Mark Copley, of Copley Scientific, and Paul Kippax, Malvern Instruments, offer a glimpse of how laser diffraction-based particle sizing can provide data on nebuliser/drug combinations that help when assessing the performance of nebuliser systems
Nebulisers are one of the most widely used inhalation delivery devices in the clinical environment. Unlike other inhalation devices, nebulisers do not deliver a pre-metered dose and so may be used with a range of different therapeutic drugs, as directed by the prescribing clinician.
Once loaded and activated, nebulisers operate continuously, delivering the drug as an aerosol cloud produced from a liquid formulation. Rapid and efficient delivery of the drug to the correct part of the respiratory tract is the defining performance characteristic, and droplet size within the aerosol is a critical factor in achieving this.1
Drug delivery from nebulisers takes place under normal tidal breathing conditions, with the user's breathing pattern determining the inhalation rate of the drug and ultimately the amount of active delivered. This is particularly true of breath-assisted nebulisers, where inhalation triggers aerosol flow from the nebuliser, reducing aerosol wastage during exhalation. The patient's inhalation effort can also be used to assist in the production of fine particles, by taking advantage of the increased pressure drop across the device observed during inhalation.
For a number of years, nebulisers were tested in accordance with the European Committee for Standardisation (CEN) Standard for Respiratory Therapy Equipment EN 13544-1. In 2006, the EMEA issued new guidance that recognised that the safety and efficacy of a nebulised product depends on the nebuliser/drug combination.
As a result, a newly proposed USP and Ph.Eur. monograph2 now defines a testing approach similar to that for other inhaled pharmaceuticals, requiring delivered dose uniformity and aerodynamic particle size distribution (as assessed using a multiple stage cascade impactor) for each inhaled drug/device combination.
The EMEA guidance acknowledges the importance of the patient's inhalation profile in determining the delivered dose. For this reason, it is recommended that a sinusoidal breath simulator is used in assessing the active substance delivery rate and total active delivered. The breathing pattern employed during testing is intended to simulate that of an adult, although different breathing patterns may be used where necessary, for example in the case of drugs intended for paediatric use.
The requirement to use simulated breathing profiles does not, however, extend to assessing the particle size distribution, because a fixed flow rate is needed when using cascade impaction. Instead, users are recommended to perform these measurements using an impactor system, calibrated for use at a flow rate not exceeding 15 l/min (typical of the mid-inhalation flow rate of a healthy adult), which allows collection and chemical analysis of the active pharmaceutical ingredient by HPLC.
Laser diffraction-based particle sizing is finding increased application in the area of nebuliser characterisation. The technique allows for the real-time measurement of the size of droplets produced during nebuliser operation.3,4 Measurements can be made at varying flow rates without affecting the accuracy of the results obtained, making it ideal for assessing the impact of different inhalation profiles on device operation. Laser diffraction therefore, provides complementary information to that yielded by cascade impaction.
The following studies, using the Spraytec (Malvern Instruments), illustrate how the laser diffraction particle sizing technique can be applied to understanding the operation of a breath-assisted nebuliser system.
Droplets are formed within this nebuliser by shearing the liquid within a compressed-air driven venturi. Changes in the air flow rate through the venturi can be used to control the delivered particle size. In addition, the design of the device is such that the flow induced by the patient during inhalation is used to aid fine droplet formation. In this case, the Copley BRS 1000 Breath Simulator (Copley Scientific) was used to actuate the nebuliser using a range of sinusoidal flow patterns, allowing the rapid assessment of how the output of the nebuliser changes in relation to the applied inhalation profile.
Figure 1 shows the changes in the median droplet size (Dv50) and concentration delivered by the breath-assisted nebuliser during a simulated inhalation profile. In this case, the nebuliser was actuated using a sinusoidal breathing rate of 10 breaths per minute, with a tidal volume of 500ml and an inhalation/exhalation ratio of 1:1. The output was monitored using the Spraytec system at a data acquisition rate of 500Hz (one measurement every 2 msec), allowing the detail of the nebuliser's operation to be followed.
The results obtained show that the nebuliser delivered droplets for around 70% of the inhalation cycle. The aerosol concentration increases rapidly at the start of inhalation, reaching a steady value at the mid-point of the breathing profile. Initially, a relatively large droplet size is reported - this relates to the coalescence of droplets within the device prior to the start of inhalation.
However, the droplet size rapidly decreases within the first 60 msec of the inhalation cycle. This is followed by a gradual increase in the Dv50 during the mid-point of the inhalation profile. Finally, towards the end of the inhalation cycle, the droplet size starts to increase more rapidly, as the atomisation process becomes less efficient. This is associated with a rapid decrease in concentration, as the valve on the nebuliser starts to close.
The breath simulator can be set to provide a different number of breaths per minute (bpm) to allow different patient groups to be modelled. Figure 2 shows the effect of increasing the breathing rate on Dv50 delivered by the nebuliser. The Dv50 decreases as the bpm rate increases, especially during the mid-point of the breathing profile.
This is confirmed in figure 3, where the change in the average Dv10 (particle size below which 10% of the volume of droplets exists), Dv50 and Dv90 (particle size below which 90% of the volume of droplets exists) calculated for all the measurements made at each breathing rate is shown. These observations relate to the increased pressure-drop across the device at higher breathing rates, which increases the energy available for liquid atomisation within the device.
All the above results relate to the operation of the nebuliser using a compressed air flow rate of 4 l/min. This air supply provides the primary source of energy for atomisation, and therefore offers another means of controlling the droplet size. This is confirmed in figure 4, where the change in droplet size distribution delivered by the device is shown for different compressed air flow rates, using a breathing rate of 20 bpm. A gradual reduction in the overall droplet size distribution is observed as the gas flow rate increases.
The use of nebulisers to deliver a range of locally acting and systemic drugs is increasing. Recently issued guidance recognises that the safety and efficacy of a nebulised product depends on the nebuliser/drug combination. This defines an approach to testing that requires assessment of delivered dose uniformity and aero-dynamic particle size for each device/drug combination.
With its ability to deliver real-time measurements of the concentration and size of droplets produced during nebuliser operation, laser diffraction-based particle sizing is finding increased application for nebuliser characterisation. Its ability to provide real-time data is proving a useful addition to routine use of cascade impaction for assessing performance of nebuliser systems.