Nebulisers - when size really matters

Correct particle size is a crucial consideration in determining the effectiveness of nebulisers as a method of drug delivery. David Higgs and Paul Kippax, of Malvern Instruments, discuss the implications

Nebulisers are widely used as a convenient and effective means of delivering drugs to the respiratory tract. These therapies include bronchodilators and steroids for asthma control, rhDNase used in cystic fibrosis, and some antibiotic treatments.For therapy to be effective, the nebuliser device must deliver the drug quickly and effectively to the appropriate part of the respiratory tract, while simultaneously avoiding wastage.

A key parameter in defining the efficiency of nebuliser treatments is the particle size of the aerosol cloud, as this defines the deposition site for the drug within the respiratory tract.¹ The smaller the particle size, the more likely it is that the droplets will be deposited in the lungs rather than the mouth or throat. However, it is equally important that care is taken to avoid the production of extremely fine particles of less than 0.5µm, as these may be exhaled.

deposition sites

Modelling studies conducted in the 1960s helped to define the deposition site for particles of different sizes (Table 1).² This work indicated that material larger than 10µm tends to be deposited in the mouth or throat, whereas for material that is between 5 and 10µm, deposition tends to occur in the upper respiratory tract. Only material below 5µm showed significant deposition in the lungs.

Based on these findings the British Standards Institute developed the following specifications for particles produced by nebuliser devices:³

• Particle diameters greater than 5µm are required for nebuliser therapies targeting the upper airways

• Particle diameters less than 5µm are required for tracheobronchial deposition

• Particle diameters less than 2µm are required for alveolar deposition

multiple measurements

Traditionally, particle size measurements for respirable materials have been made using techniques such as the industry standard cascade impactor. Although well established, this is labour-intensive, requires multiple measurements and accommodates only a constant flow rate. There are also problems associated with the measurement of liquid droplets due to evaporation and condensation within the impactor.⁴

This article describes the application of a specialised laser diffraction-based particle sizing system (Spraytec, Malvern Instruments) in measuring the particle size of aerosols produced by different devices at constant and variable flow rates.

Studies have shown a direct correlation between the median droplet size reported by laser diffraction and the percentage of material that is deposited in the lungs.⁵

high speed measuring

The Spraytec system is a high speed measurement device that is designed specifically for characterising sprays and aerosols, and which can be interfaced with standard respiratory testing equipment. Specific data inversion routines accommodate the analysis of sprays with high or rapidly changing concentrations and high temporal resolution allows fine fluctuations to be revealed. Thus the system can be used for the measurement of short duration sprays typical of nebulisers and inhalers, and to monitor changes in output of nebuliser devices over longer time periods. Measurements are not affected by flow rate changes, allowing the particle size to be monitored during a breathing cycle.

The British Standard for gas-powdered nebulisers³ specifies that the respirable fraction produced must be greater than 50%, based on the mass of material that is aerosolised.

gas flow rates

Work was carried out using the Spraytec system to measure the particle size produced by a nebuliser at different driving gas flow rates. This was done in order to define the driving gas pressure required to give the desired output. Measurements were made at a series of flow rates from 5l/min to 13l/min. An airflow rate of 30l/min was used to pull the aerosol through the measurement zone.

Figure 1 is a typical 'time-history' showing how the particle size delivered by the nebuliser changes over time, in this case using a driving gas flow rate of 12l/minute. The transmission value relates to the concentration of particles in the nebuliser cloud. This remained stable during these measurements, suggesting that the rate of aerosol production was constant, as was the particle size.

However, fluctuations were seen on the Dv90 (particle size below which 90% of the volume of particles exist) reported for the nebuliser cloud. These relate to changes in the volume of coarse particles produced by the device. These were thought to be real and to have been caused by alterations in the amount of liquid drawn through the atomisation zone of the nebuliser during operation.

The average particle size distributions (PSD) measured at different flow rates are shown in Figure 2. Table 2 shows the respirable fraction for each flow rate. As anticipated, the PSD shifted towards smaller sizes as the driving gas flow rate increased. Maximum respirable output was achieved at a flow rate of 12l/minute. Beyond this, the respirable fraction decreased. This is believed to be the result of droplet coalescence within the nebuliser chamber at high flow rates.

Using the Spraytec, particle size can be measured under varying airflow rates. This allows measurement of the properties of a nebuliser under simulated breathing conditions.

changing concentrations

Figure 3 presents data obtained for a nebuliser targeted at the upper airways using a standard sine wave pump to simulate breathing. The particle concentration increases rapidly at the start of the inhalation cycle as aerosol particles are drawn into the Spraytec mouthpiece.

The initial particle size was relatively large (Dv90>10µm). This was due to droplet coalescence in the mouthpiece prior to inhalation. The particle size then decreased rapidly and remained relatively stable during most of the inhalation phase.

Towards the end, the flow rate through the nebuliser mouthpiece decreased, leading to particle coalescence and a corresponding increase in overall particle size.

The work described gives an indication of the usefulness of Spraytec in the development and testing of nebulisers. Particle size measurements were made using nebuliser devices operated under both constant and varying flow rates. Using the Spraytec system it was possible to determine the respirable fraction under all the conditions tested. In addition, the dynamics of the nebuliser cloud during simulated breathing could be monitored, a function that is not possible with existing measurement techniques.