SubscribeParticle size in sprays and aerosols is important in controlling both drug delivery and overall product performance in a wide and growing range of pharmaceutical applications.
Within the draft guidance for the characterisation of nasal sprays, for example, the US Food and Drug Administration (FDA) has recommended the use of laser diffraction to determine the droplet size produced for a given device and formulation. This article reports on a new generation spray measurement system that uses laser diffraction to measure particle size for the analysis of nasal sprays and aerosols, and inhalers.
Why measure particle size?
Nasal sprays
Commonly applied to the delivery of treatments for local disorders (such as sinus congestion and allergic rhinitis), the nasal route is viewed increasingly as an alternative to oral administration or injection for systemic therapies. It is already being used successfully to deliver prescription medicines for pain management, migraine relief, pernicious anaemia and osteoporosis treatment, for example.
The nasal route is especially attractive for many drugs because the combination of large surface area and high density of blood vessels allows efficient absorption into the bloodstream. This promotes rapid onset of action as well as avoiding the risk of drug degradation in the gut. Since nasal administration may be a more attractive option than the alternatives for many patients, patient compliance can also be improved.
A typical nasal spray formulation consists of a bottle with a metered spray pump, containing the drug suspended or dissolved in an aqueous medium. Pump actuation by the patient delivers drug-laden droplets into the nasal cavity. One of the important considerations for nasal drug delivery is the droplet size produced by the spray pump during actuation. Most nasal spray pumps produce droplets in the size range from 20 to around 120 microns.
It is critically important that the droplets are of a size that enables their deposition within the nasal passages. If they are too small (< 10 microns), particles may pass through the nasal passages and deposit in the lungs, potentially allowing deposition of drug and excipients not approved for pulmonary absorption. The spray droplet size is therefore important in defining the deposition pattern observed within the nasal cavity.
Spray droplet sizing using in vitro techniques such as laser diffraction, along with accurate measurement of plume geometry and spray pattern using rapid imaging systems, can be used as a surrogate for US FDA in vivo bioequivalence studies [1].
Nebulisers
Nebulisers provide a convenient means of delivering drugs to the respiratory tract. Used routinely in asthma control and for the treatment of cystic fibrosis, they also have applications for delivery of some antibiotic therapies. The device must deliver the drug quickly and efficiently to the appropriate part of the respiratory tract, whilst avoiding unnecessary waste. A key parameter in defining the efficiency of nebuliser treatments is the particle size of the aerosol cloud since this determines the deposition site within the respiratory tract: the smaller the particles, the greater the likelihood of their deposition in the lungs rather than in the mouth or throat. However, the particles must not be too fine (below 0.5 micron) because of the possible risk of exhalation.
Dry powder inhalers (DPI)
Inhalers based on dry powders have a number of advantages over other formulations. These include the automatic co-ordination of drug release and inhalation (breath activation), the elimination of propellants, and an easier environment for the formulation of some "fragile" molecules such as proteins. Dose reproducibility and delivered particle size distribution are critical elements in DPI design, as particles with a size of less than 10 microns must be produced during actuation of the device if drug deposition is to occur within the respiratory tract.
Particles of this size tend to agglomerate during storage, with the patient's own inspiratory effort providing the energy for re-dispersion. Formulators and device developers must therefore account for the differences that exist in patient inspiratory flow rate and produce devices which can deliver a high respirable fraction across a wide range of flow rates.
Particle size using laser diffraction
Laser diffraction is an established technique within the pharmaceutical industry for particle size analysis. Its use for the real-time, high-speed measurement of concentrated sprays and aerosols requires specialised instrumentation and software. Since its introduction in 1997, the Spraytec system (Malvern Instruments) has been widely adopted for these pharmaceutical applications, enabling the characterisation of both pulsed and continuous spray events.
The introduction in September this year of a new generation Spraytec (Figure 1) has brought a four-fold increase in data acquisition speed, allowing increasingly detailed characterisation of spray events, and has doubled the size range across which the system operates.
Designed to support the needs of the pharmaceutical industry, the Spraytec is now driven by Standard Operating Procedures (SOPs): its full lifecycle documentation, following GAMP guidelines, provides complete design traceability, IQ/OQ documentation delivers the basic building blocks for validation, and the software allows technical compliance to the requirements of 21 CFR Part 11.
High-speed measurements are essential for accurate analysis of the dynamics of spray atomisation and dispersion and the new system has a10 kHz data acquisition rate, which gives a 100-microsecond time resolution. As a result, the rapid changes in particle size that occur during pulsed spray events, such as those seen with inhalers and nasal pump sprays, can easily be followed.
Fundamentals of operation
Laser diffraction for particle size determination requires the intensity of light scattered from the spray to be measured as a function of angle, using a series of photodetectors. Spraytec's unique optics and detector system allows the acquisition of scattering data over a wide angular range, which in turn enables the characterization of broad size distributions. The high data acquisition rate means that any temporal fluctuations in the particle size distribution can be tracked and a number of flexible triggering functions (including the ability to electronically trigger the Spraytec from another device) allow data capture to be synchronized with the spray event.
Analysis of light scattering data using Mie theory provides accurate size distributions across the entire measurement range. A patented multiple scattering analysis additionally ensures accurate measurements at high spray concentrations (up to 98% obscuration), where traditional laser diffraction systems would fail. This allows the full cycle of a spray event to be tracked.
Results
Reproducible measurements, especially between operators and sites, are critical in any pharmaceutical development, something that is aided significantly by the introduction of SOPs and automated operation. Once defined, a SOP can be saved and emailed to other users as part of method transfer. Operation then simply requires selection of the required SOP; the software will then automatically ensure that the correct measurement sequence is followed.
This includes verifying the hardware configuration, auto-alignment of the optics, activation of measurement triggers and any result processing required, such as averaging. At each point a live display allows the measurement to be followed in real-time, so that all aspects of the analysis process can be monitored. Sample preparation and handling prompts are also given.
Data analysis is rapid, with a size history display enabling frame-by-frame inspection of a given spray event. This allows users to see exactly how the spray particle size evolves over time. At each individual time point the entire size distribution can be viewed together with all relevant sample details.
Averaging or re-analysis of data simply requires dragging the cursor over the measurements of interest within the size history display. Flexible statistical functions are also available to assess the reproducibility of spray delivery across specific time periods within the spray. This is useful when trying to understand the operation of pulse-spray systems as data within a single pulse can be grouped together, averaged and compared with other spray pulses in order to show the true variability.
Application examples
Nasal pump sprays
Traditionally, actuation of nasal spray devices was carried out manually during product development and testing, but force and velocity profiles used during manual testing are operator dependent. Automation of actuation has therefore become a requirement in order to meet the FDA's recommendations for nasal spray testing.
The nasal spray system (NSS) for the Spraytec (Figure 2) allows accurate specification of the actuation profiles applied to a given pump during testing. It also permits control of both distance and angle at which measurements are made. The system can be used to understand the overall performance characteristics of a given pump and formulation, allowing determination of how the delivered droplet size varies according to the applied actuation profile.
The actuator system used within the NSS accessory can be removed and used for testing other characteristics of the pump's performance, for instance shot-weight or plume geometry measurements. This ensures that a consistent set of actuation conditions is used for all of the tests recommended by the FDA.
The FDA specifies three regions of interest during actuation of a nasal spray: the formation phase; the fully developed phase; and the dissipation phase, each of which can be recognised easily using laser diffraction measurements (Figure 3).
The formation phase is observed at the beginning of the pump actuation cycle where the pressure and flow rate through the pump are low, yielding a large particle size.
The fully developed phase occurs once the correct atomisation pressure has been reached, yielding the optimum particle size. Towards the end of the actuation cycle is the dissipation phase, where flow rate through the pump tails off, producing a large particle size. The ability of the nasal spray system to control the actuation force ensures reproducible results, allowing the identification of pump and formulation differences which would otherwise be masked by errors associated with manual pump actuation.
Nebulisers
Real-time particle size measurement allows both the tracking of drug delivery over time from a nebuliser device, and assessment of the reproducibility of that delivery. Figure 4 shows the change over time in particle size produced by a gas-driven nebuliser at a given gas flow rate.
The stability of the transmission value, which relates to the concentration of material being delivered, suggests a constant rate of aerosol production. Fluctuations in the Dv90 indicate carryover of some large particles during delivery of the aerosol.
These would normally be captured by the baffle system in the nebuliser device, but can be carried over when operating at driving gas high flow rates. The Dv50 and Dv10 values remain constant throughout. With a value of just below 5 microns, the Dv50 indicates that material is targeted for deposition in the upper airways rather than for pulmonary delivery. Measurements made using laser diffraction show good correlation with traditional nebuliser characterisation methods such as Cascade Impaction [2].
Inhalers
A major concern with dry powder inhalers is the dispersion of drug particles to a respirable size as this has to happen using only the force of the patient's inhalation. Research has therefore tended to focus on ensuring good particle dispersion; either through inhaler design or by engineering drug particles to ensure any strong particle-particle interactions are reduced, as these can lead to irreversible agglomeration during storage.
Techniques that provide an understanding of the drug release dynamics, by tracking powder dispersion during a single firing of a device, are key in the continuing development of DPI systems. Here, laser diffraction can provide a means of rapidly screening formulations for the correct dispersion properties [3].
Figure 5 illustrates data obtained for the firing of a DPI device using two separate drug formulations. Formulation A contained crystalline drug material while formulation B was produced using a micronised form of the same drug. Both were formulated with a lactose excipient having a Dv50 of around 70 microns.
Using Spraytec measurements, distinct differences in the powder release profiles were discernible. Formulation B exhibits a much finer particle size at the beginning and end of actuation and this is indicative of the easier dispersion of crystalline material compared with micronised. These results were also confirmed using traditional cascade impactor measurements.
Future developments
As nasal pump sprays, nebulisers and inhalers continue to play an increasing role in the efficient and targeted delivery of an array of different therapeutic agents, sophisticated analytical techniques are needed to support the development of both the devices themselves and the formulations they deliver. The ability to study and quantify pulsed spray events is critical for all these drug delivery systems, and the use of laser diffraction for particle size measurement is now part of the FDA's guidance for nasal spray characterisation.
The introduction of a new laser diffraction system dedicated to spray analysis, which combines increased data acquisition speed, SOP-driven operation and actuation options specific for pharmaceutical industry requirements, is expected to make a significant contribution to new product development.