow to be fully developed. Fig. 10(a) illustrates fluid flow 72 with a 7mm second distance 27 and flow 72 with a 14mm second distance 27’ where the flow rate is 60L / min. Fig. 10(b) illustrates fluid flow 72” with a 7mm second distance 27 and a flow 72’” with a 14mm second distance 27’ where the flow rate is 90 L / min.

[0110] These models show that fluid flow distributes uniformly across the filter surface, indicating that aerosols will be collected uniformly on the filter instead of accumulating in the centre, which minimises the formation of compacted in situ agglomerates.

[0111] This observation from the CFD model was confirmed in an experiment when mannitol powder was aerosolised and collected on the filter 23 of collector 9 without a second distance 27 (as illustrated in Fig. 11(a)) and with a second distance 27 of 7mm (as illustrated in Fig. 11(b)). In Fig. 11(a) it can be seen that the powder collected near the centre of the filter 23. In contrast, Fig. 11(b) that had a second distance 27 of 7mm, show substantially uniform distribution of the dyed powder across the surface of the filter 23. Consequently, the in vitro dissolution behaviour of the collected aerosol particles when an additional second distance 27 is adopted into the collector 9 design is expected to better mimic the dispersed particles in aerosols.

[0112] Results of experiment with the apparatus

[0113] To show the presence of in situ agglomerates when aerosol particles are collected in the original NGI, scanning electron microscopy was utilised. Commercial dry powder inhaler formulations Advair Diskus® (GlaxoSmithKline, North Caroline, USA) and Wixela Inhub® (Mylan Pharmaceuticals, West Virginia, USA) were employed. Advair and Wixela are reference and generic formulations, respectively. Aerosol particles retained on the filters 76 placed under the nozzles of original Next Generation Impactor 900 (i.e. placed in the collection cup 944) showed the presence of a large amount of compacted in situ agglomerates, as illustrated in Fig. 12(a), which will reduce the exposure of the collected particles to the dissolution medium during the dissolution study). In contrast, those particles collected on the filters 23 of collector 9 in the presently disclosed apparatus 1, 41 were more dispersed instead of forming compacted in situ agglomerates (as illustrated in Fig. 12(b)). These images shows that the design of the apparatus may minimise the formation of in situ agglomerates which will introduce an artefact in a subsequent in vitro dissolution study.

[0114] Process 100 for collecting respirable drug particles

[0115] The process 100 for collecting respirable drug particles 3 from a transporting fluid for further analysis will now be described with reference to Fig. 5. The process 100 may be performed using the apparatus 1 and impactor 41 described above. This can include first selecting one of stages, in the sequence, from which fluid 5 passing out of that selected stage 35 should be sampled. In the example illustrated in Figs. 2 and 3, the fourth stage is the selected stage 35 and the process can include selectively coupling the collector 9 to the aperture 43 that is in fluid connection with the interstage passageway 45 between the fourth and fifth stage. The method can also include coupling a suction source to the vacuum connector 61 (which in turn is fluidly connected to the outlet 19).

[0116] The process 100 can include ensuring the blanking plates 48 are provided on apertures 43 than are not selectively connected to the collector 9. This can be particularly important for apertures upstream of the collector 9.

[0117] In some examples, the user may desire collecting a sample of respirable drug particles from a transporting fluid from another stage. As an illustrative example, thecollector 9 is initially configured to collect from the fourth state (as illustrated in Fig. 1) and a user wishes to adjust the configuration to collect from a first stage (as illustrated in Fig. 7). This can involve reconfiguring the apparatus 1 and impactor 41 by selectively removing the collector 9 from the aperture 43 at the fourth stage (as illustrated in Figs. 2 and 4) and replacing the coupling 33 with a blanking plate 48 over the aperture 43. The blanking plate 48 covering the aperture 43 that is in fluid connection 11 with the interstage passageway 45 between the first and second stages is then removed. The collector 9 is then selectively coupled to the aperture 43 so that fluid from the first stage can be collected as illustrated in Fig. 7.

[0118] Once the collector 9 is configured, an inhaler is configured to provide a dosage to be analysed. This includes connecting the output of the inhaler to feed the transporting fluid into the inlet of the apparatus 1. The inhaler may include dry powder inhaler (DPI), metered dose inhaler (DPI), soft mist inhaler (SMI), nebuliser, etc. It is to be appreciated that other drug delivery devices that deliver respirable drug particles may be used.

[0119] The suction source is then activated assist in drawing any transporting fluid 5 through the chamber 15. The process then includes activating the inhaler to provide a dosage in a transporting fluid that is then received 110 into the inertial particle separator 7 to separate a particle size fraction from the fluid. Referring to Figs. 1 and 7, this can include the collection cup 44 collecting some of the impacted drug particles. The transporting fluid then begins travelling through an interstage passageway 45 to the next stage (if applicable). Where one or more next stages are configured, the fluid may pass through those stages for particles to be collected at respective collection cups 44. However, where the collector 9 is configured after the inertial particle separator 7, the fluid coming from that inertial particle separator 7 is diverted to the collector 9. Respirable drug particles 3 remaining in the transporting fluid 5is then collected 130 over the filter 23 in the collector 9. After passing through the filter, the remaining transporting fluid exits the chamber 15 via the outlet 19. The suction source then removes the transporting fluid.

[0120] After collection, the filter 23 (with drug particles 3) can be removed from the collector 9 for further analysis. This can include subsequent in vitro dissolution study of the particles.

[0121] Although the above example has been described with reference to sampling from fluid exiting the first stage or the fourth stage, it is to be appreciated that a user can apply this process and the collector 9 to any of the stages in the sequence of stages 30. Furthermore, although this example has been described with reference to a multiple stage impactor, it is to be appreciated that the process could be used in an impactor that has a single inertial particle separator 7 (i.e. one stage). The example illustrated in Fig. 7, although in a multiple stage impactor, illustrates collection after the transporting fluid 5 having been received through a single inertial particle separator.

[0122] Fabrication and method 200 of modifying an impactor 41

[0123] The apparatus 1 and impactor 41 may be formed from a modification of a next generation impactor 900. With reference to Fig. 6, there is a method 200 of modifying an impactor 41, 900 to utilise the disclosed collector 9. This can include modifying the Next Generation Impactor 900 illustrated in Fig. 13.

[0124] The method 200 includes defining 210 an aperture 43 at an interstage passageway 45 between two consecutive stages in the sequence of stages 30 This can typically include drilling an aperture 43 in the lid 932 of the impactor. The lid may also be drilled and tapped to receive fasteners proximal to the aperture 43 so that an attachment can be affixed to the aperture 43. The attachment may include selectively removable coupling 33 (for a collector 9) or alternatively blanking plates 48) As noted above, the selectively removable coupling 33 enables a collector 9 to secured to the aperture 43 so that it brings the collector 9 to be in flow connection with the interstage passageway 45 between a selected stage 35 and a successive stage 37 in the sequence 30. That is diverting fluid that would have flowed to the successive stage 37 to the collector 9. The collector 9, as described above, is configured with a chamber 15 and a filter, wherein the fluid has a substantially laminar fluid flow through the filter 23 to collect respirable drug particles.

[0125] Advantages

[0126] During respirable drug particle collection, the collector is connected to a vacuum pump that draws the aerosols in the moving airstream. The filter fitted inside the collector collects all the aerosols that can be used for further in vitro dissolution testing.

[0127] As noted above, one advantage of example configurations of the collector 9 and filter 23 in the apparatus is to collect particles 3 substantially uniformly over the filter. This can be assisted, at least in part, by the substantially laminar fluid flow of the transporting fluid through the filter.

[0128] Another advantage is the quality of collection of drug particles in the filter 23 compared to collection of particles at the collection cup 944. In the collection cup 944, the particles from the nozzles impacting the collection cup may result in large amount of compacted in situ agglomerates (e.g. clumps) which can reduce the exposure of the collected particles to the dissolution medium during a dissolution study. In contrast, the presently disclosed apparatus, collector, process, and method may provide more dispersed particles that are collected in the filter 23.

[0129] The present disclosure may, in some examples, be retrofitted to existing next generation impactors 900. The presently disclosed apparatus and collector may also provide flexibility as an operator can selectively couple the collector to a desired selected stage in the sequence of stages in the next generation impactor.

[0130] Variations

[0131] It is to be appreciated that features of the presently disclosed apparatus could be used in modifications or retrofitting of other types of impactors. This can include modification of Andersen Cascade Impactors (ACI).

[0132] It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0133] Experiment and results

[0134] An experiment was conducted with different first distances 25, being the lengths between the filter 23 and the proximate end 17.

[0135] The experiment included :a. Sample tested: Advair Diskus™ 100 / 50 mcg (Fluticasone propionate and Salmeterol) b. Length of first distance 25: i. 50mm; and ii.100mm c. Number of actuations: 1

[0136] i. Result of 50mm experiment

[0137] The percentage of drug recovered on a 50 mm aerosol dose collector (ADC) (that is a first part 51 of collector 9 with a first distance 25 of 50mm) when placed at different stages 31 of the modified Next Generation Impactor (NGI) (M1-M5), ranged from 60% to 90% as illustrated in the graphs in Fig. 16. This recovery rate is suboptimal, as a significant portion of both drugs, fluticasone propionate (FP) and salmeterol xinafoate (SX), is adsorbed onto the ADC surface rather than collected on the filter 23. The amount of drug recovered on the filter directly influences the rate and extent of drug dissolution, which is critical for validating the use of ADCs in dry powder inhaler dissolution studies.

[0138] ii. Result of 100mm experiment

[0139] Drug recovery analysis using a 100 mm ADC (a first part 51 of the collector 9 with a first distance 25 of 50mm) demonstrated that 90% to 100% of the drug was collected on the filter , with minimal retention of fluticasone propionate (FP) and salmeterol xinafoate (SX) in the collector as illustrated in the graphs in Fig 17. This result represents a significant improvement compared to the 50 mm ADC. These findings confirm that ADC length is a critical factor in minimizing drug retention within the collector. The reduced drug retention in the 100 mm ADC is attributed to decreased turbulent airflow and recirculation, which are more pronounced in the shorter 50 mm ADC, leading to increased drug adsorption.

Claims

CLAIMS:

1. An apparatus (1) for collecting respirable drug particles (3) from a transporting fluid (5), the apparatus comprising: an inertial particle separator (7) configured to receive the fluid (5) and separate a particle size fraction from the fluid; a collector (9) operably in flow connection (11) with the inertial particle separator (7) to receive the fluid proceeding (13) from the inertial particle separator (7), the collector (9) comprising a chamber (15) for receiving the fluid at a proximate end (17) and having an outlet (19) at a distal end (21) at which the fluid exits the chamber (15), the chamber (15) configured to have a filter (23) disposed at a first distance (25) from the proximate end (17) and at a second distance (27) from the distal end (21) to allow for a substantially laminar fluid flow through the filter (23) and disperse the respirable drug particles (3) for collection over the filter (23).

2. The apparatus of claim 1, comprising a sequence (30) of inertial particle separator stages (31), each stage in the sequence being an inertial particle separator (7) configured to separate a respective particle size fraction from the fluid, the collector (9) operably in flow connection (11) with any one stage in the sequence, wherein successive stages (37) downstream in the sequence (30) are configured to separate successively smaller particle size fractions from the fluid (5).

3. The apparatus of claim 2, wherein the collector (9) is operably in flow connection (11) with any one stage in the sequence by means of a selectively removable coupling (33), wherein the collector (9) is selectively coupled subsequent to a selected stage (35) to divert the fluid proceeding from the selected stage (35) from successive stages (37) in the sequence for receipt at the collector (9).

4. The apparatus of claim 3, wherein each stage in the sequence is a stage of an impactor (41) used for aerodynamic particle size distribution testing, the collector (9) selectively coupled subsequent to the selected stage (35) by means of the selectively removable coupling (33) securing the collector (9) at an aperture (43) provided at an interstage passage (45) between the selected stage (35) and a successive stage (37).

5. The apparatus of claim 4, wherein the impactor (41) used for aerodynamic particle size distribution testing is a Next Generation Impactor (NGI).

6. The apparatus of any one of the preceding claims, wherein the collector (9) is configured to deposit the respirable drug particles for collection substantially uniformly over the filter (23).

7. The apparatus of any one of the preceding claims, wherein a fluid flow rate in the chamber (15) is in a range of 30 L / min to 100 L / min and the first distance (25) at which the filter (23) is disposed from the proximate end (17) is greater than, or equal to, 50 mm.

8. The apparatus of claim 7, wherein the first distance (25) at which the filter (23) is disposed from the proximate end (17) is greater than, or equal to, 100 mm.

9. The apparatus of claim 8, wherein the first distance (25) at which the filter (23) is disposed from the proximate end (17) is greater than, or equal to, 200 mm.

10. The apparatus of claim 7, wherein the fluid flow rate in the chamber (15) is approximately 60 L / min and the first distance (25) is approximately 100 mm.

11. The apparatus of any one of the preceding claims, wherein the chamber (15) comprises a first part (51) defining the first distance (25) between the proximate end (17) and the filter (23), the first part (51) having a substantially conical shape (53) tapering towards the proximate end (17).

12. The apparatus of any one of the preceding claims, wherein the chamber (15) comprises a second part (55) defining the second distance (27) between the filter (23) and the distal end (21), the second part (55) having a substantially cylindrical shape.

13. The apparatus of claim 12, wherein the second distance (27) is greater than or equal to 7 mm.

14. The apparatus of claim 13, wherein the second distance (27) is greater than 10mm.

15. The apparatus of any one of the preceding claims, wherein the outlet (19) comprises a vacuum connector (61) for coupling a suction source to enable fluid flow from an inlet (18) of the chamber (15) to the outlet (19).

16. A process (100) for collecting respirable drug particles (3) from a transporting fluid(5) for solid state analysis, the process comprising: receiving (110) the fluid (5) in an inertial particle separator (7) to separate a particle size fraction from the fluid; receiving (120) the fluid (5) proceeding from the inertial particle separator (7) into a collector (9), the collector comprising: a chamber (15) for receiving the fluid at a proximate end (17) and having an outlet (19) at a distal end (21); the chamber (15) configured to have a filter (23) disposed at a first distance (25) from the proximate end (17) and at a second distance (27) from the distal end (21) to allow for a substantially laminar fluid flow through the filter (2) and disperse the respirable drug particles (3); collecting (130) the respirable drug particles (3) over the filter (23); and flowing (140) the fluid to exit the chamber (15) at the outlet (19).

17. A method (200) of modifying an impactor (41) used for aerodynamic particle size distribution testing of respirable drug particles, the impactor (41) comprising a sequence (30) of stages (31), each stage (31) comprising an inertial particle separator (7) configured to separate a particle size fraction from a fluid, the method comprising: defining (210) an aperture (43) at an interstage passage (45) between a selected stage (35) and a consecutive stage (37) of the sequence of stages; affixing (220) an attachment (33) at the aperture (43), the attachment (33) configured to selectively couple a collector (9) at the aperture (43); and securing (230) the collector (9) at the aperture (43) to operably bring the collector (9) in flow connection (11) with selected first stage (35) and divert the fluid proceeding from the selected stage (35) for receipt at a proximate end (17) of the collector (9), the collector (9) configured to have a filter (23) at a first distance (25) from the proximate end (17) and at a second distance (27) from a distal end (21) having an outlet (19) at which the fluid (5) exits the chamber (15) to allow fora substantially laminar fluid flow through the filter (23) to collect respirable drug particles (3) over the filter (23).

18. A collector (9) for an impactor (41) used for aerodynamic particle size distribution testing of respirable drug particles in a transporting fluid (5) and comprising a sequence (30) of stages (31) in flow connection by respective interstage passages (45), each stage (31) comprising an inertial particle separator (7) configured to separate a respective particle size fraction from the fluid, the collector (9) comprising: a chamber (15) having a proximate end (17) and a distal end (21), the proximate end (17) configured to be selectively coupled at an aperture (43) defined in an interstage passage (45) of the interstage passages to operably bring the collector (9) in flow connection (11) with a stage (35, 71) of the impactor (41) and divert fluid proceeding from the stage (35) from a successive stage (37) in the sequence (30) for receipt at the proximate end (17) of the collector (9); the chamber (15) configured to have a filter (23) disposed at a first distance (25) from the proximate end (17) and at a second distance (27) from the distal end (21) to allow for a substantially laminar fluid flow through the filter (23); an outlet (19) disposed at the distal end (21) and at which the fluid (5) exits the chamber (15), wherein the chamber (15) is configured to deposit the respirable drug particles (3) for collection over the filter (23).

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