Characterizing A Nasal Spray Formulation From Droplet To API Particle Size

Regulatory guidance for nasal spray products recognises the effect on drug delivery of the particle size of both the delivered droplets and the suspended active. Here we examine the application of laser diffraction and automated image analysis combined with Raman spectroscopy in this context, highlighting the role these techniques can play in fast and efficient nasal spray characterisation.
Feb 11, 2011

The way in which a suspension nasal spray product interacts with the body depends not only on the droplet size of the delivered droplet, but also on the particle size of the suspended active pharmaceutical ingredient (API). These dependencies are clearly recognised in the FDA draft guidance document 'Bioequivalance (BE) and bioavailability (BA) studies for nasal sprays and nasal aerosols for local action',1 which also recommends appropriate analytical techniques to quantify these two parameters.

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

Figure 1: Particle size profiles and averaged particle size distributions (from the stable phase), for a commercial nasal spray product actuated at 40, 70 and 100 mm/s.
Figure 1 shows laser diffraction (Spraytec, Malvern Instruments) droplet size data for a commercial nasal spray product actuated at different velocities. Investigating the impact of actuation profile on droplet size is essential since in-use operation will vary from patient to patient. Here, tests were carried out at actuation velocities of 40, 70 and 100 mm/s. Samples were measured at a distance of 30 mm from the laser beam at a frequency of one measurement every 400 µs. Measuring over a period of 400 ms the spray event is tracked through to completion. The results are presented in the form of a particle size profile — a plot of Dv50 (the particle size below which 50% of the droplet population lies) with time.

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.

Figure 2: Example particle images of API (left) and excipient (right) from a commercially available corticosteroid nasal spray formulation. The individual Circular Equivalent Diameter is indicated below each image (images are not to same scale).
The results show that as actuation velocity increases, the duration of the fully developed phase decreases; the dose is delivered more rapidly. In terms of atomisation behaviour, actuation at 70 and 100 mm/s produces similar results, generating a stable Dv50 of 35.4 µm and 32.2 µm, respectively. In contrast, the slowest actuation profile (40 mm/s), as well as producing a longer fully developed phase, atomises droplets to a much larger diameter, a Dv50 of 72.1 µm. This means that the performance of this product will be markedly different if the actuation profile applied by the patient is below a certain velocity, some way between 40 and 70 mm/s. The regulatory guidance states that pumps should be tested at velocities that are typical of hand actuation by patients, so care should be taken to select the appropriate settings for automated actuation during laser diffraction studies.