For suspensions, the guidance states that 'drug particle size may be important for rate of dissolution and availability to sites of action within the nose'. For in vitro bioequivalence studies, it recommends measurement of the API particle size distribution within the product formulation prior to actuation, and in the spray following actuation in order to characterise the influence of the device on de-agglomeration. In highlighting the presence of insoluble suspending agents/excipients as a complicating factor in this measurement, the guidance recommends the use of light microscopy, or alternative related techniques. However, it can be difficult to differentiate these excipients from the API using only light microscopy.
With respect to droplet size and particle size distribution, the regulatory guidance states, that this "is an important property influencing the nasal deposition of aerosols and sprays". Droplets in the sub-10 µm region may be drawn into the lung rather than remaining in the nasal cavity, while excessively large droplets may be deposited primarily in the front of the nose and not at the intended site of deposition. Most prescription nasal sprays achieve the maximum therapeutic effect when the droplets deposit beyond the nasal valve in the posterior two thirds of the nasal cavity. Laser diffraction is recommended for droplet size measurement.Continuing high interest in nasal drug delivery intensifies the need for fast and detailed nasal spray characterisation that meets the demands of the regulators. In the study described here, laser diffraction is used to measure droplet size and to investigate the dynamics of spray formation in a commercial device. The API particle size distribution of the formulation, before and after dispersion, is measured using an automated imaging system with Raman spectroscopy capabilities. Much faster than manual light microscopy, automated imaging techniques provide statistically relevant analysis of size, shape and, in this case composition for precise API characterisation.
Investigating the dynamics of spray formation
Laser diffraction is an ensemble particle sizing technique that measures size distributions in the range 0.1 to 3000 µm, comfortably spanning the area of interest for nasal sprays. Fast and non-destructive, laser diffraction is suitable for measuring both dry and wet samples, with instruments designed for spray analysis measuring at rates of up to 10 kHz. There are now several suppliers of laser diffraction equipment. Such systems capture the evolution of droplet size in real-time, throughout the duration of a spray event, providing detailed information on which to base decisions about a formulation or device.2
Nasal spray events can be divided into three phases: formation, fully developed/stable, and dissipation. In the formation phase, flow through the spray pump nozzle is relatively low, droplet size is large, and the output of the nasal spray product is not yet stable. Flow is also low during dissipation at the end of the spray event when the metering chamber is empty. The FDA therefore recommends that data from the fully developed phase is used for statistically valid comparisons of the performance of the product under different conditions.